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Contents
Articles
Amino acid 1
Bacteria 16
Bacteriology 40
Biochemistry 40
Biological membrane 49
Blood 51
Blood cell 67
Bone 68
Bone marrow 79
Carbohydrate 84
Cell (biology) 91
Cell biology 101
Cell membrane 105
Cell nucleus 112
Cell wall 128
Cellular microbiology 135
Collagen 136
Connective tissue 148
Copolymer 150
Cytoplasm 154
DNA 156
Fecal fat test 180
Flow cytometry 181
Glucose 188
Glycogen 197
Glycoprotein 201
Histology 205
Immunohistochemistry 211
Immunology 216
Lipid 221
Lipopolysaccharide 232
Metabolism 237
Microbial ecology 256
Microbial genetics 258
Microbiology 258
Mitochondrion 264
Molecular microbiology 282
Morphology (biology) 286
Mucin 288
Mycology 290
Myofibril 293
Nerve 296
Nissl body 298
Nucleic acid 299
Organelle 303
Parasitology 309
Peptidoglycan 312
Plant 315
Polymer 332
Polysaccharide 343
Prion 350
Protein 364
Proteoglycan 378
Red blood cell 380
RNA 391
Starch 400
Tissue (biology) 408
Virology 414
Virus 421

References
Article Sources and Contributors 449
Image Sources, Licenses and Contributors 463

Article Licenses
License 470
Amino acid 1

Amino acid
Amino acids (  /əˈmiːnoʊ/, /əˈmaɪnoʊ/, or
/ˈæmɪnoʊ/) are molecules containing an amine
group, a carboxylic acid group, and a side-chain
that is specific to each amino acid. The key
elements of an amino acid are carbon,
hydrogen, oxygen, and nitrogen. They are
particularly important in biochemistry, where
the term usually refers to alpha-amino acids.

An alpha-amino acid has the generic formula


The generic structure of an alpha amino acid in its
H2NCHRCOOH, where R is an organic
unionized form
substituent;[1] the amino group is attached to the
carbon atom immediately adjacent to the
carboxylate group (the α–carbon). Other types
of amino acid exist when the amino group is
attached to a different carbon atom; for
example, in gamma-amino acids (such as
gamma-amino-butyric acid) the carbon atom to
which the amino group attaches is separated
from the carboxylate group by two other carbon
atoms. The various alpha-amino acids differ in
which side-chain (R-group) is attached to their
alpha carbon, and can vary in size from just one
hydrogen atom in glycine to a large heterocyclic
group in tryptophan.

Amino acids serve as the building blocks of


proteins, which are linear chains of amino acids.
Amino acids can be linked together in varying
sequences to form a vast variety of proteins.[2]
Twenty amino acids are naturally incorporated
into polypeptides and are called proteinogenic
or standard amino acids. These 20 are encoded
by the universal genetic code. Nine standard
amino acids are called "essential" for humans
because they cannot be created from other
compounds by the human body, and so must be The 21 amino acids found in eukaryotes, grouped according to their
side-chains' pKas and charge at physiological pH 7.4
taken in as food.

Amino acids are important in nutrition and are commonly used in nutrition supplements, fertilizers, food technology
and industry. In industry, applications include the production of biodegradable plastics, drugs, and chiral catalysts.

History
The first few amino acids were discovered in the early 19th century. In 1806, the French chemists Louis-Nicolas
Vauquelin and Pierre Jean Robiquet isolated a compound in asparagus that was subsequently named asparagine, the
Amino acid 2

first amino acid to be discovered.[3][4] Another amino acid that was discovered in the early 19th century was cystine,
in 1810,[5] although its monomer, cysteine, was discovered much later, in 1884.[4][6] Glycine and leucine were also
discovered around this time, in 1820.[7] Usage of the term amino acid in the English language is from 1898.[8]
Proteins were found to yield amino acids after enzymatic digestion or acid hydrolysis. In 1902, Emil Fischer and
Franz Hofmeister proposed that proteins are the result of the formation of bonds between the amino group of one
amino acid with the carboxyl group of another in a linear structure which Fischer termed peptide.[9]

General structure
Further information: Proteinogenic amino acid
In the structure shown at the top of the page, R represents a side-chain specific to
each amino acid. The carbon atom next to the carboxyl group is called the α–carbon
and amino acids with a side-chain bonded to this carbon are referred to as alpha
amino acids. These are the most common form found in nature. In the alpha amino
acids, the α–carbon is a chiral carbon atom, with the exception of glycine.[10] In
amino acids that have a carbon chain attached to the α–carbon (such as lysine,
shown to the right) the carbons are labeled in order as α, β, γ, δ, and so on.[11] In
some amino acids, the amine group is attached to the β or γ-carbon, and these are
therefore referred to as beta or gamma amino acids.

Amino acids are usually classified by the properties of their side-chain into four
groups. The side-chain can make an amino acid a weak acid or a weak base, and a
hydrophile if the side-chain is polar or a hydrophobe if it is nonpolar.[10] The
chemical structures of the 22 standard amino acids, along with their chemical
Lysine with the carbon atoms in
properties, are described more fully in the article on these proteinogenic amino the side-chain labeled
acids.

The phrase "branched-chain amino acids" or BCAA refers to the amino acids having aliphatic side-chains that are
non-linear; these are leucine, isoleucine, and valine. Proline is the only proteinogenic amino acid whose side-group
links to the α-amino group and, thus, is also the only proteinogenic amino acid containing a secondary amine at this
position.[10] In chemical terms, proline is, therefore, an imino acid, since it lacks a primary amino group,[12] although
it is still classed as an amino acid in the current biochemical nomenclature,[13] and may also be called an
"N-alkylated alpha-amino acid".[14]

Isomerism
Of the standard α-amino acids, all but glycine can exist in either of two
optical isomers, called L or D amino acids, which are mirror images of
each other (see also Chirality). While L-amino acids represent all of the
amino acids found in proteins during translation in the ribosome,
D-amino acids are found in some proteins produced by enzyme
posttranslational modifications after translation and translocation to the
endoplasmic reticulum, as in exotic sea-dwelling organisms such as
The two optical isomers of alanine, D-Alanine
cone snails.[15] They are also abundant components of the
and L-Alanine
peptidoglycan cell walls of bacteria,[16] and D-serine may act as a
neurotransmitter in the brain.[17] The L and D convention for amino
acid configuration refers not to the optical activity of the amino acid itself, but rather to the optical activity of the

isomer of glyceraldehyde from which that amino acid can, in theory, be synthesized (D-glyceraldehyde is
dextrorotary; L-glyceraldehyde is levorotatory). In alternative fashion, the (S) and (R) designators are used to indicate
Amino acid 3

the absolute stereochemistry. Almost all of the amino acids in proteins are (S) at the α carbon, with cysteine being
(R) and glycine non-chiral.[18] Cysteine is unusual since it has a sulfur atom at the second position in its side-chain,
which has a larger atomic mass than the groups attached to the first carbon, which is attached to the α-carbon in the
other standard amino acids, thus the (R) instead of (S).

Zwitterions
The amine and carboxylic acid
functional groups found in amino acids
allow them to have amphiprotic
properties.[10] Carboxylic acid groups
(−CO2H) can be deprotonated to
become negative carboxylates (−CO2−
), and α-amino groups (NH2−) can be
protonated to become positive
+
α-ammonium groups ( NH3−). At pH An amino acid in its (1) unionized and (2) zwitterionic forms
values greater than the pKa of the
carboxylic acid group (mean for the 20 common amino acids is about 2.2, see the table of amino acid structures
above), the negative carboxylate ion predominates. At pH values lower than the pKa of the α-ammonium group
(mean for the 20 common α-amino acids is about 9.4), the nitrogen is predominantly protonated as a positively
charged α-ammonium group. Thus, at pH between 2.2 and 9.4, the predominant form adopted by α-amino acids
contains a negative carboxylate and a positive α-ammonium group, as shown in structure (2) on the right, so has net
zero charge. This molecular state is known as a zwitterion, from the German Zwitter meaning hermaphrodite or
hybrid.[19] Below pH 2.2, the predominant form will have a neutral carboxylic acid group and a positive
α-ammonium ion (net charge +1), and above pH 9.4, a negative carboxylate and neutral α-amino group (net charge
−1). The fully neutral form (structure (1) on the right) is a very minor species in aqueous solution throughout the pH
range (less than 1 part in 107). Amino acids also exist as zwitterions in the solid phase, and crystallize with salt-like
properties unlike typical organic acids or amines.

Isoelectric point
At pH values between the two pKa values, the zwitterion predominates, but coexists in dynamic equilibrium with
small amounts of net negative and net positive ions. At the exact midpoint between the two pKa values, the trace
amount of net negative and trace of net positive ions exactly balance, so that average net charge of all forms present
is zero.[20] This pH is known as the isoelectric point pI, so pI = ½(pKa1 + pKa2). The individual amino acids all have
slightly different pKa values, so have different isoelectric points. For amino acids with charged side-chains, the pKa
of the side-chain is involved. Thus for Asp, Glu with negative side-chains, pI = ½(pKa1 + pKaR), where pKaR is the
side-chain pKa. Cysteine also has potentially negative side-chain with pKaR = 8.14, so pI should be calculated as for
Asp and Glu, even though the side-chain is not significantly charged at neutral pH. For His, Lys, and Arg with
positive side-chains, pI = ½(pKaR + pKa2). Amino acids have zero mobility in electrophoresis at their isoelectric
point, although this behaviour is more usually exploited for peptides and proteins than single amino acids.
Zwitterions have minimum solubility at their isolectric point and some amino acids (in particular, with non-polar
side-chains) can be isolated by precipitation from water by adjusting the pH to the required isoelectric point.
Amino acid 4

Occurrence and functions in biochemistry

Standard amino acids


Amino acids are the structural units that
make up proteins. They join together to
form short polymer chains called peptides or
longer chains called either polypeptides or
proteins. These polymers are linear and
unbranched, with each amino acid within
the chain attached to two neighboring amino
acids. The process of making proteins is
called translation and involves the
step-by-step addition of amino acids to a
growing protein chain by a ribozyme that is A polypeptide is an unbranched chain of amino acids.
[21]
called a ribosome. The order in which the
amino acids are added is read through the genetic code from an mRNA template, which is a RNA copy of one of the
organism's genes.

Twenty-two amino acids are naturally incorporated into polypeptides and are called proteinogenic or natural amino
acids.[10] Of these, 20 are encoded by the universal genetic code. The remaining 2, selenocysteine and pyrrolysine,
are incorporated into proteins by unique synthetic mechanisms. Selenocysteine is incorporated when the mRNA
being translated includes a SECIS element, which causes the UGA codon to encode selenocysteine instead of a stop
codon.[22] Pyrrolysine is used by some methanogenic archaea in enzymes that they use to produce methane. It is
coded for with the codon UAG, which is normally a stop codon in other organisms.[23] This UAG codon is followed
by a PYLIS downstream sequence.[24]

Non-standard amino acids


Aside from the 22 standard amino acids, there are many other amino acids
that are called non-proteinogenic or non-standard. Those either are not
found in proteins (for example carnitine, GABA), or are not produced
directly and in isolation by standard cellular machinery (for example,
hydroxyproline and selenomethionine).
Non-standard amino acids that are found in proteins are formed by
post-translational modification, which is modification after translation
The amino acid selenocysteine during protein synthesis. These modifications are often essential for the
function or regulation of a protein; for example, the carboxylation of
glutamate allows for better binding of calcium cations,[25] and the hydroxylation of proline is critical for maintaining
connective tissues.[26] Another example is the formation of hypusine in the translation initiation factor EIF5A,
through modification of a lysine residue.[27] Such modifications can also determine the localization of the protein,
e.g., the addition of long hydrophobic groups can cause a protein to bind to a phospholipid membrane.[28]
Amino acid 5

Some nonstandard amino acids are not found in


proteins. Examples include lanthionine,
2-aminoisobutyric acid, dehydroalanine, and the
neurotransmitter gamma-aminobutyric acid.
Nonstandard amino acids often occur as intermediates
in the metabolic pathways for standard amino acids —
for example, ornithine and citrulline occur in the urea
cycle, part of amino acid catabolism (see below).[29] A
rare exception to the dominance of α-amino acids in β-alanine and its α-alanine isomer

biology is the β-amino acid beta alanine


(3-aminopropanoic acid), which is used in plants and microorganisms in the synthesis of pantothenic acid (vitamin
B5), a component of coenzyme A.[30]

In human nutrition
Further information: Protein in nutrition and Amino acid synthesis
When taken up into the human body from the diet, the 22 standard amino acids either are used to synthesize proteins
and other biomolecules or are oxidized to urea and carbon dioxide as a source of energy.[31] The oxidation pathway
starts with the removal of the amino group by a transaminase, the amino group is then fed into the urea cycle. The
other product of transamidation is a keto acid that enters the citric acid cycle.[32] Glucogenic amino acids can also be
converted into glucose, through gluconeogenesis.[33]
Pyrrolysine trait is restricted to several microbes, and only one organism has both Pyl and Sec. Of the 22 standard
amino acids, 9 are called essential amino acids because the human body cannot synthesize them from other
compounds at the level needed for normal growth, so they must be obtained from food.[34] In addition, cysteine,
taurine, tyrosine, and arginine are semiessential amino-acids in children, because the metabolic pathways that
synthesize these amino acids are not fully developed.[35][36] The amounts required also depend on the age and health
of the individual, so it is hard to make general statements about the dietary requirement for some amino acids.

Essential Nonessential

Histidine Alanine

Isoleucine Arginine*

Leucine Asparagine

Lysine Aspartic acid

Methionine Cysteine*

Phenylalanine Glutamic acid

Threonine Glutamine*

Tryptophan Glycine

Valine Ornithine*

Proline*

Selenocysteine*

Serine*

Taurine*

Tyrosine*

(*) Essential only in certain cases.[37][38]


Amino acid 6

Non-protein functions
Further information: Amino acid neurotransmitter
In humans, non-protein amino acids also have important roles as metabolic intermediates, such as in the biosynthesis
of the neurotransmitter gamma-aminobutyric acid. Many amino acids are used to synthesize other molecules, for
example:
• Tryptophan is a precursor of the neurotransmitter serotonin.[39]
• Tyrosine is a precursor of the neurotransmitter dopamine.
• Glycine is a precursor of porphyrins such as heme.[40]
• Arginine is a precursor of nitric oxide.[41]
• Ornithine and S-adenosylmethionine are precursors of polyamines.[42]
• Aspartate, glycine, and glutamine are precursors of nucleotides.[43]
• Phenylalanine is a precursor of various phenylpropanoids, which are important in plant metabolism.
However, not all of the functions of other abundant non-standard amino acids are known. For example, taurine is a
major amino acid in muscle and brain tissues, but, although many functions have been proposed, its precise role in
the body has not been determined.[44]
Some non-standard amino acids are used as defenses against herbivores in plants.[45] For example canavanine is an
analogue of arginine that is found in many legumes,[46] and in particularly large amounts in Canavalia gladiata
(sword bean).[47] This amino acid protects the plants from predators such as insects and can cause illness in people if
some types of legumes are eaten without processing.[48] The non-protein amino acid mimosine is found in other
species of legume, particularly Leucaena leucocephala.[49] This compound is an analogue of tyrosine and can poison
animals that graze on these plants.

Uses in technology
Amino acids are used for a variety of applications in industry, but their main use is as additives to animal feed. This
is necessary, since many of the bulk components of these feeds, such as soybeans, either have low levels or lack
some of the essential amino acids: Lysine, methionine, threonine, and tryptophan are most important in the
production of these feeds.[50] In this industry, amino acids are also used to chelate metal cations in order to improve
the absorption of minerals from supplements, which may be required to improve the health or production of these
animals.[51]
The food industry is also a major consumer of amino acids, in particular, glutamic acid, which is used as a flavor
enhancer,[52] and Aspartame (aspartyl-phenylalanine-1-methyl ester) as a low-calorie artificial sweetener.[53] Similar
technology to that used for animal nutrition is employed in the human nutrition industry to alleviate symptoms of
mineral deficiencies, such as anemia, by improving mineral absorption and reducing negative side effects from
inorganic mineral supplementation.[54]
The chelating ability of amino acids has been used in fertilizers for agriculture to facilitate the delivery of minerals to
plants in order to correct mineral deficiencies, such as iron chlorosis. These fertilizers are also used to prevent
deficiencies from occurring and improving the overall health of the plants.[55] The remaining production of amino
acids is used in the synthesis of drugs and cosmetics.[50]
Amino acid 7

Amino acid derivative Pharmaceutical application

5-HTP (5-hydroxytryptophan) [56]


Experimental treatment for depression.

L-DOPA (L-dihydroxyphenylalanine) [57]


Treatment for Parkinsonism.

Eflornithine [58]
Drug that inhibits ornithine decarboxylase and is used in the treatment of sleeping sickness.

Expanded genetic code


Since 2001, 40 non-natural amino acids have been added into protein by creating a unique codon (recoding) and a
corresponding transfer-RNA:aminoacyl – tRNA-synthetase pair to encode it with diverse physicochemical and
biological properties in order to be used as a tool to exploring protein structure and function or to create novel or
enhanced proteins.[59][60]

Chemical building blocks


Further information: Asymmetric synthesis
Amino acids are important as low-cost feedstocks. These compounds are used in chiral pool synthesis as
enantiomerically-pure building blocks.[61]
Amino acids have been investigated as precursors chiral catalysts, e.g., for asymmetric hydrogenation reactions,
although no commercial applications exist.[62]

Biodegradable plastics
Further information: Biodegradable plastic and Biopolymer
Amino acids are under development as components of a range of biodegradable polymers. These materials have
applications as environmentally friendly packaging and in medicine in drug delivery and the construction of
prosthetic implants. These polymers include polypeptides, polyamides, polyesters, polysulfides, and polyurethanes
with amino acids either forming part of their main chains or bonded as side-chains. These modifications alter the
physical properties and reactivities of the polymers.[63] An interesting example of such materials is polyaspartate, a
water-soluble biodegradable polymer that may have applications in disposable diapers and agriculture.[64] Due to its
solubility and ability to chelate metal ions, polyaspartate is also being used as a biodegradeable anti-scaling agent
and a corrosion inhibitor.[65][66] In addition, the aromatic amino acid tyrosine is being developed as a possible
replacement for toxic phenols such as bisphenol A in the manufacture of polycarbonates.[67]

Reactions
As amino acids have both a primary amine group and a primary carboxyl group, these chemicals can undergo most
of the reactions associated with these functional groups. These include nucleophilic addition, amide bond formation
and imine formation for the amine group and esterification, amide bond formation and decarboxylation for the
carboxylic acid group.[68] The combination of these functional groups allow amino acids to be effective polydentate
ligands for metal-amino acid chelates.[69] The multiple side-chains of amino acids can also undergo chemical
reactions.[70] The types of these reactions are determined by the groups on these side-chains and are, therefore,
different between the various types of amino acid.
Amino acid 8

Chemical synthesis
Several methods exist to synthesize
amino acids. One of the oldest methods
begins with the bromination at the
The Strecker amino acid synthesis α-carbon of a carboxylic acid.
Nucleophilic substitution with
ammonia then converts the alkyl bromide to the amino acid.[71] In alternative fashion, the Strecker amino acid
synthesis involves the treatment of an aldehyde with potassium cyanide and ammonia, this produces an α-amino
nitrile as an intermediate. Hydrolysis of the nitrile in acid then yields a α-amino acid.[72] Using ammonia or
ammonium salts in this reaction gives unsubstituted amino acids, while substituting primary and secondary amines
will yield substituted amino acids.[73] Likewise, using ketones, instead of aldehydes, gives α,α-disubstituted amino
[74]
acids. The classical synthesis gives racemic mixtures of α-amino acids as products, but several alternative
procedures using asymmetric auxiliaries [75] or asymmetric catalysts [76][77] have been developed.[78]

At the current time, the most-adopted method is an automated synthesis on a solid support (e.g., polystyrene beads),
using protecting groups (e.g., Fmoc and t-Boc) and activating groups (e.g., DCC and DIC).

Peptide bond formation


As both the amine and carboxylic acid
groups of amino acids can react to
form amide bonds, one amino acid
molecule can react with another and
become joined through an amide
linkage. This polymerization of amino
acids is what creates proteins. This
condensation reaction yields the newly
formed peptide bond and a molecule of
water. In cells, this reaction does not
occur directly; instead the amino acid
is first activated by attachment to a
transfer RNA molecule through an
ester bond. This aminoacyl-tRNA is
produced in an ATP-dependent
reaction carried out by an aminoacyl
tRNA synthetase.[79] This
The condensation of two amino acids to form a peptide bond
aminoacyl-tRNA is then a substrate for
the ribosome, which catalyzes the
attack of the amino group of the elongating protein chain on the ester bond.[80] As a result of this mechanism, all
proteins made by ribosomes are synthesized starting at their N-terminus and moving towards their C-terminus.

However, not all peptide bonds are formed in this way. In a few cases, peptides are synthesized by specific enzymes.
For example, the tripeptide glutathione is an essential part of the defenses of cells against oxidative stress. This
peptide is synthesized in two steps from free amino acids.[81] In the first step gamma-glutamylcysteine synthetase
condenses cysteine and glutamic acid through a peptide bond formed between the side-chain carboxyl of the
glutamate (the gamma carbon of this side-chain) and the amino group of the cysteine. This dipeptide is then
condensed with glycine by glutathione synthetase to form glutathione.[82]
Amino acid 9

In chemistry, peptides are synthesized by a variety of reactions. One of the most-used in solid-phase peptide
synthesis uses the aromatic oxime derivatives of amino acids as activated units. These are added in sequence onto the
growing peptide chain, which is attached to a solid resin support.[83] The ability to easily synthesize vast numbers of
different peptides by varying the types and order of amino acids (using combinatorial chemistry) has made peptide
synthesis particularly important in creating libraries of peptides for use in drug discovery through high-throughput
screening.[84]

Biosynthesis
In plants, nitrogen is first assimilated into organic compounds in the form of glutamate, formed from
alpha-ketoglutarate and ammonia in the mitochondrion. In order to form other amino acids, the plant uses
transaminases to move the amino group to another alpha-keto carboxylic acid. For example, aspartate
aminotransferase converts glutamate and oxaloacetate to alpha-ketoglutarate and aspartate.[85] Other organisms use
transaminases for amino acid synthesis, too.
Nonstandard amino acids are usually formed through modifications to standard amino acids. For example,
homocysteine is formed through the transsulfuration pathway or by the demethylation of methionine via the
intermediate metabolite S-adenosyl methionine,[44] while hydroxyproline is made by a posttranslational modification
of proline.[86]
Microorganisms and plants can synthesize many uncommon amino acids. For example, some microbes make
2-aminoisobutyric acid and lanthionine, which is a sulfide-bridged derivative of alanine. Both of these amino acids
are found in peptidic lantibiotics such as alamethicin.[87] While in plants, 1-aminocyclopropane-1-carboxylic acid is
a small disubstituted cyclic amino acid that is a key intermediate in the production of the plant hormone ethylene.[88]

Catabolism
Degradation of an amino acid often involves
deamination by moving its amino group to
alpha-ketoglutarate, forming glutamate. This
process involves transaminases, often the
same as those used in amination during
synthesis. In many vertebrates, the amino
group is then removed through the urea
cycle and is excreted in the form of urea.
However, amino acid degradation can
produce uric acid or ammonia instead. For
example, serine dehydratase converts serine
to pyruvate and ammonia.[90] After removal
of one or more amino groups, the remainder
of the molecule can sometimes be used to Catabolism of proteinogenic amino acids. Amino acids can be classified according
[89]
synthesize new amino acids, or it can be to the properties of their main products as either of the following: Glucogenic,
used for energy by entering glycolysis or the with the products having the ability to form glucose by gluconeogenesisKetogenic,
with the products not having the ability to form glucose. These products may still
citric acid cycle, as detailed in image at
be used for ketogenesis or lipid synthesis.Amino acids catabolized into both
right. glucogenic and ketogenic products.

Physicochemical properties of amino acids


Amino acid 10

The 20 amino acids encoded directly by the genetic code can be divided into several groups based on their
properties. Important factors are charge, hydrophilicity or hydrophobicity, size, and functional groups.[10] These
properties are important for protein structure and protein–protein interactions. The water-soluble proteins tend to
have their hydrophobic residues (Leu, Ile, Val, Phe, and Trp) buried in the middle of the protein, whereas
hydrophilic side-chains are exposed to the aqueous solvent. The integral membrane proteins tend to have outer rings
of exposed hydrophobic amino acids that anchor them into the lipid bilayer. In the case part-way between these two
extremes, some peripheral membrane proteins have a patch of hydrophobic amino acids on their surface that locks
onto the membrane. In similar fashion, proteins that have to bind to positively-charged molecules have surfaces rich
with negatively charged amino acids like glutamate and aspartate, while proteins binding to negatively-charged
molecules have surfaces rich with positively charged chains like lysine and arginine. There are different
hydrophobicity scales of amino acid residues.[91]
Some amino acids have special properties such as cysteine, that can form covalent disulfide bonds to other cysteine
residues, proline that forms a cycle to the polypeptide backbone, and glycine that is more flexible than other amino
acids.
Many proteins undergo a range of posttranslational modifications, when additional chemical groups are attached to
the amino acids in proteins. Some modifications can produce hydrophobic lipoproteins,[92] or hydrophilic
glycoproteins.[93] These type of modification allow the reversible targeting of a protein to a membrane. For example,
the addition and removal of the fatty acid palmitic acid to cysteine residues in some signaling proteins causes the
proteins to attach and then detach from cell membranes.[94]

Table of standard amino acid abbreviations and properties

Amino Acid [95] [95]


3-Letter 1-Letter Side-chain Side-chain charge Hydropathy Absorbance ε at λmax (x10−3
[95] [95] [96] [97] [97]
polarity (pH 7.4) index λmax(nm) M−1 cm−1)

Alanine Ala A nonpolar neutral 1.8

Arginine Arg R polar positive −4.5

Asparagine Asn N polar neutral −3.5

Aspartic acid Asp D polar negative −3.5

Cysteine Cys C polar neutral 2.5 250 0.3

Glutamic acid Glu E polar negative −3.5

Glutamine Gln Q polar neutral −3.5

Glycine Gly G nonpolar neutral −0.4

Histidine His H polar positive(10%) −3.2 211 5.9


neutral(90%)

Isoleucine Ile I nonpolar neutral 4.5

Leucine Leu L nonpolar neutral 3.8

Lysine Lys K polar positive −3.9

Methionine Met M nonpolar neutral 1.9

Phenylalanine Phe F nonpolar neutral 2.8 257, 206, 188 0.2, 9.3, 60.0

Proline Pro P nonpolar neutral −1.6

Serine Ser S polar neutral −0.8

Threonine Thr T polar neutral −0.7

Tryptophan Trp W nonpolar neutral −0.9 280, 219 5.6, 47.0


Amino acid 11

Tyrosine Tyr Y polar neutral −1.3 274, 222, 193 1.4, 8.0, 48.0

Valine Val V nonpolar neutral 4.2

In addition, there are two additional amino acids that are incorporated by overriding stop codons:

21st and 22nd amino acids 3-Letter 1-Letter

Selenocysteine Sec U

Pyrrolysine Pyl O

In addition to the specific amino acid codes, placeholders are used in cases where chemical or crystallographic
analysis of a peptide or protein cannot conclusively determine the identity of a residue.

Ambiguous Amino Acids 3-Letter 1-Letter

Asparagine or aspartic acid Asx B

Glutamine or glutamic acid Glx Z

Leucine or Isoleucine Xle J

Unspecified or unknown amino acid Xaa X

Unk is sometimes used instead of Xaa, but is less standard.


In addition, many non-standard amino acids have a specific code. For example, several peptide drugs, such as
Bortezomib and MG132, are artificially synthesized and retain their protecting groups, which have specific codes.
Bortezomib is Pyz-Phe-boroLeu, and MG132 is Z-Leu-Leu-Leu-al. To aid in the analysis of protein structure,
photocrosslinking amino acid analogues are available. These include photoleucine (pLeu) and photomethionine
(pMet).[98]

References and notes


[1] Proline is an exception to this general formula. It lacks the NH2 group because of the cyclization of the side-chain and is known as an imino
acid; it falls under the category of special structured amino acids.
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Amino acid 12

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Amino acid 15

Further reading
• Doolittle, Russell F. (1989). "Redundancies in protein sequences". In Fasman, G.D.. Predictions of Protein
Structure and the Principles of Protein Conformation. New York: Plenum Press. pp. 599–623.
ISBN 978-0-306-43131-9. LCCN 89008555.
• Nelson, David L.; Cox, Michael M. (2000). Lehninger Principles of Biochemistry (3rd ed.). Worth Publishers.
ISBN 978-1-57259-153-0. LCCN 99049137.
• Meierhenrich, Uwe (2008) (PDF, 11.2 MB). Amino acids and the asymmetry of life (http://rogov.zwz.ru/
Macroevolution/amino.pdf). Berlin: Springer Verlag. ISBN 978-3-540-76885-2. LCCN 2008930865.
• Morelli, Robert J. (1952). Studies of amino acid absorption from the small intestine. San Francisco.

External links
• The origin of the single-letter code for the amino acids (http://www.biology.arizona.edu/biochemistry/
problem_sets/aa/Dayhoff.html)
Bacteria 16

Bacteria
Bacteria

Scanning electron micrograph of Escherichia coli bacilli

Scientific classification
Domain: Bacteria

Phyla[1]
• Gram positive / no outer membrane
Actinobacteria (high-G+C)
Firmicutes (low-G+C)
Tenericutes (no wall)
• Gram negative / outer membrane present
Aquificae
Deinococcus-Thermus
Fibrobacteres–Chlorobi/Bacteroidetes (FCB group)
Fusobacteria
Gemmatimonadetes
Nitrospirae
Planctomycetes–Verrucomicrobia/Chlamydiae
(PVC group)
Proteobacteria
Spirochaetes
Synergistetes
• Unknown / ungrouped
Acidobacteria
Chloroflexi
Chrysiogenetes
Cyanobacteria
Deferribacteres
Dictyoglomi
Thermodesulfobacteria
Thermotogae

Bacteria (English pronunciation: /bækˈtɪəriə/ ( listen); singular: bacterium) are a large domain of prokaryotic
microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres
to rods and spirals. Bacteria are present in most habitats on Earth, growing in soil, acidic hot springs, radioactive
waste,[2] water, and deep in the Earth's crust, as well as in organic matter and the live bodies of plants and animals,
providing outstanding examples of mutualism in the digestive tracts of humans, termites and cockroaches. There are
typically 40 million bacterial cells in a gram of soil and a million bacterial cells in a millilitre of fresh water; in all,
there are approximately five nonillion (5×1030) bacteria on Earth,[3] forming a biomass that exceeds that of all plants
and animals.[4] Bacteria are vital in recycling nutrients, with many steps in nutrient cycles depending on these
Bacteria 17

organisms, such as the fixation of nitrogen from the atmosphere and putrefaction. In the biological communities
surrounding hydrothermal vents and cold seeps, bacteria provide the nutrients needed to sustain life by converting
dissolved compounds such as hydrogen sulphide and methane. Most bacteria have not been characterised, and only
about half of the phyla of bacteria have species that can be grown in the laboratory.[5] The study of bacteria is known
as bacteriology, a branch of microbiology.
There are approximately ten times as many bacterial cells in the human flora as there are human cells in the body,
with large numbers of bacteria on the skin and as gut flora.[6] The vast majority of the bacteria in the body are
rendered harmless by the protective effects of the immune system, and a few are beneficial. However, a few species
of bacteria are pathogenic and cause infectious diseases, including cholera, syphilis, anthrax, leprosy, and bubonic
plague. The most common fatal bacterial diseases are respiratory infections, with tuberculosis alone killing about 2
million people a year, mostly in sub-Saharan Africa.[7] In developed countries, antibiotics are used to treat bacterial
infections and in agriculture, so antibiotic resistance is becoming common. In industry, bacteria are important in
sewage treatment and the breakdown of oil spills, the production of cheese and yogurt through fermentation, the
recovery of gold, palladium, copper and other metals in the mining sector,[8] as well as in biotechnology, and the
manufacture of antibiotics and other chemicals.[9]
Once regarded as plants constituting the class Schizomycetes, bacteria are now classified as prokaryotes. Unlike
cells of animals and other eukaryotes, bacterial cells do not contain a nucleus and rarely harbour membrane-bound
organelles. Although the term bacteria traditionally included all prokaryotes, the scientific classification changed
after the discovery in the 1990s that prokaryotes consist of two very different groups of organisms that evolved
independently from an ancient common ancestor. These evolutionary domains are called Bacteria and Archaea.[10]

Etymology
The word bacteria is the plural of the New Latin bacterium, which is the latinisation of the Greek βακτήριον
(baktērion),[11] the diminutive of βακτηρία (baktēria), meaning "staff, cane",[12] because the first ones to be
discovered were rod-shaped.[13]

History of bacteriology
Bacteria were first observed by Antonie van Leeuwenhoek in 1676,
using a single-lens microscope of his own design.[14] He called them
"animalcules" and published his observations in a series of letters to
the Royal Society.[15][16][17] The name Bacterium was introduced
much later, by Christian Gottfried Ehrenberg in 1828.[18] In fact,
Bacterium was a genus that contained non-spore-forming rod-shaped
bacteria,[19] as opposed to Bacillus, a genus of spore-forming
rod-shaped bacteria defined by Ehrenberg in 1835.[20]

Louis Pasteur demonstrated in 1859 that the fermentation process is


caused by the growth of microorganisms, and that this growth is not
due to spontaneous generation. (Yeasts and molds, commonly
associated with fermentation, are not bacteria, but rather fungi.) Along
with his contemporary Robert Koch, Pasteur was an early advocate of
Antonie van Leeuwenhoek, the first
the germ theory of disease.[21] Robert Koch was a pioneer in medical microbiologist and the first person to observe
microbiology and worked on cholera, anthrax and tuberculosis. In his bacteria using a microscope.
research into tuberculosis, Koch finally proved the germ theory, for
which he was awarded a Nobel Prize in 1905.[22] In Koch's postulates, he set out criteria to test if an organism is the
cause of a disease, and these postulates are still used today.[23]
Bacteria 18

Though it was known in the nineteenth century that bacteria are the cause of many diseases, no effective antibacterial
treatments were available.[24] In 1910, Paul Ehrlich developed the first antibiotic, by changing dyes that selectively
stained Treponema pallidum — the spirochaete that causes syphilis — into compounds that selectively killed the
pathogen.[25] Ehrlich had been awarded a 1908 Nobel Prize for his work on immunology, and pioneered the use of
stains to detect and identify bacteria, with his work being the basis of the Gram stain and the Ziehl-Neelsen stain.[26]
A major step forward in the study of bacteria was the recognition in 1977 by Carl Woese that archaea have a separate
line of evolutionary descent from bacteria.[27] This new phylogenetic taxonomy was based on the sequencing of 16S
ribosomal RNA, and divided prokaryotes into two evolutionary domains, as part of the three-domain system.[28]

Origin and early evolution


The ancestors of modern bacteria were single-celled microorganisms that were the first forms of life to appear on
Earth, about 4 billion years ago. For about 3 billion years, all organisms were microscopic, and bacteria and archaea
were the dominant forms of life.[29][30] Although bacterial fossils exist, such as stromatolites, their lack of distinctive
morphology prevents them from being used to examine the history of bacterial evolution, or to date the time of
origin of a particular bacterial species. However, gene sequences can be used to reconstruct the bacterial phylogeny,
and these studies indicate that bacteria diverged first from the archaeal/eukaryotic lineage.[31]
Bacteria were also involved in the second great evolutionary divergence, that of the archaea and eukaryotes. Here,
eukaryotes resulted from ancient bacteria entering into endosymbiotic associations with the ancestors of eukaryotic
cells, which were themselves possibly related to the Archaea.[32][33] This involved the engulfment by
proto-eukaryotic cells of alpha-proteobacterial symbionts to form either mitochondria or hydrogenosomes, which are
still found in all known Eukarya (sometimes in highly reduced form, e.g. in ancient "amitochondrial" protozoa).
Later on, some eukaryotes that already contained mitochondria also engulfed cyanobacterial-like organisms. This led
to the formation of chloroplasts in algae and plants. There are also some algae that originated from even later
endosymbiotic events. Here, eukaryotes engulfed a eukaryotic algae that developed into a "second-generation"
plastid.[34][35] This is known as secondary endosymbiosis.
Bacteria 19

Morphology
Further information: Bacterial cellular morphologies
Bacteria display a wide diversity of
shapes and sizes, called morphologies.
Bacterial cells are about one tenth the
size of eukaryotic cells and are
typically 0.5–5.0 micrometres in
length. However, a few species — for
example, Thiomargarita namibiensis
and Epulopiscium fishelsoni — are up
to half a millimetre long and are visible
to the unaided eye;[36] E. fishelsoni
reaches 0.7 mm.[37] Among the
smallest bacteria are members of the
genus Mycoplasma, which measure
only 0.3 micrometres, as small as the
largest viruses.[38] Some bacteria may
be even smaller, but these
ultramicrobacteria are not
[39]
well-studied.

Most bacterial species are either Bacteria display many cell morphologies and arrangements

spherical, called cocci (sing. coccus,


from Greek κόκκος-kókkos, grain, seed), or rod-shaped, called bacilli (sing. bacillus, from Latin baculus, stick).
Elongation is associated with swimming.[40] Some rod-shaped bacteria, called vibrio, are slightly curved or
comma-shaped; others, can be spiral-shaped, called spirilla, or tightly coiled, called spirochaetes. A small number of
species even have tetrahedral or cuboidal shapes.[41] More recently, bacteria were discovered deep under the Earth's
crust that grow as long rods with a star-shaped cross-section. The large surface area to volume ratio of this
morphology may give these bacteria an advantage in nutrient-poor environments.[42] This wide variety of shapes is
determined by the bacterial cell wall and cytoskeleton, and is important because it can influence the ability of
bacteria to acquire nutrients, attach to surfaces, swim through liquids and escape predators.[43][44]

Many bacterial species exist simply as single cells, others associate in


characteristic patterns: Neisseria form diploids (pairs), Streptococcus
form chains, and Staphylococcus group together in "bunch of grapes"
clusters. Bacteria can also be elongated to form filaments, for example
the Actinobacteria. Filamentous bacteria are often surrounded by a
sheath that contains many individual cells. Certain types, such as
species of the genus Nocardia, even form complex, branched
filaments, similar in appearance to fungal mycelia.[45]
A biofilm of thermophilic bacteria in the outflow
of Mickey Hot Springs, Oregon, approximately
20 mm thick.
Bacteria 20

Bacteria often attach to surfaces and form dense aggregations called


biofilms or bacterial mats. These films can range from a few
micrometers in thickness to up to half a meter in depth, and may
contain multiple species of bacteria, protists and archaea. Bacteria
living in biofilms display a complex arrangement of cells and
extracellular components, forming secondary structures such as
microcolonies, through which there are networks of channels to enable
better diffusion of nutrients.[46][47] In natural environments, such as
soil or the surfaces of plants, the majority of bacteria are bound to
The range of sizes shown by prokaryotes, relative
surfaces in biofilms.[48] Biofilms are also important in medicine, as
to those of other organisms and biomolecules these structures are often present during chronic bacterial infections or
in infections of implanted medical devices, and bacteria protected
within biofilms are much harder to kill than individual isolated bacteria.[49]

Even more complex morphological changes are sometimes possible. For example, when starved of amino acids,
Myxobacteria detect surrounding cells in a process known as quorum sensing, migrate towards each other, and
aggregate to form fruiting bodies up to 500 micrometres long and containing approximately 100,000 bacterial
cells.[50] In these fruiting bodies, the bacteria perform separate tasks; this type of cooperation is a simple type of
multicellular organisation. For example, about one in 10 cells migrate to the top of these fruiting bodies and
differentiate into a specialised dormant state called myxospores, which are more resistant to drying and other adverse
environmental conditions than are ordinary cells.[51]

Cellular structure

Intracellular structures
The bacterial cell is surrounded by a lipid membrane, or cell
membrane, which encloses the contents of the cell and acts as a barrier
to hold nutrients, proteins and other essential components of the
cytoplasm within the cell. As they are prokaryotes, bacteria do not tend
to have membrane-bound organelles in their cytoplasm and thus
contain few large intracellular structures. They consequently lack a
true nucleus, mitochondria, chloroplasts and the other organelles
present in eukaryotic cells, such as the Golgi apparatus and
endoplasmic reticulum.[52] Bacteria were once seen as simple bags of Structure and contents of a typical Gram positive
[53][54] bacterial cell
cytoplasm, but elements such as prokaryotic cytoskeleton, and
the localization of proteins to specific locations within the
cytoplasm[53] have been found to show levels of complexity. These subcellular compartments have been called
"bacterial hyperstructures".[55]

Micro-compartments such as carboxysome[56] provides a further level of organization, which are compartments
within bacteria that are surrounded by polyhedral protein shells, rather than by lipid membranes.[57] These
"polyhedral organelles" localize and compartmentalize bacterial metabolism, a function performed by the
membrane-bound organelles in eukaryotes.[58][59]
Many important biochemical reactions, such as energy generation, occur by concentration gradients across
membranes, a potential difference also found in a battery. The general lack of internal membranes in bacteria means
reactions such as electron transport occur across the cell membrane between the cytoplasm and the periplasmic
space.[60] However, in many photosynthetic bacteria the plasma membrane is highly folded and fills most of the cell
Bacteria 21

with layers of light-gathering membrane.[61] These light-gathering complexes may even form lipid-enclosed
structures called chlorosomes in green sulfur bacteria.[62] Other proteins import nutrients across the cell membrane,
or to expel undesired molecules from the cytoplasm.
Most bacteria do not have a
membrane-bound nucleus, and their
genetic material is typically a single
circular chromosome located in the
cytoplasm in an irregularly shaped
body called the nucleoid.[64] The
nucleoid contains the chromosome
with associated proteins and RNA. The
order Planctomycetes are an exception
to the general absence of internal
Carboxysomes are protein-enclosed bacterial organelles. Top left is an electron
microscope image of carboxysomes in Halothiobacillus neapolitanus, below is an image
membranes in bacteria, because they
of purified carboxysomes. On the right is a model of their structure. Scale bars are have a double membrane around their
[63]
100 nm. nucleoids and contain other
membrane-bound cellular
[65]
structures. Like all living organisms, bacteria contain ribosomes for the production of proteins, but the structure
of the bacterial ribosome is different from those of eukaryotes and Archaea.[66]

Some bacteria produce intracellular nutrient storage granules, such as glycogen,[67] polyphosphate,[68] sulfur[69] or
polyhydroxyalkanoates.[70] These granules enable bacteria to store compounds for later use. Certain bacterial
species, such as the photosynthetic Cyanobacteria, produce internal gas vesicles, which they use to regulate their
buoyancy – allowing them to move up or down into water layers with different light intensities and nutrient
levels.[71]

Extracellular structures
In most bacteria a cell wall is present on the outside of the cytoplasmic membrane. A common bacterial cell wall
material is peptidoglycan (called murein in older sources), which is made from polysaccharide chains cross-linked
by peptides containing D-amino acids.[72] Bacterial cell walls are different from the cell walls of plants and fungi,
which are made of cellulose and chitin, respectively.[73] The cell wall of bacteria is also distinct from that of
Archaea, which do not contain peptidoglycan. The cell wall is essential to the survival of many bacteria, and the
antibiotic penicillin is able to kill bacteria by inhibiting a step in the synthesis of peptidoglycan.[73]
There are broadly speaking two different types of cell wall in bacteria, called Gram-positive and Gram-negative. The
names originate from the reaction of cells to the Gram stain, a test long-employed for the classification of bacterial
species.[74]
Gram-positive bacteria possess a thick cell wall containing many layers of peptidoglycan and teichoic acids. In
contrast, Gram-negative bacteria have a relatively thin cell wall consisting of a few layers of peptidoglycan
surrounded by a second lipid membrane containing lipopolysaccharides and lipoproteins. Most bacteria have the
Gram-negative cell wall, and only the Firmicutes and Actinobacteria (previously known as the low G+C and high
G+C Gram-positive bacteria, respectively) have the alternative Gram-positive arrangement.[75] These differences in
structure can produce differences in antibiotic susceptibility; for instance, vancomycin can kill only Gram-positive
bacteria and is ineffective against Gram-negative pathogens, such as Haemophilus influenzae or Pseudomonas
aeruginosa.[76]
In many bacteria an S-layer of rigidly arrayed protein molecules covers the outside of the cell.[77] This layer provides
chemical and physical protection for the cell surface and can act as a macromolecular diffusion barrier. S-layers have
Bacteria 22

diverse but mostly poorly understood functions, but are known to act as virulence factors in Campylobacter and
contain surface enzymes in Bacillus stearothermophilus.[78]
Flagella are rigid protein structures, about 20 nanometres in diameter
and up to 20 micrometres in length, that are used for motility. Flagella
are driven by the energy released by the transfer of ions down an
electrochemical gradient across the cell membrane.[79]
Fimbriae are fine filaments of protein, just 2–10 nanometres in
diameter and up to several micrometers in length. They are distributed
over the surface of the cell, and resemble fine hairs when seen under
the electron microscope. Fimbriae are believed to be involved in
Helicobacter pylori electron micrograph,
showing multiple flagella on the cell surface attachment to solid surfaces or to other cells and are essential for the
virulence of some bacterial pathogens.[80] Pili (sing. pilus) are cellular
appendages, slightly larger than fimbriae, that can transfer genetic material between bacterial cells in a process called
conjugation (see bacterial genetics, below).[81]

Capsules or slime layers are produced by many bacteria to surround their cells, and vary in structural complexity:
ranging from a disorganised slime layer of extra-cellular polymer, to a highly structured capsule or glycocalyx.
These structures can protect cells from engulfment by eukaryotic cells, such as macrophages.[82] They can also act as
antigens and be involved in cell recognition, as well as aiding attachment to surfaces and the formation of
biofilms.[83]
The assembly of these extracellular structures is dependent on bacterial secretion systems. These transfer proteins
from the cytoplasm into the periplasm or into the environment around the cell. Many types of secretion systems are
known and these structures are often essential for the virulence of pathogens, so are intensively studied.[84]

Endospores
Certain genera of Gram-positive bacteria, such as Bacillus,
Clostridium, Sporohalobacter, Anaerobacter and Heliobacterium, can
form highly resistant, dormant structures called endospores.[85] In
almost all cases, one endospore is formed and this is not a reproductive
process, although Anaerobacter can make up to seven endospores in a
single cell.[86] Endospores have a central core of cytoplasm containing
DNA and ribosomes surrounded by a cortex layer and protected by an
impermeable and rigid coat.
Bacillus anthracis (stained purple) growing in
Endospores show no detectable metabolism and can survive extreme cerebrospinal fluid
physical and chemical stresses, such as high levels of UV light, gamma
radiation, detergents, disinfectants, heat, freezing, pressure and desiccation.[87] In this dormant state, these organisms
may remain viable for millions of years,[88][89] and endospores even allow bacteria to survive exposure to the
vacuum and radiation in space.[90] According to scientist Dr. Steinn Sigurdsson, "There are viable bacterial spores
that have been found that are 40 million years old on Earth — and we know they're very hardened to radiation."[91]
Endospore-forming bacteria can also cause disease: for example, anthrax can be contracted by the inhalation of
Bacillus anthracis endospores, and contamination of deep puncture wounds with Clostridium tetani endospores
causes tetanus.[92]
Bacteria 23

Metabolism
Bacteria exhibit an extremely wide variety of metabolic types.[93] The distribution of metabolic traits within a group
of bacteria has traditionally been used to define their taxonomy, but these traits often do not correspond with modern
genetic classifications.[94] Bacterial metabolism is classified into nutritional groups on the basis of three major
criteria: the kind of energy used for growth, the source of carbon, and the electron donors used for growth. An
additional criterion of respiratory microorganisms are the electron acceptors used for aerobic or anaerobic
respiration.[95]

Nutritional types in bacterial metabolism


Nutritional Source of Source of carbon Examples
type energy

Phototrophs Sunlight Organic compounds (photoheterotrophs) or carbon Cyanobacteria, Green sulfur bacteria, Chloroflexi,
fixation (photoautotrophs) or Purple bacteria

Lithotrophs Inorganic Organic compounds (lithoheterotrophs) or carbon Thermodesulfobacteria, Hydrogenophilaceae, or


compounds fixation (lithoautotrophs) Nitrospirae

Organotrophs Organic Organic compounds (chemoheterotrophs) or carbon Bacillus, Clostridium or Enterobacteriaceae


compounds fixation (chemoautotrophs)

Carbon metabolism in bacteria is either heterotrophic, where organic carbon compounds are used as carbon sources,
or autotrophic, meaning that cellular carbon is obtained by fixing carbon dioxide. Heterotrophic bacteria include
parasitic types. Typical autotrophic bacteria are phototrophic cyanobacteria, green sulfur-bacteria and some purple
bacteria, but also many chemolithotrophic species, such as nitrifying or sulfur-oxidising bacteria.[96] Energy
metabolism of bacteria is either based on phototrophy, the use of light through photosynthesis, or based on
chemotrophy, the use of chemical substances for energy, which are mostly oxidised at the expense of oxygen or
alternative electron acceptors (aerobic/anaerobic respiration).
Finally, bacteria are further divided into lithotrophs that use inorganic
electron donors and organotrophs that use organic compounds as
electron donors. Chemotrophic organisms use the respective electron
donors for energy conservation (by aerobic/anaerobic respiration or
fermentation) and biosynthetic reactions (e.g. carbon dioxide fixation),
whereas phototrophic organisms use them only for biosynthetic
purposes. Respiratory organisms use chemical compounds as a source
of energy by taking electrons from the reduced substrate and
transferring them to a terminal electron acceptor in a redox reaction.
This reaction releases energy that can be used to synthesise ATP and
drive metabolism. In aerobic organisms, oxygen is used as the electron Filaments of photosynthetic cyanobacteria

acceptor. In anaerobic organisms other inorganic compounds, such as


nitrate, sulfate or carbon dioxide are used as electron acceptors. This leads to the ecologically important processes of
denitrification, sulfate reduction and acetogenesis, respectively.

Another way of life of chemotrophs in the absence of possible electron acceptors is fermentation, where the electrons
taken from the reduced substrates are transferred to oxidised intermediates to generate reduced fermentation products
(e.g. lactate, ethanol, hydrogen, butyric acid). Fermentation is possible, because the energy content of the substrates
is higher than that of the products, which allows the organisms to synthesise ATP and drive their metabolism.[97][98]
These processes are also important in biological responses to pollution; for example, sulfate-reducing bacteria are
largely responsible for the production of the highly toxic forms of mercury (methyl- and dimethylmercury) in the
environment.[99] Non-respiratory anaerobes use fermentation to generate energy and reducing power, secreting
Bacteria 24

metabolic by-products (such as ethanol in brewing) as waste. Facultative anaerobes can switch between fermentation
and different terminal electron acceptors depending on the environmental conditions in which they find themselves.
Lithotrophic bacteria can use inorganic compounds as a source of energy. Common inorganic electron donors are
hydrogen, carbon monoxide, ammonia (leading to nitrification), ferrous iron and other reduced metal ions, and
several reduced sulfur compounds. Unusually, the gas methane can be used by methanotrophic bacteria as both a
source of electrons and a substrate for carbon anabolism.[100] In both aerobic phototrophy and chemolithotrophy,
oxygen is used as a terminal electron acceptor, while under anaerobic conditions inorganic compounds are used
instead. Most lithotrophic organisms are autotrophic, whereas organotrophic organisms are heterotrophic.
In addition to fixing carbon dioxide in photosynthesis, some bacteria also fix nitrogen gas (nitrogen fixation) using
the enzyme nitrogenase. This environmentally important trait can be found in bacteria of nearly all the metabolic
types listed above, but is not universal.[101]
Regardless of the type of metabolic process they employ, the majority of bacteria are only able to take in raw
materials in the form of relatively small molecules, which enter the cell by diffusion or through molecular channels
in cell membranes. The Planctomycetes are the exception (as they are in possessing membranes around their nuclear
material). It has recently been shown that Gemmata obscuriglobus is able to take in large molecules via a process
that in some ways resembles endocytosis, the process used by eukaryotic cells to engulf external items.[37][102]

Growth and reproduction


Unlike in multicellular organisms, increases in cell size (cell growth and
reproduction by cell division) are tightly linked in unicellular organisms.
Bacteria grow to a fixed size and then reproduce through binary fission, a form
of asexual reproduction.[103] Under optimal conditions, bacteria can grow and
divide extremely rapidly, and bacterial populations can double as quickly as
every 9.8 minutes.[104] In cell division, two identical clone daughter cells are
produced. Some bacteria, while still reproducing asexually, form more complex
reproductive structures that help disperse the newly formed daughter cells.
Many bacteria reproduce through
Examples include fruiting body formation by Myxobacteria and aerial hyphae
binary fission
formation by Streptomyces, or budding. Budding involves a cell forming a
protrusion that breaks away and produces a daughter cell.

In the laboratory, bacteria are usually grown using solid or liquid media. Solid growth
media such as agar plates are used to isolate pure cultures of a bacterial strain.
However, liquid growth media are used when measurement of growth or large volumes
of cells are required. Growth in stirred liquid media occurs as an even cell suspension,
making the cultures easy to divide and transfer, although isolating single bacteria from
liquid media is difficult. The use of selective media (media with specific nutrients
added or deficient, or with antibiotics added) can help identify specific organisms.[106]

A colony of Escherichia Most laboratory techniques for growing bacteria use high levels of nutrients to produce
[105]
coli large amounts of cells cheaply and quickly. However, in natural environments nutrients
are limited, meaning that bacteria cannot continue to reproduce indefinitely. This
nutrient limitation has led the evolution of different growth strategies (see r/K selection theory). Some organisms can
grow extremely rapidly when nutrients become available, such as the formation of algal (and cyanobacterial) blooms
that often occur in lakes during the summer.[107] Other organisms have adaptations to harsh environments, such as
the production of multiple antibiotics by Streptomyces that inhibit the growth of competing microorganisms.[108] In

nature, many organisms live in communities (e.g., biofilms) that may allow for increased supply of nutrients and
protection from environmental stresses.[48] These relationships can be essential for growth of a particular organism
Bacteria 25

or group of organisms (syntrophy).[109]


Bacterial growth follows three phases. When a population of bacteria first enter a high-nutrient environment that
allows growth, the cells need to adapt to their new environment. The first phase of growth is the lag phase, a period
of slow growth when the cells are adapting to the high-nutrient environment and preparing for fast growth. The lag
phase has high biosynthesis rates, as proteins necessary for rapid growth are produced.[110] The second phase of
growth is the logarithmic phase (log phase), also known as the exponential phase. The log phase is marked by rapid
exponential growth. The rate at which cells grow during this phase is known as the growth rate (k), and the time it
takes the cells to double is known as the generation time (g). During log phase, nutrients are metabolised at
maximum speed until one of the nutrients is depleted and starts limiting growth. The final phase of growth is the
stationary phase and is caused by depleted nutrients. The cells reduce their metabolic activity and consume
non-essential cellular proteins. The stationary phase is a transition from rapid growth to a stress response state and
there is increased expression of genes involved in DNA repair, antioxidant metabolism and nutrient transport.[111]

Genetics
Most bacteria have a single circular chromosome that can range in size from only 160,000 base pairs in the
endosymbiotic bacteria Candidatus Carsonella ruddii,[112] to 12,200,000 base pairs in the soil-dwelling bacteria
Sorangium cellulosum.[113] Spirochaetes of the genus Borrelia are a notable exception to this arrangement, with
bacteria such as Borrelia burgdorferi, the cause of Lyme disease, containing a single linear chromosome.[114] The
genes in bacterial genomes are usually a single continuous stretch of DNA and although several different types of
introns do exist in bacteria, these are much more rare than in eukaryotes.[115]
Bacteria may also contain plasmids, which are small extra-chromosomal DNAs that may contain genes for antibiotic
resistance or virulence factors.
Bacteria, as asexual organisms, inherit identical copies of their parent's genes (i.e., they are clonal). However, all
bacteria can evolve by selection on changes to their genetic material DNA caused by genetic recombination or
mutations. Mutations come from errors made during the replication of DNA or from exposure to mutagens. Mutation
rates vary widely among different species of bacteria and even among different clones of a single species of
bacteria.[116] Genetic changes in bacterial genomes come from either random mutation during replication or
"stress-directed mutation", where genes involved in a particular growth-limiting process have an increased mutation
rate.[117]
Some bacteria also transfer genetic material between cells. This can occur in three main ways. First, bacteria can take
up exogenous DNA from their environment, in a process called transformation. Genes can also be transferred by the
process of transduction, when the integration of a bacteriophage introduces foreign DNA into the chromosome. The
third method of gene transfer is bacterial conjugation, where DNA is transferred through direct cell contact. This
gene acquisition from other bacteria or the environment is called horizontal gene transfer and may be common under
natural conditions.[118] Gene transfer is particularly important in antibiotic resistance as it allows the rapid transfer of
resistance genes between different pathogens.[119]

Bacteriophages
Bacteriophages are viruses that infect bacteria. Many types of bacteriophage exist, some simply infect and lyse their
host bacteria, while others insert into the bacterial chromosome. A bacteriophage can contain genes that contribute to
its host's phenotype: for example, in the evolution of Escherichia coli O157:H7 and Clostridium botulinum, the toxin
genes in an integrated phage converted a harmless ancestral bacterium into a lethal pathogen.[120] Bacteria resist
phage infection through restriction modification systems that degrade foreign DNA,[121] and a system that uses
CRISPR sequences to retain fragments of the genomes of phage that the bacteria have come into contact with in the
past, which allows them to block virus replication through a form of RNA interference.[122][123] This CRISPR
system provides bacteria with acquired immunity to infection.
Bacteria 26

Behavior

Secretion
Bacteria frequently secrete chemicals into their environment in order to modify it favorably. The secretions are often
proteins and may act as enzymes that digest some form of food in the environment.

Bioluminescence
A few bacteria have chemical systems that generate light. This bioluminescence often occurs in bacteria that live in
association with fish, and the light probably serves to attract fish or other large animals.[124] – see Milky seas effect

Multicellularity
(See also: Prokaryote#Sociality)
Bacteria often function as multicellular aggregates known as biofilms, exchanging a variety of molecular signals for
inter-cell communication, and engaging in coordinated multicellular behavior.[125][126]
The communal benefits of multicellular cooperation include a cellular division of labor, accessing resources that
cannot effectively be utilized by single cells, collectively defending against antagonists, and optimizing population
survival by differentiating into distinct cell types.[125] For example, bacteria in biofilms can have more than 500
times increased resistance to antibacterial agents than individual "planktonic" bacteria of the same species.[126]
One type of inter-cellular communication by a molecular signal is called quorum sensing, which serves the purpose
of determining whether there is a local population density that is sufficiently high that it is productive to invest in
processes that are only successful if large numbers of similar organisms behave similarly, as in excreting digestive
enzymes or emitting light.
Quorum sensing allows bacteria to coordinate gene expression, and enables them to produce, release and detect
autoinducers or pheromones which accumulate with the growth in cell population.[127]
Bacteria 27

Movement
Many bacteria can move using a variety of mechanisms: flagella are used for swimming through water; bacterial
gliding and twitching motility move bacteria across surfaces; and changes of buoyancy allow vertical motion.[128]
Swimming bacteria frequently move
near 10 body lengths per second and a
few as fast as 100. This makes them at
least as fast as fish, on a relative
scale.[129]
In twitching motility, bacterial use
their type IV pili as a grappling hook,
repeatedly extending it, anchoring it
and then retracting it with remarkable
force (>80 pN).[130]
Flagella are semi-rigid cylindrical
structures that are rotated and function
much like the propeller on a ship.
Objects as small as bacteria operate a
low Reynolds number and cylindrical
forms are more efficient than the flat,
paddle-like, forms appropriate at
human size scale.[131] Flagellum of Gram-negative Bacteria. The base drives the rotation of the hook and
filament.
Bacterial species differ in the number
and arrangement of flagella on their
surface; some have a single flagellum (monotrichous), a flagellum at each end (amphitrichous), clusters of flagella at
the poles of the cell (lophotrichous), while others have flagella distributed over the entire surface of the cell
(peritrichous). The bacterial flagella is the best-understood motility structure in any organism and is made of about
20 proteins, with approximately another 30 proteins required for its regulation and assembly.[128] The flagellum is a
rotating structure driven by a reversible motor at the base that uses the electrochemical gradient across the membrane
for power.[132] This motor drives the motion of the filament, which acts as a propeller.

Many bacteria (such as E. coli) have two distinct modes of movement: forward movement (swimming) and
tumbling. The tumbling allows them to reorient and makes their movement a three-dimensional random walk.[133]
(See external links below for link to videos.) The flagella of a unique group of bacteria, the spirochaetes, are found
between two membranes in the periplasmic space. They have a distinctive helical body that twists about as it
moves.[128]
Motile bacteria are attracted or repelled by certain stimuli in behaviors called taxes: these include chemotaxis,
phototaxis, energy taxis and magnetotaxis.[134][135][136] In one peculiar group, the myxobacteria, individual bacteria
move together to form waves of cells that then differentiate to form fruiting bodies containing spores.[51] The
myxobacteria move only when on solid surfaces, unlike E. coli, which is motile in liquid or solid media.
Several Listeria and Shigella species move inside host cells by usurping the cytoskeleton, which is normally used to
move organelles inside the cell. By promoting actin polymerization at one pole of their cells, they can form a kind of
tail that pushes them through the host cell's cytoplasm.[137]
Bacteria 28

Classification and identification


Classification seeks to describe the diversity of bacterial species by
naming and grouping organisms based on similarities. Bacteria can be
classified on the basis of cell structure, cellular metabolism or on
differences in cell components such as DNA, fatty acids, pigments,
antigens and quinones.[106] While these schemes allowed the
identification and classification of bacterial strains, it was unclear
whether these differences represented variation between distinct
species or between strains of the same species. This uncertainty was
due to the lack of distinctive structures in most bacteria, as well as
Streptococcus mutans visualized with a Gram
lateral gene transfer between unrelated species.[138] Due to lateral gene
stain
transfer, some closely related bacteria can have very different
morphologies and metabolisms. To overcome this uncertainty, modern
bacterial classification emphasizes molecular systematics, using genetic techniques such as guanine cytosine ratio
determination, genome-genome hybridization, as well as sequencing genes that have not undergone extensive lateral
gene transfer, such as the rRNA gene.[139] Classification of bacteria is determined by publication in the International
Journal of Systematic Bacteriology,[140] and Bergey's Manual of Systematic Bacteriology.[141] The International
Committee on Systematic Bacteriology (ICSB) maintains international rules for the naming of bacteria and
taxonomic categories and for the ranking of them in the International Code of Nomenclature of Bacteria.

The term "bacteria" was traditionally applied to all microscopic, single-cell prokaryotes. However, molecular
systematics showed prokaryotic life to consist of two separate domains, originally called Eubacteria and
Archaebacteria, but now called Bacteria and Archaea that evolved independently from an ancient common
ancestor.[10] The archaea and eukaryotes are more closely related to each other than either is to the bacteria. These
two domains, along with Eukarya, are the basis of the three-domain system, which is currently the most widely used
classification system in microbiolology.[142] However, due to the relatively recent introduction of molecular
systematics and a rapid increase in the number of genome sequences that are available, bacterial classification
remains a changing and expanding field.[5][143] For example, a few biologists argue that the Archaea and Eukaryotes
evolved from Gram-positive bacteria.[144]
Identification of bacteria in the laboratory is particularly relevant in medicine, where the correct treatment is
determined by the bacterial species causing an infection. Consequently, the need to identify human pathogens was a
major impetus for the development of techniques to identify bacteria.
Bacteria 29

The Gram stain, developed in 1884 by


Hans Christian Gram, characterises
bacteria based on the structural
characteristics of their cell walls.[74]
The thick layers of peptidoglycan in
the "Gram-positive" cell wall stain
purple, while the thin "Gram-negative"
cell wall appears pink. By combining
morphology and Gram-staining, most
bacteria can be classified as belonging
to one of four groups (Gram-positive
cocci, Gram-positive bacilli,
Gram-negative cocci and
Gram-negative bacilli). Some
Phylogenetic tree showing the diversity of bacteria, compared to other
organisms.Ciccarelli FD, Doerks T, von Mering C, Creevey CJ, Snel B, Bork P (2006). organisms are best identified by stains
"Toward automatic reconstruction of a highly resolved tree of life". Science 311 (5765): other than the Gram stain, particularly
1283–7. Bibcode 2006Sci...311.1283C. doi:10.1126/science.1123061. PMID 16513982.  mycobacteria or Nocardia, which show
Eukaryotes are colored red, archaea green and bacteria blue.
acid-fastness on Ziehl–Neelsen or
similar stains.[145] Other organisms
may need to be identified by their growth in special media, or by other techniques, such as serology.

Culture techniques are designed to promote the growth and identify particular bacteria, while restricting the growth
of the other bacteria in the sample. Often these techniques are designed for specific specimens; for example, a
sputum sample will be treated to identify organisms that cause pneumonia, while stool specimens are cultured on
selective media to identify organisms that cause diarrhoea, while preventing growth of non-pathogenic bacteria.
Specimens that are normally sterile, such as blood, urine or spinal fluid, are cultured under conditions designed to
grow all possible organisms.[106][146] Once a pathogenic organism has been isolated, it can be further characterised
by its morphology, growth patterns such as (aerobic or anaerobic growth, patterns of hemolysis) and staining.

As with bacterial classification, identification of bacteria is increasingly using molecular methods. Diagnostics using
such DNA-based tools, such as polymerase chain reaction, are increasingly popular due to their specificity and
speed, compared to culture-based methods.[147] These methods also allow the detection and identification of "viable
but nonculturable" cells that are metabolically active but non-dividing.[148] However, even using these improved
methods, the total number of bacterial species is not known and cannot even be estimated with any certainty.
Following present classification, there are a little less than 9,300 known species of prokaryotes, which includes
bacteria and archaea.[149] but attempts to estimate the true level of bacterial diversity have ranged from 107 to 109
total species – and even these diverse estimates may be off by many orders of magnitude.[150][151]
Bacteria 30

Interactions with other organisms


Despite their apparent simplicity, bacteria can form complex associations with other organisms. These symbiotic
associations can be divided into parasitism, mutualism and commensalism. Due to their small size, commensal
bacteria are ubiquitous and grow on animals and plants exactly as they will grow on any other surface. However,
their growth can be increased by warmth and sweat, and large populations of these organisms in humans are the
cause of body odor.

Predators
Some species of bacteria kill and then consume other microorganisms, these species called predatory bacteria.[152]
These include organisms such as Myxococcus xanthus, which forms swarms of cells that kill and digest any bacteria
they encounter.[153] Other bacterial predators either attach to their prey in order to digest them and absorb nutrients,
such as Vampirococcus, or invade another cell and multiply inside the cytosol, such as Daptobacter.[154] These
predatory bacteria are thought to have evolved from saprophages that consumed dead microorganisms, through
adaptations that allowed them to entrap and kill other organisms.[155]

Mutualists
Certain bacteria form close spatial associations that are essential for their survival. One such mutualistic association,
called interspecies hydrogen transfer, occurs between clusters of anaerobic bacteria that consume organic acids such
as butyric acid or propionic acid and produce hydrogen, and methanogenic Archaea that consume hydrogen.[156] The
bacteria in this association are unable to consume the organic acids as this reaction produces hydrogen that
accumulates in their surroundings. Only the intimate association with the hydrogen-consuming Archaea keeps the
hydrogen concentration low enough to allow the bacteria to grow.
In soil, microorganisms that reside in the rhizosphere (a zone that includes the root surface and the soil that adheres
to the root after gentle shaking) carry out nitrogen fixation, converting nitrogen gas to nitrogenous compounds.[157]
This serves to provide an easily absorbable form of nitrogen for many plants, which cannot fix nitrogen themselves.
Many other bacteria are found as symbionts in humans and other organisms. For example, the presence of over 1,000
bacterial species in the normal human gut flora of the intestines can contribute to gut immunity, synthesise vitamins
such as folic acid, vitamin K and biotin, convert sugars to lactic acid (see Lactobacillus), as well as fermenting
complex undigestible carbohydrates.[158][159][160] The presence of this gut flora also inhibits the growth of
potentially pathogenic bacteria (usually through competitive exclusion) and these beneficial bacteria are
consequently sold as probiotic dietary supplements.[161]

Pathogens
If bacteria form a parasitic association with other organisms, they are
classed as pathogens. Pathogenic bacteria are a major cause of human
death and disease and cause infections such as tetanus, typhoid fever,
diphtheria, syphilis, cholera, foodborne illness, leprosy and
tuberculosis. A pathogenic cause for a known medical disease may
only be discovered many years after, as was the case with Helicobacter
pylori and peptic ulcer disease. Bacterial diseases are also important in
agriculture, with bacteria causing leaf spot, fire blight and wilts in
plants, as well as Johne's disease, mastitis, salmonella and anthrax in Color-enhanced scanning electron micrograph
farm animals. showing Salmonella typhimurium (red) invading
cultured human cells
Bacteria 31

Each species of pathogen has a characteristic spectrum of interactions with its human hosts. Some organisms, such as
Staphylococcus or Streptococcus, can cause skin infections, pneumonia, meningitis and even overwhelming sepsis, a
systemic inflammatory response producing shock, massive vasodilation and death.[162] Yet these organisms are also
part of the normal human flora and usually exist on the skin or in the nose without causing any disease at all. Other
organisms invariably cause disease in humans, such as the Rickettsia, which are obligate intracellular parasites able
to grow and reproduce only within the cells of other organisms. One species of Rickettsia causes typhus, while
another causes Rocky Mountain spotted fever. Chlamydia, another phylum of obligate intracellular parasites,
contains species that can cause pneumonia, or urinary tract infection and may be involved in coronary heart
disease.[163] Finally, some species such as Pseudomonas aeruginosa, Burkholderia cenocepacia, and Mycobacterium
avium are opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic
fibrosis.[164][165]
Bacterial infections may be treated
with antibiotics, which are classified as
bacteriocidal if they kill bacteria, or
bacteriostatic if they just prevent
bacterial growth. There are many types
of antibiotics and each class inhibits a
process that is different in the pathogen
from that found in the host. An
example of how antibiotics produce
selective toxicity are chloramphenicol
and puromycin, which inhibit the
bacterial ribosome, but not the
structurally different eukaryotic
[168]
ribosome. Antibiotics are used
both in treating human disease and in
intensive farming to promote animal
growth, where they may be
contributing to the rapid development
of antibiotic resistance in bacterial
[166][167]
populations.[169] Infections can be
Overview of bacterial infections and main species involved.
prevented by antiseptic measures such
as sterilizing the skin prior to piercing
it with the needle of a syringe, and by proper care of indwelling catheters. Surgical and dental instruments are also
sterilized to prevent contamination by bacteria. Disinfectants such as bleach are used to kill bacteria or other
pathogens on surfaces to prevent contamination and further reduce the risk of infection.

Significance in technology and industry


Bacteria, often lactic acid bacteria such as Lactobacillus and Lactococcus, in combination with yeasts and molds,
have been used for thousands of years in the preparation of fermented foods such as cheese, pickles, soy sauce,
sauerkraut, vinegar, wine and yogurt.[170][171]
The ability of bacteria to degrade a variety of organic compounds is remarkable and has been used in waste
processing and bioremediation. Bacteria capable of digesting the hydrocarbons in petroleum are often used to clean
up oil spills.[172] Fertilizer was added to some of the beaches in Prince William Sound in an attempt to promote the
growth of these naturally occurring bacteria after the 1989 Exxon Valdez oil spill. These efforts were effective on
beaches that were not too thickly covered in oil. Bacteria are also used for the bioremediation of industrial toxic
Bacteria 32

wastes.[173] In the chemical industry, bacteria are most important in the production of enantiomerically pure
chemicals for use as pharmaceuticals or agrichemicals.[174]
Bacteria can also be used in the place of pesticides in the biological pest control. This commonly involves Bacillus
thuringiensis (also called BT), a Gram-positive, soil dwelling bacterium. Subspecies of this bacteria are used as a
Lepidopteran-specific insecticides under trade names such as Dipel and Thuricide.[175] Because of their specificity,
these pesticides are regarded as environmentally friendly, with little or no effect on humans, wildlife, pollinators and
most other beneficial insects.[176][177]
Because of their ability to quickly grow and the relative ease with which they can be manipulated, bacteria are the
workhorses for the fields of molecular biology, genetics and biochemistry. By making mutations in bacterial DNA
and examining the resulting phenotypes, scientists can determine the function of genes, enzymes and metabolic
pathways in bacteria, then apply this knowledge to more complex organisms.[178] This aim of understanding the
biochemistry of a cell reaches its most complex expression in the synthesis of huge amounts of enzyme kinetic and
gene expression data into mathematical models of entire organisms. This is achievable in some well-studied bacteria,
with models of Escherichia coli metabolism now being produced and tested.[179][180] This understanding of bacterial
metabolism and genetics allows the use of biotechnology to bioengineer bacteria for the production of therapeutic
proteins, such as insulin, growth factors, or antibodies.[181][182]

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[174] Liese A, Filho M (1999). "Production of fine chemicals using biocatalysis". Curr Opin Biotechnol 10 (6): 595–603.
doi:10.1016/S0958-1669(99)00040-3. PMID 10600695.
[175] Aronson AI, Shai Y (2001). "Why Bacillus thuringiensis insecticidal toxins are so effective: unique features of their mode of action".
FEMS Microbiol. Lett. 195 (1): 1–8. doi:10.1111/j.1574-6968.2001.tb10489.x. PMID 11166987.
[176] Bozsik A (2006). "Susceptibility of adult Coccinella septempunctata (Coleoptera: Coccinellidae) to insecticides with different modes of
action". Pest Manag Sci 62 (7): 651–4. doi:10.1002/ps.1221. PMID 16649191.
[177] Chattopadhyay A, Bhatnagar N, Bhatnagar R (2004). "Bacterial insecticidal toxins". Crit Rev Microbiol 30 (1): 33–54.
doi:10.1080/10408410490270712. PMID 15116762.
[178] Serres MH, Gopal S, Nahum LA, Liang P, Gaasterland T, Riley M (2001). "A functional update of the Escherichia coli K-12 genome"
(http:/ / genomebiology. com/ 1465-6906/ 2/ RESEARCH0035). Genome Biology 2 (9): RESEARCH0035.
doi:10.1186/gb-2001-2-9-research0035. PMC 56896. PMID 11574054. .
[179] Almaas E, Kovács B, Vicsek T, Oltvai Z, Barabási A (2004). "Global organization of metabolic fluxes in the bacterium Escherichia coli".
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[182] Graumann K, Premstaller A (2006). "Manufacturing of recombinant therapeutic proteins in microbial systems". Biotechnol J 1 (2): 164–86.
doi:10.1002/biot.200500051. PMID 16892246.

Further reading
• Alcamo IE (2001). Fundamentals of microbiology. Boston: Jones and Bartlett. ISBN 0-7637-1067-9.
• Atlas RM (1995). Principles of microbiology. St. Louis: Mosby. ISBN 0-8016-7790-4.
• Martinko JM, Madigan MT (2005). Brock Biology of Microorganisms (11th ed.). Englewood Cliffs, N.J: Prentice
Hall. ISBN 0-13-144329-1.
• Holt JC, Bergey DH (1994). Bergey's manual of determinative bacteriology (9th ed.). Baltimore: Williams &
Wilkins. ISBN 0-683-00603-7.
• Hugenholtz P, Goebel BM, Pace NR (15 September 1998). "Impact of culture-independent studies on the
emerging phylogenetic view of bacterial diversity" (http://jb.asm.org/cgi/content/full/180/18/
4765?view=full&pmid=9733676). J Bacteriol 180 (18): 4765–74. PMC 107498. PMID 9733676.
• Funke BR, Tortora GJ, Case CL (2004). Microbiology: an introduction (8th ed.). San Francisco: Benjamin
Cummings. ISBN 0-8053-7614-3.
• Shively, Jessup M. (2006). Complex Intracellular Structures in Prokaryotes (Microbiology Monographs). Berlin:
Springer. ISBN 3-540-32524-7.
Bacteria 39

External links
• MicrobeWiki (http://microbewiki.kenyon.edu/index.php/MicrobeWiki), an extensive wiki about bacteria
(http://microbewiki.kenyon.edu/index.php/Microbial_Biorealm) and viruses (http://microbewiki.kenyon.
edu/index.php/Viral_Biorealm)
• Bacteria that affect crops and other plants (http://www.ncppb.com)
• Bacterial Nomenclature Up-To-Date from DSMZ (http://www.dsmz.de/bactnom/bactname.htm)
• Genera of the domain Bacteria (http://www.bacterio.cict.fr/eubacteria.html) – list of Prokaryotic names with
Standing in Nomenclature
• The largest bacteria (http://www.sciencenews.org/pages/sn_arc99/4_17_99/fob5.htm)
• Tree of Life: Eubacteria (http://tolweb.org/tree?group=Eubacteria&contgroup=Life_on_Earth)
• Videos (http://www.rowland.harvard.edu/labs/bacteria/index_movies.html) of bacteria swimming and
tumbling, use of optical tweezers and other videos.
• Planet of the Bacteria (http://www.stephenjaygould.org/library/gould_bacteria.html) by Stephen Jay Gould
• On-line text book on bacteriology (http://www.textbookofbacteriology.net/)
• Animated guide to bacterial cell structure. (http://www.blackwellpublishing.com/trun/artwork/Animations/
Overview/overview.html)
• Bacteria Make Major Evolutionary Shift in the Lab (http://www.newscientist.com/channel/life/
dn14094-bacteria-make-major-evolutionary-shift-in-the-lab.html)
• Online collaboration for bacterial taxonomy. (http://esciencenews.com/articles/2009/02/19/online.
collaboration.identifies.bacteria)
• PATRIC (http://patricbrc.org/), a Bioinformatics Resource Center for bacterial pathogens, funded by NIAID
(http://www.niaid.nih.gov/)
• Bacterial Chemotaxis Interactive Simulator (http://wormweb.org/bacteriachemo) – A web-app that uses several
simple algorithms to simulate bacterial chemotaxis.
• Cell-Cell Communication in Bacteria (http://ascb.org/ibioseminars/Bassler/Bassler1.cfm) on-line lecture by
Bonnie Bassler, and TED: Discovering bacteria's amazing communication system (http://www.ted.com/index.
php/talks/bonnie_bassler_on_how_bacteria_communicate.html)
Bacteriology 40

Bacteriology
Bacteriology is the study of bacteria. This subdivision of microbiology involves the identification, classification, and
characterization of bacterial species.[1] A person who studies bacteriology is a bacteriologist.

Bacteriology and microbiology


Because of the similarity of thinking and working with microorganisms other than bacteria, such as protozoa, fungi,
and viruses, there has been a tendency for the field of bacteriology to extend as microbiology.[2] The terms were
formerly often used interchangeably.[3] However, bacteriology can be classified as a distinct science.

References
[1] Wassenaar, T. M.. "Bacteriology: the study of bacteria" (http:/ / www. bacteriamuseum. org/ cms/ bacteria/
bacteriology-the-study-of-bacteria. html). www.mmgc.eu. . Retrieved 18 June 2011.
[2] Ward J. MacNeal; Herbert Upham Williams (1914). Pathogenic micro-organisms; a text-book of microbiology for physicians and students of
medicine (http:/ / books. google. com/ books?id=ijQRAAAAYAAJ& pg=PA1). P. Blakiston's sons & co.. pp. 1–. . Retrieved 18 June 2011.
[3] Jeanne Stove Poindexter (30 November 1986). Methods and special applications in bacterial ecology (http:/ / books. google. com/
books?id=BYGRgeBChYYC& pg=PA87). Springer. p. 87. ISBN 978-0-306-42346-8. . Retrieved 18 June 2011.

Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms,
including, but not limited to, living matter. The laws of biochemistry govern all living organisms and living
processes. By controlling information flow through biochemical signalling and the flow of chemical energy through
metabolism, biochemical processes give rise to the complexity of life.
Much of biochemistry deals with the structures, functions and interactions of cellular components such as proteins,
carbohydrates, lipids, nucleic acids and other biomolecules —although increasingly processes rather than individual
molecules are the main focus. Among the vast number of different biomolecules, many are complex and large
molecules (called biopolymers), which are composed of similar repeating subunits (called monomers). Each class of
polymeric biomolecule has a different set of subunit types.[1] For example, a protein is a polymer whose subunits are
selected from a set of 20 or more amino acids. Biochemistry studies the chemical properties of important biological
molecules, like proteins, and in particular the chemistry of enzyme-catalyzed reactions.
The biochemistry of cell metabolism and the endocrine system has been extensively described. Other areas of
biochemistry include the genetic code (DNA, RNA), protein synthesis, cell membrane transport and signal
transduction.
Over the last 40 years biochemistry has become so successful at explaining living processes that now almost all areas
of the life sciences from botany to medicine are engaged in biochemical research. Today the main focus of pure
biochemistry is in understanding how biological molecules give rise to the processes that occur within living cells,
which in turn relates greatly to the study and understanding of whole organisms.
Biochemistry 41

History
It once was generally believed that life and its materials had some essential
property or substance distinct from any found in non-living matter, and it
was thought that only living beings could produce the molecules of life.
Then, in 1828, Friedrich Wöhler published a paper on the synthesis of urea,
proving that organic compounds can be created artificially.[2][3]
The dawn of biochemistry may have been the discovery of the first enzyme,
diastase (today called amylase), in 1833 by Anselme Payen. Eduard
Buchner contributed the first demonstration of a complex biochemical
process outside of a cell in 1896: alcoholic fermentation in cell extracts of
yeast. Although the term “biochemistry” seems to have been first used in
1882, it is generally accepted that the formal coinage of biochemistry
occurred in 1903 by Carl Neuberg, a German chemist. Previous to this
time, this area would have been referred to as physiological chemistry. Gerty Cori and Carl Cori jointly won the
Nobel Prize in 1947 for their discovery of
Since then, biochemistry has advanced, especially since the mid-20th
the Cori cycle at RPMI.
century, with the development of new techniques such as chromatography,
X-ray diffraction, dual polarisation interferometry, NMR spectroscopy,
radioisotopic labeling, electron microscopy, and molecular dynamics simulations. These techniques allowed for the
discovery and detailed analysis of many molecules and metabolic pathways of the cell, such as glycolysis and the
Krebs cycle (citric acid cycle).

Another significant historic event in biochemistry is the discovery of the gene and its role in the transfer of
information in the cell. This part of biochemistry is often called molecular biology. In the 1950s, James D. Watson,
Francis Crick, Rosalind Franklin, and Maurice Wilkins were instrumental in solving DNA structure and suggesting
its relationship with genetic transfer of information. In 1958, George Beadle and Edward Tatum received the Nobel
Prize for work in fungi showing that one gene produces one enzyme. In 1988, Colin Pitchfork was the first person
convicted of murder with DNA evidence, which led to growth of forensic science. More recently, Andrew Z. Fire
and Craig C. Mello received the 2006 Nobel Prize for discovering the role of RNA interference (RNAi), in the
silencing of gene expression.

Starting materials: the chemical elements of life


Around two dozen of the 94 naturally-occurring chemical elements are essential to various kinds of biological life.
Most rare elements on Earth are not needed by life (exceptions being selenium and iodine), while a few common
ones (aluminum and titanium) are not used. Most organisms share element needs, but there are a few differences
between plants and animals. For example ocean algae use bromine but land plants and animals seem to need none.
All animals require sodium, but some plants do not. Plants need boron and silicon, but animals may not (or may need
ultra-small amounts).
Just six elements—carbon, hydrogen, nitrogen, oxygen, calcium, and phosphorus—make up almost 99% of the mass
of a human body (see composition of the human body for a complete list). In addition to the six major elements that
compose most of the human body, humans require smaller amounts of possibly 18 more.[4]
Biochemistry 42

Biomolecules
The four main classes of molecules in biochemistry are carbohydrates, lipids, proteins, and nucleic acids. Many
biological molecules are polymers: in this terminology, monomers are relatively small micromolecules that are
linked together to create large macromolecules, which are known as polymers. When monomers are linked together
to synthesize a biological polymer, they undergo a process called dehydration synthesis. Different macromolecules
can assemble in larger complexes, often needed for biological activity.

Carbohydrates
Carbohydrates are made from monomers called monosaccharides.
Some of these monosaccharides include glucose (C6H12O6), fructose
(C6H12O6), and deoxyribose (C5H10O4). When two monosaccharides
undergo dehydration synthesis, water is produced, as two hydrogen
atoms and one oxygen atom are lost from the two monosaccharides'
hydroxyl group.
A molecule of sucrose (glucose + fructose), a
disaccharide.

Lipids
Lipids are usually made from one molecule of glycerol combined with other
molecules. In triglycerides, the main group of bulk lipids, there is one
molecule of glycerol and three fatty acids. Fatty acids are considered the
monomer in that case, and may be saturated (no double bonds in the carbon
chain) or unsaturated (one or more double bonds in the carbon chain).
A triglyceride with a glycerol molecule
on the left and three fatty acids coming Lipids, especially phospholipids, are also used in various pharmaceutical
off it. products, either as co-solubilisers (e.g., in parenteral infusions) or else as drug
carrier components (e.g., in a liposome or transfersome).

Proteins
Proteins are very large molecules – macro-biopolymers – made from
monomers called amino acids. There are 20 standard amino acids, each
containing a carboxyl group, an amino group, and a side-chain (known as
an "R" group). The "R" group is what makes each amino acid different, and
the properties of the side-chains greatly influence the overall
three-dimensional conformation of a protein. When amino acids combine,
they form a special bond called a peptide bond through dehydration
synthesis, and become a polypeptide, or protein.
The general structure of an α-amino acid,
In order to determine whether two proteins are related, or in other words to with the amino group on the left and the
carboxyl group on the right.
decide whether they are homologous or not, scientists use
sequence-comparison methods. Methods like Sequence Alignments and
Structural Alignments are powerful tools that help scientists identify homologies between related molecules.
The relevance of finding homologies among proteins goes beyond forming an evolutionary pattern of protein
families. By finding how similar two protein sequences are, we acquire knowledge about their structure and
therefore their function.
Biochemistry 43

Nucleic acids
Nucleic acids are the molecules that make up DNA, an extremely
important substance that all cellular organisms use to store their
genetic information. The most common nucleic acids are
deoxyribonucleic acid and ribonucleic acid. Their monomers are
called nucleotides. The most common nucleotides are adenine,
cytosine, guanine, thymine, and uracil. Adenine binds with
thymine and uracil; Thymine binds only with adenine; and
cytosine and guanine can bind only with each other.

Carbohydrates
The function of carbohydrates includes energy storage and
providing structure. Sugars are carbohydrates, but not all
carbohydrates are sugars. There are more carbohydrates on Earth
than any other known type of biomolecule; they are used to store
The structure of deoxyribonucleic acid (DNA), the
picture shows the monomers being put together.
energy and genetic information, as well as play important roles in
cell to cell interactions and communications.

Monosaccharides
The simplest type of carbohydrate is a monosaccharide, which among
other properties contains carbon, hydrogen, and oxygen, mostly in a
ratio of 1:2:1 (generalized formula CnH2nOn, where n is at least 3).
Glucose, one of the most important carbohydrates, is an example of a
monosaccharide. So is fructose, the sugar commonly associated with
the sweet taste of fruits.[5][a] Some carbohydrates (especially after
condensation to oligo- and polysaccharides) contain less carbon Glucose
relative to H and O, which still are present in 2:1 (H:O) ratio.
Monosaccharides can be grouped into aldoses (having an aldehyde group at the end of the chain, e.g. glucose) and
ketoses (having a keto group in their chain; e.g. fructose). Both aldoses and ketoses occur in an equilibrium (starting
with chain lengths of C4) cyclic forms. These are generated by bond formation between one of the hydroxyl groups
of the sugar chain with the carbon of the aldehyde or keto group to form a hemiacetal bond. This leads to saturated
five-membered (in furanoses) or six-membered (in pyranoses) heterocyclic rings containing one O as heteroatom.

Disaccharides
Two monosaccharides can be joined together using dehydration
synthesis, in which a hydrogen atom is removed from the end of one
molecule and a hydroxyl group (—OH) is removed from the other; the
remaining residues are then attached at the sites from which the atoms
were removed. The H—OH or H2O is then released as a molecule of
water, hence the term dehydration. The new molecule, consisting of
two monosaccharides, is called a disaccharide and is conjoined Sucrose: ordinary table sugar and probably the
together by a glycosidic or ether bond. The reverse reaction can also most familiar carbohydrate.
Biochemistry 44

occur, using a molecule of water to split up a disaccharide and break the glycosidic bond; this is termed hydrolysis.
The most well-known disaccharide is sucrose, ordinary sugar (in scientific contexts, called table sugar or cane sugar
to differentiate it from other sugars). Sucrose consists of a glucose molecule and a fructose molecule joined together.
Another important disaccharide is lactose, consisting of a glucose molecule and a galactose molecule. As most
humans age, the production of lactase, the enzyme that hydrolyzes lactose back into glucose and galactose, typically
decreases. This results in lactase deficiency, also called lactose intolerance.
Sugar polymers are characterised by having reducing or non-reducing ends. A reducing end of a carbohydrate is a
carbon atom that can be in equilibrium with the open-chain aldehyde or keto form. If the joining of monomers takes
place at such a carbon atom, the free hydroxy group of the pyranose or furanose form is exchanged with an
OH-side-chain of another sugar, yielding a full acetal. This prevents opening of the chain to the aldehyde or keto
form and renders the modified residue non-reducing. Lactose contains a reducing end at its glucose moiety, whereas
the galactose moiety form a full acetal with the C4-OH group of glucose. Saccharose does not have a reducing end
because of full acetal formation between the aldehyde carbon of glucose (C1) and the keto carbon of fructose (C2).

Oligosaccharides and polysaccharides


When a few (around three to six) monosaccharides are joined together,
it is called an oligosaccharide (oligo- meaning "few"). These
molecules tend to be used as markers and signals, as well as having
some other uses. Many monosaccharides joined together make a
polysaccharide. They can be joined together in one long linear chain,
or they may be branched. Two of the most common polysaccharides
Cellulose as polymer of β-D-glucose
are cellulose and glycogen, both consisting of repeating glucose
monomers.

• Cellulose is made by plants and is an important structural component of their cell walls. Humans can neither
manufacture nor digest it.
• Glycogen, on the other hand, is an animal carbohydrate; humans and other animals use it as a form of energy
storage.

Use of carbohydrates as an energy source


Glucose is the major energy source in most life forms. For instance, polysaccharides are broken down into their
monomers (glycogen phosphorylase removes glucose residues from glycogen). Disaccharides like lactose or sucrose
are cleaved into their two component monosaccharides.

Glycolysis (anaerobic)
Glucose is mainly metabolized by a very important ten-step pathway called glycolysis, the net result of which is to
break down one molecule of glucose into two molecules of pyruvate; this also produces a net two molecules of ATP,
the energy currency of cells, along with two reducing equivalents in the form of converting NAD+ to NADH. This
does not require oxygen; if no oxygen is available (or the cell cannot use oxygen), the NAD is restored by converting
the pyruvate to lactate (lactic acid) (e.g., in humans) or to ethanol plus carbon dioxide (e.g., in yeast). Other
monosaccharides like galactose and fructose can be converted into intermediates of the glycolytic pathway.
Biochemistry 45

Aerobic
In aerobic cells with sufficient oxygen, as in most human cells, the pyruvate is further metabolized. It is irreversibly
converted to acetyl-CoA, giving off one carbon atom as the waste product carbon dioxide, generating another
reducing equivalent as NADH. The two molecules acetyl-CoA (from one molecule of glucose) then enter the citric
acid cycle, producing two more molecules of ATP, six more NADH molecules and two reduced (ubi)quinones (via
FADH2 as enzyme-bound cofactor), and releasing the remaining carbon atoms as carbon dioxide. The produced
NADH and quinol molecules then feed into the enzyme complexes of the respiratory chain, an electron transport
system transferring the electrons ultimately to oxygen and conserving the released energy in the form of a proton
gradient over a membrane (inner mitochondrial membrane in eukaryotes). Thus, oxygen is reduced to water and the
original electron acceptors NAD+ and quinone are regenerated. This is why humans breathe in oxygen and breathe
out carbon dioxide. The energy released from transferring the electrons from high-energy states in NADH and quinol
is conserved first as proton gradient and converted to ATP via ATP synthase. This generates an additional 28
molecules of ATP (24 from the 8 NADH + 4 from the 2 quinols), totaling to 32 molecules of ATP conserved per
degraded glucose (two from glycolysis + two from the citrate cycle). It is clear that using oxygen to completely
oxidize glucose provides an organism with far more energy than any oxygen-independent metabolic feature, and this
is thought to be the reason why complex life appeared only after Earth's atmosphere accumulated large amounts of
oxygen.

Gluconeogenesis
In vertebrates, vigorously contracting skeletal muscles (during weightlifting or sprinting, for example) do not receive
enough oxygen to meet the energy demand, and so they shift to anaerobic metabolism, converting glucose to lactate.
The liver regenerates the glucose, using a process called gluconeogenesis. This process is not quite the opposite of
glycolysis, and actually requires three times the amount of energy gained from glycolysis (six molecules of ATP are
used, compared to the two gained in glycolysis). Analogous to the above reactions, the glucose produced can then
undergo glycolysis in tissues that need energy, be stored as glycogen (or starch in plants), or be converted to other
monosaccharides or joined into di- or oligosaccharides. The combined pathways of glycolysis during exercise,
lactate's crossing via the bloodstream to the liver, subsequent gluconeogenesis and release of glucose into the
bloodstream is called the Cori cycle.

Proteins
Like carbohydrates, some proteins perform largely structural roles. For
instance, movements of the proteins actin and myosin ultimately are
responsible for the contraction of skeletal muscle. One property many
proteins have is that they specifically bind to a certain molecule or class of
molecules—they may be extremely selective in what they bind. Antibodies
are an example of proteins that attach to one specific type of molecule. In
fact, the enzyme-linked immunosorbent assay (ELISA), which uses
antibodies, is currently one of the most sensitive tests modern medicine
uses to detect various biomolecules. Probably the most important proteins,
however, are the enzymes. These molecules recognize specific reactant
molecules called substrates; they then catalyze the reaction between them. A schematic of hemoglobin. The red and
By lowering the activation energy, the enzyme speeds up that reaction by a blue ribbons represent the protein globin;

rate of 1011 or more: a reaction that would normally take over 3,000 years the green structures are the heme groups.

to complete spontaneously might take less than a second with an enzyme.

The enzyme itself is not used up in the process, and is free to catalyze the same reaction with a new set of substrates.
Using various modifiers, the activity of the enzyme can be regulated, enabling control of the biochemistry of the cell
Biochemistry 46

as a whole.
In essence, proteins are chains of amino acids. An amino acid consists of a carbon atom bound to four groups. One is
an amino group, —NH2, and one is a carboxylic acid group, —COOH (although these exist as —NH3+ and —COO−
under physiologic conditions). The third is a simple hydrogen atom. The fourth is commonly denoted "—R" and is
different for each amino acid. There are twenty standard amino acids. Some of these have functions by themselves or
in a modified form; for instance, glutamate functions as an important neurotransmitter.
Amino acids can be joined together via
a peptide bond. In this dehydration
synthesis, a water molecule is removed
and the peptide bond connects the
nitrogen of one amino acid's amino
group to the carbon of the other's
Generic amino acids (1) in neutral form, (2) as they exist physiologically, and (3) joined
carboxylic acid group. The resulting
together as a dipeptide.
molecule is called a dipeptide, and
short stretches of amino acids (usually,
fewer than thirty) are called peptides or polypeptides. Longer stretches merit the title proteins. As an example, the
important blood serum protein albumin contains 585 amino acid residues.

The structure of proteins is traditionally described in a hierarchy of four levels. The primary structure of a protein
simply consists of its linear sequence of amino acids; for instance,
"alanine-glycine-tryptophan-serine-glutamate-asparagine-glycine-lysine-…". Secondary structure is concerned with
local morphology (morphology being the study of structure). Some combinations of amino acids will tend to curl up
in a coil called an α-helix or into a sheet called a β-sheet; some α-helixes can be seen in the hemoglobin schematic
above. Tertiary structure is the entire three-dimensional shape of the protein. This shape is determined by the
sequence of amino acids. In fact, a single change can change the entire structure. The alpha chain of hemoglobin
contains 146 amino acid residues; substitution of the glutamate residue at position 6 with a valine residue changes
the behavior of hemoglobin so much that it results in sickle-cell disease. Finally, quaternary structure is concerned
with the structure of a protein with multiple peptide subunits, like hemoglobin with its four subunits. Not all proteins
have more than one subunit.
Ingested proteins are usually broken up into single amino acids or dipeptides in the small intestine, and then
absorbed. They can then be joined together to make new proteins. Intermediate products of glycolysis, the citric acid
cycle, and the pentose phosphate pathway can be used to make all twenty amino acids, and most bacteria and plants
possess all the necessary enzymes to synthesize them. Humans and other mammals, however, can synthesize only
half of them. They cannot synthesize isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan,
and valine. These are the essential amino acids, since it is essential to ingest them. Mammals do possess the enzymes
to synthesize alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine, the
nonessential amino acids. While they can synthesize arginine and histidine, they cannot produce it in sufficient
amounts for young, growing animals, and so these are often considered essential amino acids.
If the amino group is removed from an amino acid, it leaves behind a carbon skeleton called an α-keto acid.
Enzymes called transaminases can easily transfer the amino group from one amino acid (making it an α-keto acid) to
another α-keto acid (making it an amino acid). This is important in the biosynthesis of amino acids, as for many of
the pathways, intermediates from other biochemical pathways are converted to the α-keto acid skeleton, and then an
amino group is added, often via transamination. The amino acids may then be linked together to make a protein.
A similar process is used to break down proteins. It is first hydrolyzed into its component amino acids. Free
ammonia (NH3), existing as the ammonium ion (NH4+) in blood, is toxic to life forms. A suitable method for
excreting it must therefore exist. Different strategies have evolved in different animals, depending on the animals'
needs. Unicellular organisms, of course, simply release the ammonia into the environment. Likewise, bony fish can
Biochemistry 47

release the ammonia into the water where it is quickly diluted. In general, mammals convert the ammonia into urea,
via the urea cycle.

Lipids
The term lipid comprises a diverse range of molecules and to some extent is a catchall for relatively water-insoluble
or nonpolar compounds of biological origin, including waxes, fatty acids, fatty-acid derived phospholipids,
sphingolipids, glycolipids, and terpenoids (e.g., retinoids and steroids). Some lipids are linear aliphatic molecules,
while others have ring structures. Some are aromatic, while others are not. Some are flexible, while others are rigid.
Most lipids have some polar character in addition to being largely nonpolar. In general, the bulk of their structure is
nonpolar or hydrophobic ("water-fearing"), meaning that it does not interact well with polar solvents like water.
Another part of their structure is polar or hydrophilic ("water-loving") and will tend to associate with polar solvents
like water. This makes them amphiphilic molecules (having both hydrophobic and hydrophilic portions). In the case
of cholesterol, the polar group is a mere -OH (hydroxyl or alcohol). In the case of phospholipids, the polar groups are
considerably larger and more polar, as described below.
Lipids are an integral part of our daily diet. Most oils and milk products that we use for cooking and eating like
butter, cheese, ghee etc., are composed of fats. Vegetable oils are rich in various polyunsaturated fatty acids (PUFA).
Lipid-containing foods undergo digestion within the body and are broken into fatty acids and glycerol, which are the
final degradation products of fats and lipids.

Nucleic acids
A nucleic acid is a complex, high-molecular-weight biochemical macromolecule composed of nucleotide chains that
convey genetic information. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid
(RNA). Nucleic acids are found in all living cells and viruses. Aside from the genetic material of the cell, nucleic
acids often play a role as second messengers, as well as forming the base molecule for adenosine triphosphate, the
primary energy-carrier molecule found in all living organisms.
Nucleic acid, so called because of its prevalence in cellular nuclei, is the generic name of the family of biopolymers.
The monomers are called nucleotides, and each consists of three components: a nitrogenous heterocyclic base (either
a purine or a pyrimidine), a pentose sugar, and a phosphate group. Different nucleic acid types differ in the specific
sugar found in their chain (e.g., DNA or deoxyribonucleic acid contains 2-deoxyriboses). Also, the nitrogenous bases
possible in the two nucleic acids are different: adenine, cytosine, and guanine occur in both RNA and DNA, while
thymine occurs only in DNA and uracil occurs in RNA.
Biochemistry 48

Relationship to other "molecular-scale" biological sciences


Researchers in biochemistry use specific techniques
native to biochemistry, but increasingly combine these
with techniques and ideas developed in the fields of
genetics, molecular biology and biophysics. There has
never been a hard-line between these disciplines in
terms of content and technique. Today, the terms
molecular biology and biochemistry are nearly
interchangeable. The following figure is a schematic
that depicts one possible view of the relationship
between the fields:

• Biochemistry is the study of the chemical substances


and vital processes occurring in living organisms.
Biochemists focus heavily on the role, function, and
structure of biomolecules. The study of the
chemistry behind biological processes and the
Schematic relationship between biochemistry, genetics, and
synthesis of biologically active molecules are molecular biology
examples of biochemistry.
• Genetics is the study of the effect of genetic differences on organisms. Often this can be inferred by the absence
of a normal component (e.g., one gene). The study of "mutants" – organisms with a changed gene that leads to the
organism being different with respect to the so-called "wild type" or normal phenotype. Genetic interactions
(epistasis) can often confound simple interpretations of such "knock-out" or "knock-in" studies.
• Molecular biology is the study of molecular underpinnings of the process of replication, transcription and
translation of the genetic material. The central dogma of molecular biology where genetic material is transcribed
into RNA and then translated into protein, despite being an oversimplified picture of molecular biology, still
provides a good starting point for understanding the field. This picture, however, is undergoing revision in light of
emerging novel roles for RNA.
• Chemical Biology seeks to develop new tools based on small molecules that allow minimal perturbation of
biological systems while providing detailed information about their function. Further, chemical biology employs
biological systems to create non-natural hybrids between biomolecules and synthetic devices (for example
emptied viral capsids that can deliver gene therapy or drug molecules).

Notes
a.   It should be noted that fructose is not the only sugar found in fruits. Glucose and sucrose are also found in
varying quantities in various fruits, and indeed sometimes exceed the fructose present. For example, 32 % of the
edible portion of date is glucose, compared with 23.70 % fructose and 8.20 % sucrose. However, peaches contain
more sucrose (6.66 %) than they do fructose (0.93 %) or glucose (1.47 %).[6]

References
[1] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[2] Wöhler, F. (1828). "Ueber künstliche Bildung des Harnstoffs". Ann. Phys. Chem. 12: 253–256.
[3] Kauffman, G. B. and Chooljian, S.H. (2001). "Friedrich Wöhler (1800–1882), on the Bicentennial of His Birth". The Chemical Educator 6
(2): 121–133. doi:10.1007/s00897010444a.
[4] Ultratrace minerals. Authors: Nielsen, Forrest H. USDA, ARS Source: Modern nutrition in health and disease / editors, Maurice E. Shils ... et
al.. Baltimore : Williams & Wilkins, c1999., p. 283-303. Issue Date: 1999 URI: (http:/ / hdl. handle. net/ 10113/ 46493)
Biochemistry 49

[5] Whiting, G.C (1970). "Sugars". In A.C. Hulme. The Biochemistry of Fruits and their Products. Volume 1. London & New York: Academic
Press. pp. 1=31
[6] Whiting, G.C. (1970), p.5

Further reading
• Hunter, Graeme K. (2000). Vital Forces: The Discovery of the Molecular Basis of Life. San Diego: Academic
Press. ISBN 0-12-361810-X. OCLC 162129355 191848148 44187710.

External links
• The Virtual Library of Biochemistry and Cell Biology (http://www.biochemweb.org/)
• Biochemistry, 5th ed. (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=stryer.
TOC&depth=2) Full text of Berg, Tymoczko, and Stryer, courtesy of NCBI.
• Biochemistry, 2nd ed. (http://www.web.virginia.edu/Heidi/home.htm) Full text of Garrett and Grisham.
• Biochemistry Animation (http://www.1lec.com/Biochemistry/) (Narrated Flash animations.)
• SystemsX.ch - The Swiss Initiative in Systems Biology (http://www.systemsX.ch/)
• Biochemistry Online Resources (http://www.icademic.org/97445/Biochemistry/) – Lists of Biochemistry
departments, websites, journals, books and reviews, employment opportunities and events.
biochemical families: proteins (amino acids/intermediates) · nucleic acids (constituents/intermediates) · carbohydrates (glycoproteins, alcohols,
glycosides)
lipids (fatty acids/intermediates, phospholipids, steroids, sphingolipids, eicosanoids) · tetrapyrroles/intermediates

Biological membrane
A biological membrane or biomembrane is an enclosing or
separating membrane that acts as a selective barrier, within or
around a cell. It consists of a lipid bilayer with embedded proteins
that may constitute close to 50% of membrane content.[1] The
cellular membranes should not be confused with isolating tissues
formed by layers of cells, such as mucous and basement
membranes.

Function
Membranes in cells typically define enclosed spaces or
compartments in which cells may maintain a chemical or
biochemical environment that differs from the outside. For
example, the membrane around peroxisomes shields the rest of the
cell from peroxides, and the cell membrane separates a cell from
its surrounding medium. Most organelles are defined by such Cross section view of the structures that can be formed
membranes, and are called "membrane-bound" organelles. by phospholipids in aqueous solutions

Probably the most important feature of a biomembrane is that it is


a selectively permeable structure. This means that the size, charge, and other chemical properties of the atoms and
molecules attempting to cross it will determine whether they succeed in doing so. Selective permeability is essential
for effective separation of a cell or organelle from its surroundings. Biological membranes also have certain
mechanical or elastic properties.
Biological membrane 50

Particles that are required for cellular function but are unable to diffuse freely across a membrane enter through a
membrane transport protein or are taken in by means of endocytosis.

Diversity of biological membranes


Many types of specialized plasma membranes can separate cell from external environment: apical, basolateral,
presynaptic and postsynaptic ones, membranes of flagella, cilia, microvillus, filopodia and lamellipodia, the
sarcolemma of muscle cells, as well as specialized myelin and dendritic spine membranes of neurons. Plasma
membranes can also form different types of "supramembrane" structures such as caveola, postsynaptic density,
podosome, invadopodium, desmosome, hemidesmosome, focal adhesion, and cell junctions. These types of
membranes differ in lipid and protein composition.
Distinct types of membranes also create intracellular organelles: endosome; smooth and rough endoplasmic
reticulum; sarcoplasmic reticulum; Golgi apparatus; lysosome; mitochondrion (inner and outer membranes); nucleus
(inner and outer membranes); peroxisome; vacuole; cytoplasmic granules; cell vesicles (phagosome, autophagosome,
clathrin-coated vesicles, COPI-coated and COPII-coated vesicles) and secretory vesicles (including synaptosome,
acrosomes, melanosomes, and chromaffin granules).
Different types of biological membranes have diverse lipid and protein compositions. The content of membranes
defines their physical and biological properties. Some components of membranes play a key role in medicine, such
as the efflux pumps that pump drugs out of a cell.

References
[1] Mark L. Latash (2007). Neurophysiological basis of movement. Human Kinetics Publishers. ISBN 978-0-7360-6367-8.

• von Heijne G, Rees D (August 2008). "Membranes: reading between the lines" (http://linkinghub.elsevier.com/
retrieve/pii/S0959-440X(08)00091-2). Curr. Opin. Struct. Biol. 18 (4): 403–5. doi:10.1016/j.sbi.2008.06.003.
PMID 18634876.

External links
• Membranes (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Membranes) at the US
National Library of Medicine Medical Subject Headings (MeSH)
Blood 51

Blood
Blood is a specialized bodily fluid in
animals that delivers necessary substances
such as nutrients and oxygen to the cells and
transports metabolic waste products away
from those same cells.
In vertebrates, it is composed of blood cells
suspended in a liquid called blood plasma.
Plasma, which constitutes 55% of blood
fluid, is mostly water (92% by volume),[1]
and contains dissipated proteins, glucose,
mineral ions, hormones, carbon dioxide
(plasma being the main medium for
excretory product transportation), and blood
Human blood smear:
cells themselves. Albumin is the main a – erythrocytes; b – neutrophil;
protein in plasma, and it functions to c – eosinophil; d – lymphocyte.
regulate the colloidal osmotic pressure of
blood. The blood cells are mainly red blood
cells (also called RBCs or erythrocytes) and
white blood cells, including leukocytes and
platelets. The most abundant cells in
vertebrate blood are red blood cells. These
contain hemoglobin, an iron-containing
protein, which facilitates transportation of
oxygen by reversibly binding to this
respiratory gas and greatly increasing its A scanning electron microscope (SEM) image of
solubility in blood. In contrast, carbon a normal red blood cell, a platelet, and a white
blood cell.
dioxide is almost entirely transported
extracellularly dissolved in plasma as
bicarbonate ion.

Vertebrate blood is bright red when its hemoglobin is oxygenated. Some animals, such as crustaceans and mollusks,
use hemocyanin to carry oxygen, instead of hemoglobin. Insects and some mollusks use a fluid called hemolymph
instead of blood, the difference being that hemolymph is not contained in a closed circulatory system. In most
insects, this "blood" does not contain oxygen-carrying molecules such as hemoglobin because their bodies are small
enough for their tracheal system to suffice for supplying oxygen.
Blood 52

Jawed vertebrates have an adaptive immune system, based largely on


white blood cells. White blood cells help to resist infections and
parasites. Platelets are important in the clotting of blood.[2] Arthropods,
using hemolymph, have hemocytes as part of their immune system.
Blood is circulated around the body through blood vessels by the
pumping action of the heart. In animals with lungs, arterial blood
carries oxygen from inhaled air to the tissues of the body, and venous
blood carries carbon dioxide, a waste product of metabolism produced
by cells, from the tissues to the lungs to be exhaled.
Medical terms related to blood often begin with hemo- or hemato-
(also spelled haemo- and haemato-) from the Ancient Greek word
αἷμα (haima) for "blood". In terms of anatomy and histology, blood is
considered a specialized form of connective tissue, given its origin in
the bones and the presence of potential molecular fibers in the form of
fibrinogen.

Blood circulation:
Red = oxygenated
Blue = deoxygenated

Human blood magnified 600 times

Frog blood magnified 600 times


Blood 53

Fish blood magnified 600 times

Functions
Blood performs many important functions within the body including:
• Supply of oxygen to tissues (bound to hemoglobin, which is carried
in red cells)
• Supply of nutrients such as glucose, amino acids, and fatty acids
(dissolved in the blood or bound to plasma proteins (e.g., blood
lipids))
• Removal of waste such as carbon dioxide, urea, and lactic acid
• Immunological functions, including circulation of white blood cells,
and detection of foreign material by antibodies
• Coagulation, which is one part of the body's self-repair mechanism
(blood clotting after an open wound in order to stop bleeding)
• Messenger functions, including the transport of hormones and the Hemoglobin
green = heme groups
signaling of tissue damage
red & blue = protein subunits
• Regulation of body pH
• Regulation of core body temperature
• Hydraulic functions

Heme
Blood 54

Constituents of human blood


Blood accounts for 8% of the human body weight,[3] with an average density of
approximately 1060 kg/m3, very close to pure water's density of 1000 kg/m3.[4]
The average adult has a blood volume of roughly 5 liters (1.3 gal), composed of
plasma and several kinds of cells (occasionally called corpuscles); these formed
elements of the blood are erythrocytes (red blood cells, RBCs), leukocytes (white
blood cells), and thrombocytes (platelets). By volume, the red blood cells
constitute about 45% of whole blood, the plasma about 54.3%, and white cells
about 0.7%.

Whole blood (plasma and cells) exhibits non-Newtonian fluid dynamics; its flow
properties are adapted to flow effectively through tiny capillary blood vessels
with less resistance than plasma by itself. In addition, if all human hemoglobin
were free in the plasma rather than being contained in RBCs, the circulatory fluid
Two tubes of EDTA-anticoagulated
would be too viscous for the cardiovascular system to function effectively. blood.
Left tube: after standing, the RBCs
have settled at the bottom of the tube.
Cells Right tube: contains freshly drawn
blood.
Further information: Complete blood count
One microliter of blood contains:
• 4.7 to 6.1 million (male), 4.2 to 5.4 million (female) Erythrocytes:[5] Red blood cells contain the blood's
hemoglobin and distribute oxygen. Mature red blood cells lack a nucleus and organelles in mammals. The red
blood cells (together with endothelial vessel cells and other cells) are also marked by glycoproteins that define the
different blood types. The proportion of blood occupied by red blood cells is referred to as the hematocrit, and is
normally about 45%. The combined surface area of all red blood cells of the human body would be roughly 2,000
times as great as the body's exterior surface.[6]
• 4,000–11,000 Leukocytes:[7] White blood cells are part of the body's immune system; they destroy and remove
old or aberrant cells and cellular debris, as well as attack infectious agents (pathogens) and foreign substances.
The cancer of leukocytes is called leukemia.
• 200,000–500,000 Thrombocytes:[7]: Also called platelets, thrombocytes are responsible for blood clotting
(coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto which red blood cells collect
and clot, which then stops more blood from leaving the body and also helps to prevent bacteria from entering the
body.

Constitution of normal blood


Parameter Value

Hematocrit 45 ± 7 (38–52%) for males


42 ± 5 (37–47%) for females

pH 7.35–7.45

base excess −3 to +3

PO2 10–13 kPa (80–100 mm Hg)

PCO2 4.8–5.8 kPa (35–45 mm Hg)

21–27 mM
HCO3−

Oxygen saturation Oxygenated: 98–99%


Deoxygenated: 75%
Blood 55

Plasma
About 55% of blood is blood plasma, a fluid that is the blood's liquid medium, which by itself is straw-yellow in
color. The blood plasma volume totals of 2.7–3.0 liters (2.8–3.2 quarts) in an average human. It is essentially an
aqueous solution containing 92% water, 8% blood plasma proteins, and trace amounts of other materials. Plasma
circulates dissolved nutrients, such as glucose, amino acids, and fatty acids (dissolved in the blood or bound to
plasma proteins), and removes waste products, such as carbon dioxide, urea, and lactic acid.
Other important components include:
• Serum albumin
• Blood-clotting factors (to facilitate coagulation)
• Immunoglobulins (antibodies)
• lipoprotein particles
• Various other proteins
• Various electrolytes (mainly sodium and chloride)
The term serum refers to plasma from which the clotting proteins have been removed. Most of the proteins
remaining are albumin and immunoglobulins.

Narrow range of pH values


Blood pH is regulated to stay within the narrow range of 7.35 to 7.45, making it slightly alkaline.[8][9] Blood that has
a pH below 7.35 is too acidic, whereas blood pH above 7.45 is too alkaline. Blood pH, partial pressure of oxygen
(pO2), partial pressure of carbon dioxide (pCO2), and HCO3− are carefully regulated by a number of homeostatic
mechanisms, which exert their influence principally through the respiratory system and the urinary system in order to
control the acid-base balance and respiration. An arterial blood gas will measure these. Plasma also circulates
hormones transmitting their messages to various tissues. The list of normal reference ranges for various blood
electrolytes is extensive.
Bones are especially affected by blood pH as they tend to be used as a mineral source for pH buffering. Consuming a
high ratio of animal protein to vegetable protein is implicated in bone loss in women.[10]

Blood in non-human vertebrates


Human blood is typical of that of mammals, although the precise details concerning cell numbers, size, protein
structure, and so on, vary somewhat between species. In non-mammalian vertebrates, however, there are some key
differences:[11]
• Red blood cells of non-mammalian vertebrates are flattened and ovoid in form, and retain their cell nuclei
• There is considerable variation in the types and proportions of white blood cells; for example, acidophils are
generally more common than in humans
• Platelets are unique to mammals; in other vertebrates, small nucleated, spindle cells are responsible for blood
clotting instead
Blood 56

Physiology

Cardiovascular system
Blood is circulated around the body through blood vessels by the
pumping action of the heart. In humans, blood is pumped from the
strong left ventricle of the heart through arteries to peripheral tissues
and returns to the right atrium of the heart through veins. It then enters
the right ventricle and is pumped through the pulmonary artery to the
lungs and returns to the left atrium through the pulmonary veins. Blood
then enters the left ventricle to be circulated again. Arterial blood
carries oxygen from inhaled air to all of the cells of the body, and
venous blood carries carbon dioxide, a waste product of metabolism by
cells, to the lungs to be exhaled. However, one exception includes
pulmonary arteries, which contain the most deoxygenated blood in the
body (which is a blue purple color), while the pulmonary veins contain The circulation of blood through the human heart
oxygenated blood.

Additional return flow may be generated by the movement of skeletal muscles, which can compress veins and push
blood through the valves in veins toward the right atrium.
The blood circulation was famously described by William Harvey in 1628.[12]

Production and degradation of blood cells


In vertebrates, the various cells of blood are made in the bone marrow in a process called hematopoiesis, which
includes erythropoiesis, the production of red blood cells; and myelopoiesis, the production of white blood cells and
platelets. During childhood, almost every human bone produces red blood cells; as adults, red blood cell production
is limited to the larger bones: the bodies of the vertebrae, the breastbone (sternum), the ribcage, the pelvic bones, and
the bones of the upper arms and legs. In addition, during childhood, the thymus gland, found in the mediastinum, is
an important source of lymphocytes.[13] The proteinaceous component of blood (including clotting proteins) is
produced predominantly by the liver, while hormones are produced by the endocrine glands and the watery fraction
is regulated by the hypothalamus and maintained by the kidney.
Healthy erythrocytes have a plasma life of about 120 days before they are degraded by the spleen, and the Kupffer
cells in the liver. The liver also clears some proteins, lipids, and amino acids. The kidney actively secretes waste
products into the urine.
Blood 57

Oxygen transport
About 98.5% of the oxygen in a sample of arterial blood in a healthy
human breathing air at sea-level pressure is chemically combined with
the Hgb. About 1.5% is physically dissolved in the other blood liquids
and not connected to Hgb. The hemoglobin molecule is the primary
transporter of oxygen in mammals and many other species (for
exceptions, see below). Hemoglobin has an oxygen binding capacity of
between 1.36 and 1.37 ml O2 per gram Hemoglobin,[14] which
increases the total blood oxygen capacity seventyfold,[15] compared to
if oxygen solely was carried by its solubility of 0.03 mL O2 per liter
blood per mmHg partial pressure of oxygen (approximately 100 mmHg
in arteries).[15]
Basic hemoglobin saturation curve. It is moved to
With the exception of pulmonary and umbilical arteries and their the right in higher acidity (more dissolved carbon
corresponding veins, arteries carry oxygenated blood away from the dioxide) and to the left in lower acidity (less
dissolved carbon dioxide)
heart and deliver it to the body via arterioles and capillaries, where the
oxygen is consumed; afterwards, venules, and veins carry
deoxygenated blood back to the heart.
Under normal conditions in adult humans at rest; hemoglobin in blood leaving the lungs is about 98–99% saturated
with oxygen, achieving an oxygen delivery of between 950 - 1150 mL/min[16] to the body. In a healthy adult at rest,
oxygen consumption is approximately 200 - 250 mL/min,[16] and deoxygenated blood returning to the lungs is still
approximately 75%[17][18] (70 to 78%)[16] saturated. Increased oxygen consumption during sustained exercise
reduces the oxygen saturation of venous blood, which can reach less than 15% in a trained athlete; although
breathing rate and blood flow increase to compensate, oxygen saturation in arterial blood can drop to 95% or less
under these conditions.[19] Oxygen saturation this low is considered dangerous in an individual at rest (for instance,
during surgery under anesthesia. Sustained hypoxia (oxygenation of less than 90%), is dangerous to health, and
severe hypoxia (saturations of less than 30%) may be rapidly fatal.[20]
A fetus, receiving oxygen via the placenta, is exposed to much lower oxygen pressures (about 21% of the level found
in an adult's lungs), and, so, fetuses produce another form of hemoglobin with a much higher affinity for oxygen
(hemoglobin F) in order to function under these conditions.[21]

Carbon dioxide transport


CO2 is carried in blood in three different ways. (The exact percentages vary depending whether it is arterial or
venous blood). Most of it (about 70% to 80%) is converted to bicarbonate ions HCO by the enzyme carbonic
anhydrase in the red blood cells,[22] by the reaction CO2 + H2O → H2CO3 → H+ + HCO 5% – 10% is dissolved in
the plasma,[22] and 5% – 10% is bound to hemoglobin as carbamino compounds[22]
Hemoglobin, the main oxygen-carrying molecule in red blood cells, carries both oxygen and carbon dioxide.
However, the CO2 bound to hemoglobin does not bind to the same site as oxygen. Instead, it combines with the
N-terminal groups on the four globin chains. However, because of allosteric effects on the hemoglobin molecule, the
binding of CO2 decreases the amount of oxygen that is bound for a given partial pressure of oxygen. The decreased
binding to carbon dioxide in the blood due to increased oxygen levels is known as the Haldane effect, and is
important in the transport of carbon dioxide from the tissues to the lungs. A rise in the partial pressure of CO2 or a
lower pH will cause offloading of oxygen from hemoglobin, which is known as the Bohr effect.
Blood 58

Transport of hydrogen ions


Some oxyhemoglobin loses oxygen and becomes deoxyhemoglobin. Deoxyhemoglobin binds most of the hydrogen
ions as it has a much greater affinity for more hydrogen than does oxyhemoglobin.

Lymphatic system
In mammals, blood is in equilibrium with lymph, which is continuously formed in tissues from blood by capillary
ultrafiltration. Lymph is collected by a system of small lymphatic vessels and directed to the thoracic duct, which
drains into the left subclavian vein where lymph rejoins the systemic blood circulation.

Thermoregulation
Blood circulation transports heat throughout the body, and adjustments to this flow are an important part of
thermoregulation. Increasing blood flow to the surface (e.g., during warm weather or strenuous exercise) causes
warmer skin, resulting in faster heat loss. In contrast, when the external temperature is low, blood flow to the
extremities and surface of the skin is reduced and to prevent heat loss and is circulated to the important organs of the
body, preferentially.

Hydraulic functions
The restriction of blood flow can also be used in specialized tissues to cause engorgement, resulting in an erection of
that tissue; examples are the erectile tissue in the penis and clitoris.
Another example of a hydraulic function is the jumping spider, in which blood forced into the legs under pressure
causes them to straighten for a powerful jump, without the need for bulky muscular legs.[23]

Invertebrates
In insects, the blood (more properly called hemolymph) is not involved in the transport of oxygen. (Openings called
tracheae allow oxygen from the air to diffuse directly to the tissues). Insect blood moves nutrients to the tissues and
removes waste products in an open system.
Other invertebrates use respiratory proteins to increase the oxygen-carrying capacity. Hemoglobin is the most
common respiratory protein found in nature. Hemocyanin (blue) contains copper and is found in crustaceans and
mollusks. It is thought that tunicates (sea squirts) might use vanabins (proteins containing vanadium) for respiratory
pigment (bright-green, blue, or orange).
In many invertebrates, these oxygen-carrying proteins are freely soluble in the blood; in vertebrates they are
contained in specialized red blood cells, allowing for a higher concentration of respiratory pigments without
increasing viscosity or damaging blood filtering organs like the kidneys.
Giant tube worms have unusual hemoglobins that allow them to live in extraordinary environments. These
hemoglobins also carry sulfides normally fatal in other animals.
Blood 59

Color

Hemoglobin
Hemoglobin is the principal determinant of the color of blood in
vertebrates. Each molecule has four heme groups, and their interaction
with various molecules alters the exact color. In vertebrates and other
hemoglobin-using creatures, arterial blood and capillary blood are
bright red, as oxygen imparts a strong red color to the heme group.
Deoxygenated blood is a darker shade of red; this is present in veins,
and can be seen during blood donation and when venous blood samples
are taken. Blood in carbon monoxide poisoning is bright red, because
carbon monoxide causes the formation of carboxyhemoglobin. In
Capillary blood from a bleeding finger
cyanide poisoning, the body cannot utilize oxygen, so the venous blood
remains oxygenated, increasing the redness. While
hemoglobin-containing blood is never blue, there are several
conditions and diseases wherein the color of the heme groups make the
skin appear blue. If the heme is oxidized, methaemoglobin, which is
more brownish and cannot transport oxygen, is formed. In the rare
condition sulfhemoglobinemia, arterial hemoglobin is partially
oxygenated, and appears dark red with a bluish hue (cyanosis).

Veins in the skin appear blue for a variety of reasons only weakly
dependent on the color of the blood. Light scattering in the skin, and
Venous blood collected during blood donation
the visual processing of color play roles as well.[24]
Skinks in the genus Prasinohaema have green blood due to a buildup of the waste product biliverdin.[25]

Hemocyanin
The blood of most mollusks – including cephalopods and gastropods – as well as some arthropods, such as
horseshoe crabs, is blue, as it contains the copper-containing protein hemocyanin at concentrations of about
50 grams per liter.[26] Hemocyanin is colorless when deoxygenated and dark blue when oxygenated. The blood in the
circulation of these creatures, which generally live in cold environments with low oxygen tensions, is grey-white to
pale yellow,[26] and it turns dark blue when exposed to the oxygen in the air, as seen when they bleed.[26] This is due
to change in color of hemocyanin when it is oxidized.[26] Hemocyanin carries oxygen in extracellular fluid, which is
in contrast to the intracellular oxygen transport in mammals by hemoglobin in RBCs.[26]
Blood 60

Hemovanadin
The blood of some species of ascidians and tunicates, also known as sea squirts and sea cucumbers, contains proteins
called vanabins. These proteins are based on vanadium, and give the creatures a concentration of vanadium in their
bodies 100 times higher than the surrounding sea water. It is not clear whether these vanabins actually carry oxygen.
When exposed to oxygen, however, vanabins turn a mustard yellow.

Pathology

General medical disorders


• Disorders of volume
• Injury can cause blood loss through bleeding.[27] A healthy adult can lose almost 20% of blood volume (1 L)
before the first symptom, restlessness, begins, and 40% of volume (2 L) before shock sets in. Thrombocytes
are important for blood coagulation and the formation of blood clots, which can stop bleeding. Trauma to the
internal organs or bones can cause internal bleeding, which can sometimes be severe.
• Dehydration can reduce the blood volume by reducing the water content of the blood. This would rarely result
in shock (apart from the very severe cases) but may result in orthostatic hypotension and fainting.
• Disorders of circulation
• Shock is the ineffective perfusion of tissues, and can be caused by a variety of conditions including blood loss,
infection, poor cardiac output.
• Atherosclerosis reduces the flow of blood through arteries, because atheroma lines arteries and narrows them.
Atheroma tends to increase with age, and its progression can be compounded by many causes including
smoking, high blood pressure, excess circulating lipids (hyperlipidemia), and diabetes mellitus.
• Coagulation can form a thrombosis, which can obstruct vessels.
• Problems with blood composition, the pumping action of the heart, or narrowing of blood vessels can have
many consequences including hypoxia (lack of oxygen) of the tissues supplied. The term ischemia refers to
tissue that is inadequately perfused with blood, and infarction refers to tissue death (necrosis), which can occur
when the blood supply has been blocked (or is very inadequate)

Hematological disorders
• Anemia
• Insufficient red cell mass (anemia) can be the result of bleeding, blood disorders like thalassemia, or nutritional
deficiencies; and may require blood transfusion. Several countries have blood banks to fill the demand for
transfusable blood. A person receiving a blood transfusion must have a blood type compatible with that of the
donor.
• Sickle-cell anemia
• Disorders of cell proliferation
• Leukemia is a group of cancers of the blood-forming tissues.
• Non-cancerous overproduction of red cells (polycythemia vera) or platelets (essential thrombocytosis) may be
premalignant.
• Myelodysplastic syndromes involve ineffective production of one or more cell lines.
• Disorders of coagulation
• Hemophilia is a genetic illness that causes dysfunction in one of the blood's clotting mechanisms. This can
allow otherwise inconsequential wounds to be life-threatening, but more commonly results in hemarthrosis, or
bleeding into joint spaces, which can be crippling.
• Ineffective or insufficient platelets can also result in coagulopathy (bleeding disorders).
Blood 61

• Hypercoagulable state (thrombophilia) results from defects in regulation of platelet or clotting factor function,
and can cause thrombosis.
• Infectious disorders of blood
• Blood is an important vector of infection. HIV, the virus that causes AIDS, is transmitted through contact with
blood, semen or other body secretions of an infected person. Hepatitis B and C are transmitted primarily
through blood contact. Owing to blood-borne infections, bloodstained objects are treated as a biohazard.
• Bacterial infection of the blood is bacteremia or sepsis. Viral Infection is viremia. Malaria and trypanosomiasis
are blood-borne parasitic infections.

Carbon monoxide poisoning


Substances other than oxygen can bind to hemoglobin; in some cases this can cause irreversible damage to the body.
Carbon monoxide, for example, is extremely dangerous when carried to the blood via the lungs by inhalation,
because carbon monoxide irreversibly binds to hemoglobin to form carboxyhemoglobin, so that less hemoglobin is
free to bind oxygen, and fewer oxygen molecules can be transported throughout the blood. This can cause
suffocation insidiously. A fire burning in an enclosed room with poor ventilation presents a very dangerous hazard,
since it can create a build-up of carbon monoxide in the air. Some carbon monoxide binds to hemoglobin when
smoking tobacco.

Medical treatments

Blood products
Further information: Blood transfusion
Blood for transfusion is obtained from human donors by blood donation and stored in a blood bank. There are many
different blood types in humans, the ABO blood group system, and the Rhesus blood group system being the most
important. Transfusion of blood of an incompatible blood group may cause severe, often fatal, complications, so
crossmatching is done to ensure that a compatible blood product is transfused.
Other blood products administered intravenously are platelets, blood plasma, cryoprecipitate, and specific
coagulation factor concentrates.

Intravenous administration
Many forms of medication (from antibiotics to chemotherapy) are administered intravenously, as they are not readily
or adequately absorbed by the digestive tract.
After severe acute blood loss, liquid preparations, generically known as plasma expanders, can be given
intravenously, either solutions of salts (NaCl, KCl, CaCl2 etc.) at physiological concentrations, or colloidal solutions,
such as dextrans, human serum albumin, or fresh frozen plasma. In these emergency situations, a plasma expander is
a more effective life-saving procedure than a blood transfusion, because the metabolism of transfused red blood cells
does not restart immediately after a transfusion.
Blood 62

Bloodletting
In modern evidence-based medicine, bloodletting is used in management of a few rare diseases, including
hemochromatosis and polycythemia. However, bloodletting and leeching were common unvalidated interventions
used until the 19th century, as many diseases were incorrectly thought to be due to an excess of blood, according to
Hippocratic medicine.

History
According to the Oxford English Dictionary, the word "blood" dates to the oldest English, circa 1000 AD. The word
is derived from Middle English, which is derived from the Old English word blôd, which is akin to the Old High
German word bluot, meaning blood. The modern German word is (das) Blut.

Classical Greek medicine


In classical Greek medicine, blood was associated with air, with Springtime, and with a merry and gluttonous
(sanguine) personality. It was also believed to be produced exclusively by the liver.

Hippocratic medicine
In Hippocratic medicine, blood was considered to be one of the four humors, the others being phlegm, yellow bile,
and black bile.

Cultural and religious beliefs


Due to its importance to life, blood is associated with a large number of beliefs. One of the most basic is the use of
blood as a symbol for family relationships through birth/parentage; to be "related by blood" is to be related by
ancestry or descendance, rather than marriage. This bears closely to bloodlines, and sayings such as "blood is thicker
than water" and "bad blood", as well as "Blood brother". Blood is given particular emphasis in the Jewish and
Christian religions because Leviticus 17:11 says "the life of a creature is in the blood." This phrase is part of the
Levitical law forbidding the drinking of blood or eating meat with the blood still intact instead of being poured off.
Mythic references to blood can sometimes be connected to the life-giving nature of blood, seen in such events as
childbirth, as contrasted with the blood of injury or death.

Indigenous Australians
In many indigenous Australian Aboriginal peoples' traditions, ochre (particularly red) and blood, both high in iron
content and considered Maban, are applied to the bodies of dancers for ritual. As Lawlor states:
In many Aboriginal rituals and ceremonies, red ochre is rubbed all over the naked bodies of the dancers.
In secret, sacred male ceremonies, blood extracted from the veins of the participant's arms is exchanged
and rubbed on their bodies. Red ochre is used in similar ways in less-secret ceremonies. Blood is also
used to fasten the feathers of birds onto people's bodies. Bird feathers contain a protein that is highly
magnetically sensitive.[28]
Lawlor comments that blood employed in this fashion is held by these peoples to attune the dancers to the invisible
energetic realm of the Dreamtime. Lawlor then connects these invisible energetic realms and magnetic fields,
because iron is magnetic.
Blood 63

European paganism
Among the Germanic tribes (such as the Anglo-Saxons and the Norsemen), blood was used during their sacrifices;
the Blóts. The blood was considered to have the power of its originator, and, after the butchering, the blood was
sprinkled on the walls, on the statues of the gods, and on the participants themselves. This act of sprinkling blood
was called blóedsian in Old English, and the terminology was borrowed by the Roman Catholic Church becoming to
bless and blessing. The Hittite word for blood, ishar was a cognate to words for "oath" and "bond", see Ishara. The
Ancient Greeks believed that the blood of the gods, ichor, was a substance that was poisonous to mortals.
As a relic of Germanic Law the cruentation, an ordeal where the corpse of the victim was supposed to start bleeding
in the presence of the murderer was used until the early 17th. century.

Judaism
In Judaism, animal blood cannot be consumed even in the smallest quantity (Leviticus 3:17 and elsewhere); this is
reflected in Jewish dietary laws (Kashrut). Blood is purged from meat by salting and soaking in water. Blood from
fish however, need not be removed.
Another ritual involving blood involves the covering of the blood of fowl and game after slaughtering (Leviticus
17:13); the reason given by the Torah is: "Because the life of the animal is [in] its blood" (ibid 17:14).
Also if a person of the orthodox Jewish faith suffers a violent death, religious laws order the collection of their blood
for burial with them.

Christianity
Some Christian churches, including Roman Catholicism, Eastern Orthodoxy, Oriental Orthodoxy, and the Assyrian
Church of the East teach that, when consecrated, the Eucharistic wine actually becomes the blood of Jesus for
worshippers to drink. Thus in the consecrated wine, Jesus becomes spiritually and physically present. This teaching
is rooted in the Last Supper, as written in the four gospels of the Bible, in which Jesus stated to his disciples that the
bread that they ate was his body, and the wine was his blood. "This cup is the new testament in my blood, which is
shed for you." (Luke 22:20).
Most forms of Protestantism, especially those of a Wesleyan or Presbyterian lineage, teach that the wine is no more
than a symbol of the blood of Christ, who is spiritually but not physically present. Lutheran theology teaches that the
body and blood is present together "in, with, and under" the bread and wine of the Eucharistic feast.
Christ's blood is the means for the atonement of sins. Also, ″… the blood of Jesus Christ his [God] Son cleanseth us
from all sin.” (1 John 1:7), “… Unto him [God] that loved us, and washed us from our sins in his own blood.”
(Revelation 1:5), and “And they overcame him (Satan) by the blood of the Lamb [Jesus the Christ], and by the word
of their testimony …” (Revelation 12:11).
At the Council of Jerusalem, the apostles prohibited Christians from consuming blood (except Jesus'), probably
because this was a command given to Noah (Genesis 9:4, see Noahide Law). This command continued to be
observed by the Eastern Orthodox.
It is also found in the Bible that when the Angel of Death came around to the Hebrew house that the first born child
would not die if the angel saw lambs blood wiped across the doorway.
Blood 64

Islam
Consumption of food containing blood is forbidden by Islamic dietary laws. This is derived from the statement in the
Qur'an, sura Al-Ma'ida (5:3): "Forbidden to you (for food) are: dead meat, blood, the flesh of swine, and that on
which has been invoked the name of other than Allah."
Blood is considered as unclean and in Islam cleanliness is part of the faith, hence there are specific methods to obtain
physical and ritual status of cleanliness once bleeding has occurred. Specific rules and prohibitions apply to
menstruation, postnatal bleeding and irregular vaginal bleeding.

Jehovah's Witnesses
Based on their interpretation of scriptures such as Acts 15:28, 29 ("Keep abstaining...from blood."), Jehovah's
Witnesses neither consume blood nor accept transfusions of whole blood or its major components: red blood cells,
white blood cells, platelets (thrombocytes), and plasma. Members may personally decide whether they will accept
medical procedures that involve their own blood or substances that are further fractionated from the four major
components.[29]

East Asian culture


In Chinese popular culture, it is often said that if a man's nose produces a small flow of blood, he is experiencing
sexual desire. This often appears in Chinese-language and Hong Kong films as well as in Japanese and Korean
culture parodied in anime, manga, and drama. Characters, mostly males, will often be shown with a nosebleed if they
have just seen someone nude or in little clothing, or if they have had an erotic thought or fantasy; this is based on the
idea that a male's blood pressure will spike dramatically when aroused.[30]

Blood libel
Various religious and other groups have been falsely accused of using human blood in rituals; such accusations are
known as blood libel. The most common form of this is blood libel against Jews. Although there is no ritual
involving human blood in Jewish law or custom, fabrications of this nature (often involving the murder of children)
were widely used during the Middle Ages to justify Antisemitic persecution.

Vampire legends
Vampires are mythical creatures that drink blood directly for sustenance, usually with a preference for human blood.
Cultures all over the world have myths of this kind; for example the 'Nosferatu' legend, a human who achieves
damnation and immortality by drinking the blood of others, originates from Eastern European folklore. Ticks,
leeches, female mosquitoes, vampire bats, and an assortment of other natural creatures do consume the blood of
other animals, but only bats are associated with vampires. This has no relation to vampire bats, which are new world
creatures discovered well after the origins of the European myths.
Blood 65

Applications

In the applied sciences


Blood residue can help forensic investigators identify weapons, reconstruct a criminal action, and link suspects to the
crime. Through bloodstain pattern analysis, forensic information can also be gained from the spatial distribution of
bloodstains.
Blood residue analysis is also a technique used in archeology.

In art
Blood is one of the body fluids that has been used in art.[31] In particular, the performances of Viennese Actionist
Hermann Nitsch, Franko B, Lennie Lee, Ron Athey, Yang Zhichao, and Kira O' Reilly, along with the photography
of Andres Serrano, have incorporated blood as a prominent visual element. Marc Quinn has made sculptures using
frozen blood, including a cast of his own head made using his own blood.

In genealogy and family history


The term, blood, is used in genealogical circles to refer to one's ancestry, origins, and ethnic background, as in the
word, bloodline. Other terms where blood is used in a family history sense are blue-blood, royal blood, mixed-blood
and blood relative.

References
[1] The Franklin Institute Inc.. "Blood – The Human Heart" (http:/ / www. fi. edu/ learn/ heart/ blood/ blood. html). . Retrieved 19 March 2009.
[2] Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993).
Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. ISBN 0-13-981176-1.
[3] Alberts, Bruce (2005). "Leukocyte functions and percentage breakdown" (http:/ / www. ncbi. nlm. nih. gov/ sites/ entrez?cmd=Search&
db=books& doptcmdl=GenBookHL& rid=mboc4. table. 4143). Molecular Biology of the Cell. NCBI Bookshelf. . Retrieved 2007-04-14.
[4] Shmukler, Michael (2004). "Density of Blood" (http:/ / hypertextbook. com/ facts/ 2004/ MichaelShmukler. shtml). The Physics Factbook. .
Retrieved 2006-10-04.
[5] "Medical Encyclopedia: RBC count" (http:/ / www. nlm. nih. gov/ medlineplus/ ency/ article/ 003644. htm#Normal Values). Medline Plus. .
Retrieved 18 November 2007.
[6] Robert B. Tallitsch; Martini, Frederic; Timmons, Michael J. (2006). Human anatomy (5th ed.). San Francisco: Pearson/Benjamin Cummings.
p. 529. ISBN 0-8053-7211-3.
[7] Ganong, William F. (2003). Review of medical physiology (21 ed.). New York: Lange Medical Books/McGraw-Hill. p. 518.
ISBN 0-07-121765-7.
[8] Waugh, Anne; Grant, Allison (2007). "2". Anatomy ans Physiology in Health and Illness (Tenth ed.). Churchill Livingstone Elsevier. pp. 22.
ISBN 978-0-443-10102-1.
[9] Acid-Base Regulation and Disorders (http:/ / www. merck. com/ mmpe/ sec12/ ch157/ ch157a. html) at Merck Manual of Diagnosis and
Therapy Professional Edition
[10] Sellmeyer DE, Stone KL, Sebastian A, Cummings SR (January 2001). "A high ratio of dietary animal to vegetable protein increases the rate
of bone loss and the risk of fracture in postmenopausal women. Study of Osteoporotic Fractures Research Group" (http:/ / www. ajcn. org/ cgi/
content/ full/ 73/ 1/ 118). Am. J. Clin. Nutr. 73 (1): 118–22. PMID 11124760. .
[11] Romer, Alfred Sherwood; Parsons, Thomas S. (1977). The Vertebrate Body. Philadelphia, PA: Holt-Saunders International. pp. 404–406.
ISBN 0-03-910284-X.
[12] Harvey, William (1628). "[[Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus (http:/ / www. rarebookroom. org/ Control/
hvyexc/ index. html)]"] (in Latin). .
[13] Williams, Peter W.; Gray, Henry David (1989). Gray's anatomy (37th ed.). New York: C. Livingstone. ISBN 0-443-02588-6.
[14] Dominguez de Villota ED, Ruiz Carmona MT, Rubio JJ, de Andrés S (December 1981). "Equality of the in vivo and in vitro
oxygen-binding capacity of haemoglobin in patients with severe respiratory disease". Br J Anaesth 53 (12): 1325–8.
doi:10.1093/bja/53.12.1325. PMID 7317251.
[15] Costanzo, Linda S. (2007). Physiology. Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN 0-7817-7311-3.
[16] Edwards Lifesciences LLC > Normal Hemodynamic Parameters – Adult (http:/ / www. edwards. com/ SiteCollectionImages/ edwards/
products/ presep/ ar04313hemodynpocketcard. pdf) 2009
[17] Ventilation and Endurance Performance (http:/ / home. hia. no/ ~stephens/ ventphys. htm)
Blood 66

[18] Transplant Support- Lung, Heart/Lung, Heart (http:/ / groups. msn. com/ TransplantSupportLungHeartLungHeart/ oxygen2. msnw) MSN
groups
[19] Mortensen SP, Dawson EA, Yoshiga CC, et al. (July 2005). "Limitations to systemic and locomotor limb muscle oxygen delivery and
uptake during maximal exercise in humans". J. Physiol. (Lond.) 566 (Pt 1): 273–85. doi:10.1113/jphysiol.2005.086025. PMC 1464731.
PMID 15860533.
[20] The 'St George' Guide To Pulmonary Artery Catheterisation (http:/ / www. manbit. com/ PAC/ chapters/ P30. cfm)
[21] Oxygen Carriage in Blood - High Altitude (http:/ / members. aol. com/ Bio50/ LecNotes/ lecnot20. html)
[22] "Carbon dioxide" (http:/ / www. solarnavigator. net/ solar_cola/ carbon_dioxide. htm). solarnavigator.net. . Retrieved 2007-10-12.
[23] "Spiders: circulatory system" (http:/ / www. britannica. com/ eb/ topic-559817/ spider). Encyclopædia Britannica online. . Retrieved
2007-11-25.
[24] Kienle, Alwin; Lothar Lilge, I. Alex Vitkin, Michael S. Patterson, Brian C. Wilson, Raimund Hibst, and Rudolf Steiner (March 1, 1996).
"Why do veins appear blue? A new look at an old question" (http:/ / www. imt. liu. se/ edu/ courses/ TBMT36/ pdf/ blue. pdf) (PDF). Applied
Optics 35 (7): 1151–60. doi:10.1364/AO.35.001151. PMID 21085227. .
[25] Austin CC, Perkins SL (2006). "Parasites in a biodiversity hotspot: a survey of hematozoa and a molecular phylogenetic analysis of
Plasmodium in New Guinea skinks". J. Parasitol. 92 (4): 770–7. doi:10.1645/GE-693R.1. PMID 16995395.
[26] Shuster, Carl N (2004). "Chapter 11: A blue blood: the circulatory system" (http:/ / books. google. com/ ?id=0OSAKny-6M4C&
printsec=frontcover#PRA1-PA276,M1). In Shuster, Carl N, Jr; Barlow, Robert B; Brockmann, H. Jane. The American Horseshoe Crab.
Harvard University Press. pp. 276–7. ISBN 0-674-01159-7. .
[27] "Blood - The Human heart" (http:/ / www. fi. edu/ learn/ heart/ blood/ blood. html). The Franklin Institute. . Retrieved 19 March 2009.
[28] Lawlor, Robert (1991). Voices of the first day: awakening in the Aboriginal dreamtime. Rochester, Vt: Inner Traditions International.
pp. 102–3. ISBN 0-89281-355-5.
[29] The Watchtower 15 June 2004, page 22, "Be Guided by the Living God"
[30] Law of Anime #40 aka Law of Nasal Sanguination at ABCB.com (http:/ / www. abcb. com/ laws/ index. htm), The Anime Cafe.
[31] "Nostalgia" (http:/ / artscad. com/ A. nsf/ Opra/ SRVV-6MDNX5) Artwork in blood

External links
• Blood Groups and Red Cell Antigens. (http://www.ncbi.nlm.nih.gov/books/NBK2261) Free online book at
NCBI Bookshelf ID: NBK2261
• Blood (http://www.bbc.co.uk/programmes/p00548ym) on In Our Time at the BBC. ( listen now (http://
www.bbc.co.uk/iplayer/console/p00548ym/In_Our_Time_Blood))
Blood cell 67

Blood cell
A blood cell, also called a haematocyte, is a cell produced by
haematopoiesis and normally found in blood. In mammals, these fall
into three general categories:
• Red blood cells — Erythrocytes
• White blood cells — Leukocytes
• Platelets — Thrombocytes.
Together, these three kinds of blood cells add up to a total 45% of the
blood tissue by volume, with the remaining 55% of the volume
composed of plasma, the liquid component of blood.[1] This volume
percentage (e.g., 45%) of cells to total volume is called hematocrit,
determined by centrifuge or flow cytometry. Hemoglobin (the main
component of red blood cells) is an iron-containing protein that Red and white human blood cells as seen under a
microscope using a blue slide stain
facilitates transportation of oxygen and other respiratory gases to
tissues.

Red blood cells (Erythrocytes)


Red blood cells primarily carry oxygen and some carbon dioxide through the use of hemoglobin, and have a lifetime
of about 120 days. In the process of being formed they go through being a monopotent stem cell.

White blood cells (Leukocytes)


White blood cells, or leukocytes (also spelled "leucocytes", leuco- Ancient Greek "white"), are cells of the immune
system involved in defending the body against both infectious disease and foreign materials. Five[1] different and
diverse types of leukocytes exist, but they are all produced and derived from a multipotent cell in the bone marrow
known as a hematopoietic stem cell. They live for about 3 to 4 days in the average human body. Leukocytes are
found throughout the body, including the blood and lymphatic system.

Platelets (Thrombocytes)
Platelets, or thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are small, irregularly shaped clear cell
fragments (i.e. cells that do not have a nucleus containing DNA), 2–3 µm in diameter, which derive from
fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days. Platelets
are a natural source of growth factors. They circulate in the blood of mammals and are involved in hemostasis,
leading to the formation of blood clots. Platelets release thread-like fibers to form these clots.
If the number of platelets is too low, excessive bleeding can occur. However, if the number of platelets is too high,
blood clots can form (thrombosis), which may obstruct blood vessels and result in such events as a stroke,
myocardial infarction, pulmonary embolism—or blockage of blood vessels to other parts of the body, such as the
extremities of the arms or legs. An abnormality or disease of the platelets is called a thrombocytopathy, which can be
either a low number of platelets (thrombocytopenia), a decrease in function of platelets (thrombasthenia), or an
increase in the number of platelets (thrombocytosis). There are disorders that reduce the number of platelets, such as
heparin-induced thrombocytopenia (HIT) or thrombotic thrombocytopenic purpura (TTP) that typically cause
thromboses, or clots, instead of bleeding.
Platelets release a multitude of growth factors including Platelet-derived growth factor (PDGF), a potent chemotactic
agent, and TGF beta, which stimulates the deposition of extracellular matrix. Both of these growth factors have been
Blood cell 68

shown to play a significant role in the repair and regeneration of connective tissues. Other healing-associated growth
factors produced by platelets include basic fibroblast growth factor, insulin-like growth factor 1, platelet-derived
epidermal growth factor, and vascular endothelial growth factor. Local application of these factors in increased
concentrations through Platelet-rich plasma (PRP) has been used as an adjunct to wound healing for several decades

References
[1] Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993).
Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. ISBN 0-13-981176-1.

External links
• What is Blood? (http://gslc.genetics.utah.edu/units/basics/blood/blood.cfm) from the Genetic Science
Learning Center at the University of Utah.
• Cells of the blood (http://www.microbiologybytes.com/iandi/bloodmap/Blood.html)

Bone
Bones are rigid organs that constitute part of the endoskeleton of
vertebrates. They support and protect the various organs of the body,
produce red and white blood cells and store minerals. Bone tissue is a
type of dense connective tissue. Bones come in a variety of shapes and
have a complex internal and external structure, are lightweight yet
strong and hard, and serve multiple functions. One of the types of
tissue that makes up bone is the mineralized osseous tissue, also called
bone tissue, that gives it rigidity and a coral-like three-dimensional
internal structure. Other types of tissue found in bones include marrow,
endosteum, periosteum, nerves, blood vessels and cartilage. At birth,
there are over 270 bones in an infant human's body,[1] but many of
these fuse together as the child grows, leaving a total of 206 separate
bones in an adult. The largest bone in the human body is the femur and
the smallest bones are auditory ossicles.[2]

Functions
Drawing of a human femur
Bones have eleven main functions:

Mechanical
• Protection — bones can serve to protect internal organs, such as the skull protecting the brain or the ribs
protecting the heart and lungs.
• Structure — bones provide a frame to keep the body supported.
• Movement — bones, skeletal muscles, tendons, ligaments and joints function together to generate and transfer
forces so that individual body parts or the whole body can be manipulated in three-dimensional space. The
interaction between bone and muscle is studied in biomechanics.
• Sound transduction — bones are important in the mechanical aspect of overshadowed hearing.
Bone 69

Synthetic
• Blood production — the marrow, located within the medullary cavity of long bones and interstices of cancellous
bone, produces blood cells in a process called hematopoiesis.

Metabolic
• Mineral storage — bones act as reserves of minerals important for the body, most notably calcium and
phosphorus.
• Growth factor storage — mineralized bone matrix stores important growth factors such as insulin-like growth
factors, transforming growth factor, bone morphogenetic proteins and others.
• Fat storage — the yellow bone marrow acts as a storage reserve of fatty acids.
• Acid-base balance — bone buffers the blood against excessive pH changes by absorbing or releasing alkaline
salts.
• Detoxification — bone tissues can also store heavy metals and other foreign elements, removing them from the
blood and reducing their effects on other tissues. These can later be gradually released for excretion.
• Endocrine organ — bone controls phosphate metabolism by releasing fibroblast growth factor – 23 (FGF-23),
which acts on kidneys to reduce phosphate reabsorption. Bone cells also release a hormone called osteocalcin,
which contributes to the regulation of blood sugar (glucose) and fat deposition. Osteocalcin increases both the
insulin secretion and sensitivity, in addition to boosting the number of insulin-producing cells and reducing stores
of fat.[3]

Mechanical properties
The primary tissue of bone, osseous tissue, is a relatively hard and lightweight composite material, formed mostly of
calcium phosphate in the chemical arrangement termed calcium hydroxylapatite (this is the osseous tissue that gives
bones their rigidity). It has relatively high compressive strength, of about 170 MPa (1800 kgf/cm²)[4] but poor tensile
strength of 104–121 MPa and very low shear stress strength (51.6 MPa),[5] meaning it resists pushing forces well,
but not pulling or torsional forces. While bone is essentially brittle, it does have a significant degree of elasticity,
contributed chiefly by collagen. All bones consist of living and dead cells embedded in the mineralized organic
matrix that makes up the osseous tissue.

Structure

Bone structure

An illustration
Bone 70

A femur head with a cortex of compact bone and medulla of trabecular bone

Bone is not a uniformly solid material, but rather has some spaces between its hard elements.

Compact (cortical) bone


The hard outer layer of bones is composed of compact bone tissue, so-called due to its minimal gaps and spaces. Its
porosity is 5–30%.[6] This tissue gives bones their smooth, white, and solid appearance, and accounts for 80% of the
total bone mass of an adult skeleton. Compact bone may also be referred to as dense bone.

Trabecular (cancellous) bone


Filling the interior of the bone is the trabecular bone tissue (an open cell porous network also called cancellous or
spongy bone), which is composed of a network of rod- and plate-like elements that make the overall organ lighter
and allow room for blood vessels and marrow. Trabecular bone accounts for the remaining 20% of total bone mass
but has nearly ten times the surface area of compact bone. Its porosity is 30–90%.[6] If, for any reason, there is an
alteration in the strain the cancellous is subjected to, there is a rearrangement of the trabeculae. The microscopic
difference between compact and cancellous bone is that compact bone consists of haversian sites and osteons, while
cancellous bones do not. Also, bone surrounds blood in the compact bone, while blood surrounds bone in the
cancellous bone.

Cellular structure
There are several types of cells constituting the bone;
• Osteoblasts are mononucleate bone-forming cells that descend from osteoprogenitor cells. They are located on the
surface of osteoid seams and make a protein mixture known as osteoid, which mineralizes to become bone. The
osteiod seam is a narrow region of newly formed organic matrix, not yet mineralized, located on the surface of a
bone. Osteoid is primarily composed of Type I collagen. Osteoblasts also manufacture hormones, such as
prostaglandins, to act on the bone itself. They robustly produce alkaline phosphatase, an enzyme that has a role in
the mineralisation of bone, as well as many matrix proteins. Osteoblasts are the immature bone cells, and
eventually become entrapped in the bone matrix to become osteocytes- the mature bone cell.
• Bone lining cells are essentially inactive osteoblasts. They cover all of the available bone surface and function as
a barrier for certain ions.
• Osteocytes originate from osteoblasts that have migrated into and become trapped and surrounded by bone matrix
that they themselves produce. The spaces they occupy are known as lacunae. Osteocytes have many processes
that reach out to meet osteoblasts and other osteocytes probably for the purposes of communication. Their
functions include, to varying degrees: formation of bone; matrix maintenance; and calcium homeostasis. They
have also been shown to act as mechano-sensory receptors — regulating the bone's response to stress and
mechanical load. They are mature bone cells.
• Osteoclasts are the cells responsible for bone resorption, thus they break down bone. New bone is then formed by
the osteoblasts (remodeling of bone to reduce its volume). Osteoclasts are large, multinucleated cells located on
Bone 71

bone surfaces in what are called Howship's lacunae or resorption pits. These lacunae, or resorption pits, are left
behind after the breakdown of the bone surface. Because the osteoclasts are derived from a monocyte stem-cell
lineage, they are equipped with phagocytic-like mechanisms similar to circulating macrophages. Osteoclasts
mature and/or migrate to discrete bone surfaces. Upon arrival, active enzymes, such as tartrate resistant acid
phosphatase, are secreted against the mineral substrate.

Molecular structure

Matrix
The majority of bone is made of the bone matrix. It has inorganic and organic parts. Bone is formed by the hardening
of this matrix entrapping the cells. When these cells become entrapped from osteoblasts they become osteocytes.

Inorganic

The inorganic composition of bone (bone mineral) is formed from


carbonated hydroxyapatite [7][8] (Ca10(PO4)6(OH)2) with lower
crystallinity.[7][9] The matrix is initially laid down as unmineralised
osteoid (manufactured by osteoblasts). Mineralisation involves
osteoblasts secreting vesicles containing alkaline phosphatase. This
cleaves the phosphate groups and acts as the foci for calcium and
phosphate deposition. The vesicles then rupture and act as a centre for
crystals to grow on. More particularly, bone mineral is formed from
globular and plate structures,[9][10] distributed among the collagen
Electronic micrography 10000 magnification of
fibrils of bone and forming yet larger structure.
Bone mineral

Organic
The organic part of matrix is mainly composed of Type I collagen. This is synthesised intracellularly as
tropocollagen and then exported, forming fibrils. The organic part is also composed of various growth factors, the
functions of which are not fully known. Factors present include glycosaminoglycans, osteocalcin, osteonectin, bone
sialo protein, osteopontin and Cell Attachment Factor. One of the main things that distinguishes the matrix of a bone
from that of another cell is that the matrix in bone is hard.

Woven or lamellar
Two types of bone can be identified microscopically according to the
pattern of collagen forming the osteoid (collagenous support tissue of
type I collagen embedded in glycosaminoglycan gel):
• Woven bone, which is characterized by haphazard organization of
collagen fibers and is mechanically weak
• Lamellar bone, which has a regular parallel alignment of collagen
into sheets (lamellae) and is mechanically strong
Woven bone is produced when osteoblasts produce osteoid rapidly,
Collagen fibers of woven bone which occurs initially in all fetal bones (but is later replaced by more
resilient lamellar bone). In adults woven bone is created after fractures
Bone 72

or in Paget's disease. Woven bone is weaker, with a smaller number of randomly oriented collagen fibers, but forms
quickly; it is for this appearance of the fibrous matrix that the bone is termed woven. It is soon replaced by lamellar
bone, which is highly organized in concentric sheets with a much lower proportion of osteocytes to surrounding
tissue. Lamellar bone, which makes its first appearance in the fetus during the third trimester,[11] is stronger and
filled with many collagen fibers parallel to other fibers in the same layer (these parallel columns are called osteons).
In cross-section, the fibers run in opposite directions in alternating layers, much like in plywood, assisting in the
bone's ability to resist torsion forces. After a fracture, woven bone forms initially and is gradually replaced by
lamellar bone during a process known as "bony substitution." Compared to woven bone, lamellar bone formation
takes place more slowly. The orderly deposition of collagen fibers restricts the formation of osteoid to about 1 to
2 µm per day. Lamellar bone also requires a relatively flat surface to lay the collagen fibers in parallel or concentric
layers.
These terms are histologic, in that a microscope is necessary to differentiate between the two.

Types
There are five types of bones in the human body: long,
short, flat, irregular, and sesamoid.
• Long bones are characterized by a shaft, the
diaphysis, that is much longer than it is wide. They
are made up mostly of compact bone, with lesser
amounts of marrow, located within the medullary
cavity, and spongy bone. Most bones of the limbs,
including those of the fingers and toes, are long
bones. The exceptions are those of the wrist, ankle
and kneecap.
• Short bones are roughly cube-shaped, and have only
a thin layer of compact bone surrounding a spongy
interior. The bones of the wrist and ankle are short
bones, as are the sesamoid bones.
• Flat bones are thin and generally curved, with two
parallel layers of compact bones sandwiching a layer
of spongy bone. Most of the bones of the skull are
flat bones, as is the sternum.
• Sesamoid bones are bones embedded in tendons.
Since they act to hold the tendon further away from
the joint, the angle of the tendon is increased and
thus the leverage of the muscle is increased. Examples of sesamoid bones are the patella and the pisiform.
• Irregular bones do not fit into the above categories. They consist of thin layers of compact bone surrounding a
spongy interior. As implied by the name, their shapes are irregular and complicated. The bones of the spine and
hips are irregular bones.
Bone 73

Formation
The formation of bone during the fetal stage of development occurs by two processes: Intramembranous ossification
and endochondral ossification.

Intramembranous ossification
Intramembranous ossification mainly occurs during formation of the flat bones of the skull but also the mandible,
maxilla, and clavicles; the bone is formed from connective tissue such as mesenchyme tissue rather than from
cartilage. The steps in intramembranous ossification are:
1. Development of ossification center
2. Calcification
3. Formation of trabeculae
4. Development of periosteum

Endochondral ossification
Endochondral ossification, on the other
hand, occurs in long bones and most of
the rest of the bones in the body; it
involves an initial hyaline cartilage that
continues to grow. The steps in
endochondral ossification are:
1. Development of cartilage model
2. Growth of cartilage model
3. Development of the primary
ossification center
4. Development of the secondary
ossification center
5. Formation of articular cartilage and Endochondral ossification

epiphyseal plate

Endochondral ossification begins with points in the cartilage called "primary ossification centers." They mostly
appear during fetal development, though a few short bones begin their primary ossification after birth. They are
responsible for the formation of the diaphyses of long bones, short bones and certain parts of irregular bones.
Secondary ossification occurs after birth, and forms the epiphyses of long bones and the extremities of irregular and
flat bones. The diaphysis and both epiphyses of a long bone are separated by a growing zone of cartilage (the
epiphyseal plate). When the child reaches skeletal maturity (18 to 25 years of age), all of the cartilage is replaced by
bone, fusing the diaphysis and both epiphyses together (epiphyseal closure).
Bone 74

Bone marrow
Bone marrow can be found in almost any bone that holds cancellous tissue. In newborns, all such bones are filled
exclusively with red marrow, but as the child ages it is mostly replaced by yellow, or fatty marrow. In adults, red
marrow is mostly found in the marrow bones of the femur, the ribs, the vertebrae and pelvic bones.

Remodeling
Remodeling or bone turnover is the process of resorption followed by replacement of bone with little change in
shape and occurs throughout a person's life. Osteoblasts and osteoclasts, coupled together via paracrine cell
signalling, are referred to as bone remodeling units.

Purpose
The purpose of remodeling is to regulate calcium homeostasis, repair micro-damaged bones (from everyday stress)
but also to shape and sculpture the skeleton during growth.

Calcium balance
The process of bone resorption by the osteoclasts releases stored calcium into the systemic circulation and is an
important process in regulating calcium balance. As bone formation actively fixes circulating calcium in its mineral
form, removing it from the bloodstream, resorption actively unfixes it thereby increasing circulating calcium levels.
These processes occur in tandem at site-specific locations.

Bone volume
Bone volume is determined by the rates of bone formation and bone resorption. Recent research has suggested that
certain growth factors may work to locally alter bone formation by increasing osteoblast activity. Numerous
bone-derived growth factors have been isolated and classified via bone cultures. These factors include insulin-like
growth factors I and II, transforming growth factor-beta, fibroblast growth factor, platelet-derived growth factor, and
bone morphogenetic proteins.[12] Evidence suggests that bone cells produce growth factors for extracellular storage
in the bone matrix. The release of these growth factors from the bone matrix could cause the proliferation of
osteoblast precursors. Essentially, bone growth factors may act as potential determinants of local bone formation.[12]
Research has suggested that trabecular bone volume in postemenopausal osteoporosis may be determined by the
relationship between the total bone forming surface and the percent of surface resorption.[13]

Repair
Repeated stress, such as weight-bearing exercise or bone healing, results in the bone thickening at the points of
maximum stress (Wolff's law). It has been hypothesized that this is a result of bone's piezoelectric properties, which
cause bone to generate small electrical potentials under stress.[14]

Paracrine cell signalling


The action of osteoblasts and osteoclasts are controlled by a number of chemical factors that either promote or
inhibit the activity of the bone remodeling cells, controlling the rate at which bone is made, destroyed, or changed in
shape. The cells also use paracrine signalling to control the activity of each other.
Bone 75

Osteoblast stimulation
Osteoblasts can be stimulated to increase bone mass through increased secretion of osteoid and by inhibiting the
ability of osteoclasts to break down osseous tissue.
Bone building through increased secretion of osteoid is stimulated by the secretion of growth hormone by the
pituitary, thyroid hormone and the sex hormones (estrogens and androgens). These hormones also promote increased
secretion of osteoprotegerin.[15] Osteoblasts can also be induced to secrete a number of cytokines that promote
reabsorbtion of bone by stimulating osteoclast activity and differentiation from progenitor cells. Vitamin D,
parathyroid hormone and stimulation from osteocytes induce osteoblasts to increase secretion of RANK-ligand and
interleukin 6, which cytokines then stimulate increased reabsorbtion of bone by osteoclasts. These same compounds
also increase secretion of macrophage colony-stimulating factor by osteoblasts, which promotes the differentiation of
progenitor cells into osteoclasts, and decrease secretion of osteoprotegerin.

Osteoclast inhibition
The rate at which osteoclasts resorb bone is inhibited by calcitonin and osteoprotegerin. Calcitonin is produced by
parafollicular cells in the thyroid gland, and can bind to receptors on osteoclasts to directly inhibit osteoclast activity.
Osteoprotegerin is secreted by osteoblasts and is able to bind RANK-L, inhibiting osteoclast stimulation.[15]

Disorders
There are many disorders of the skeleton. One of the more prominent is osteoporosis.

Osteoporosis
Osteoporosis is a disease of bone, leading to an increased risk of fracture. In osteoporosis, the bone mineral density
(BMD) is reduced, bone microarchitecture is disrupted, and the amount and variety of non-collagenous proteins in
bone is altered. Osteoporosis is defined by the World Health Organization (WHO) in women as a bone mineral
density 2.5 standard deviations below peak bone mass (20-year-old sex-matched healthy person average) as
measured by DEXA; the term "established osteoporosis" includes the presence of a fragility fracture.[16]
Osteoporosis is most common in women after the menopause, when it is called postmenopausal osteoporosis, but
may develop in men and premenopausal women in the presence of particular hormonal disorders and other chronic
diseases or as a result of smoking and medications, specifically glucocorticoids, when the disease is called steroid-
or glucocorticoid-induced osteoporosis (SIOP or GIOP).
Osteoporosis can be prevented with lifestyle advice and medication, and preventing falls in people with known or
suspected osteoporosis is an established way to prevent fractures. Osteoporosis can be treated with bisphosphonates
and various other medical treatments.

Other
Other disorders of bone include:
• Bone fractures
• Bone mineral
• Osteomyelitis
• Osteosarcoma
• Osteogenesis imperfecta
• Osteochondritis dissecans
• Bone metastases
• Neurofibromatosis type I
Bone 76

Osteology
The study of bones and teeth is referred to as osteology. It is frequently used in anthropology, archeology and
forensic science for a variety of tasks. This can include determining the nutritional, health, age or injury status of the
individual the bones were taken from. Preparing fleshed bones for these types of studies can involve maceration –
boiling fleshed bones to remove large particles, then hand-cleaning.
Typically anthropologists and archeologists study bone tools made by Homo sapiens and Homo neanderthalensis.
Bones can serve a number of uses such as projectile points or artistic pigments, and can be made from endoskeletal
or external bones such as antler or tusk.

Alternatives to bony endoskeletons


There are several evolutionary alternatives to mammillary bone; though they have some similar functions, they are
not completely functionally analogous to bone.
• Exoskeletons offer support, protection and levers for movement similar to endoskeletal bone. Different types of
exoskeletons include shells, carapaces (consisting of calcium compounds or silica) and chitinous exoskeletons.
• A true endoskeleton (that is, protective tissue derived from mesoderm) is also present in Echinoderms. Porifera
(sponges) possess simple endoskeletons that consist of calcareous or siliceous spicules and a spongin fiber
network.

Exposed bone
Bone penetrating the skin and being exposed to the outside can be both a natural process in some animals, and due to
injury:
• A deer's antlers are composed of bone.[17]
• Instead of teeth, the extinct predatory fish Dunkleosteus had sharp edges of hard exposed bone along its jaws.
• A compound fracture occurs when the edges of a broken bone puncture the skin.
• Though not strictly speaking exposed, a bird's beak is primarily bone covered in a layer of keratin over a vascular
layer containing blood vessels and nerve endings.

Uses
Bones from slaughtered animals have a number of uses. It has been used as crafting material for buttons, handles,
ornaments etc. A special genre is scrimshaw. Ground bones are used an organic phosphorus-nitrogen fertilizer and as
additive in animal feed. Bones, in particular after calcination to bone ash is used as source of calcium phosphate for
the production of bone china and previously also phosphorus chemicals.

Terminology
Several terms are used to refer to features and components of bones throughout the body:
Bone 77

Bone feature Definition

articular process A projection that contacts an adjacent bone.

articulation The region where adjacent bones contact each other — a joint.

canal A long, tunnel-like foramen, usually a passage for notable nerves or blood vessels.

condyle A large, rounded articular process.

crest A prominent ridge.

eminence A relatively small projection or bump.

epicondyle A projection near to a condyle but not part of the joint.

facet A small, flattened articular surface.

foramen An opening through a bone.

fossa A broad, shallow depressed area.

fovea A small pit on the head of a bone.

labyrinth A cavity within a bone.

line A long, thin projection, often with a rough surface. Also known as a ridge.

malleolus One of two specific protuberances of bones in the ankle.

meatus A short canal that finishes as a dead end, so it has only the entrance.

process A relatively large projection or prominent bump.(gen.)

ramus An arm-like branch off the body of a bone.

sinus A cavity within a cranial bone.

spine A relatively long, thin projection or bump.

suture Articulation between cranial bones.

trochanter One of two specific tuberosities located on the femur.

tubercle A projection or bump with a roughened surface, generally smaller than a tuberosity.

tuberosity A projection or bump with a roughened surface.

Several terms are used to refer to specific features of long bones:

Bone feature Definition

diaphysis The long, relatively straight main body of a long bone; region of primary ossification. Also known as the shaft.

epiphysis The end regions of a long bone; regions of secondary ossification.

epiphyseal Also known as the growth plate or physis. In a long bone it is a thin disc of hyaline cartilage that is positioned transversely between
plate the epiphysis and metaphysis. In the long bones of humans, the epiphyseal plate disappears by twenty years of age.

head The proximal articular end of the bone.

metaphysis The region of a long bone lying between the epiphysis and diaphysis.

neck The region of bone between the head and the shaft.
Bone 78

Footnotes
[1] Steele, D. Gentry; Claud A. Bramblett (1988). The Anatomy and Biology of the Human Skeleton. Texas A&M University Press. p. 4.
ISBN 0-89096-300-2.
[2] Schmiedeler, Edgar; Mary Rosa McDonough (1934). Parent and Child: An Introductory Study of Parent Education. D. Appleton-Century.
p. 31.
[3] Lee, Na Kyung; et al. (10 August 2007). "Endocrine Regulation of Energy Metabolism by the Skeleton" (http:/ / download. cell. com/ pdfs/
0092-8674/ PIIS0092867407007015. pdf). Cell 130 (3): 456–469. doi:10.1016/j.cell.2007.05.047. PMC 2013746. PMID 17693256. .
Retrieved 2008-03-15.
[4] Schmidt-Nielsen, Knut (1984). Scaling: Why is animal size so important?. Cambridge: Cambridge University Press. p. 6. ISBN 05213198700
.
[5] Turner, C.H.; Wang, T.; Burr, D.B. (2001). "Shear Strength and Fatigue Properties of Human Cortical Bone Determined from Pure Shear
Tests". Calcified Tissue International 69 (6): 373–378. doi:10.1007/s00223-001-1006-1. PMID 11800235.
[6] Hall, Susan. (2007) Basic Biomechanics. Fifth Edition. p. 88 ISBN 0-07-126041-2
[7] Legros, R; Balmain, N; Bonel, G (1987). "Age-related changes in mineral of rat and bovine cortical bone". Calcified tissue international 41
(3): 137–44. PMID 3117340.
[8] Field, RA; Riley, ML; Mello, FC; Corbridge, MH; Kotula, AW (1974). "Bone composition in cattle, pigs, sheep and poultry". Journal of
animal science 39 (3): 493–9. PMID 4412232.
[9] Bertazzo, S. & Bertran, C. A. (2006). "Morphological and dimensional characteristics of bone mineral crystals". Bioceramics 309–311 (Pt. 1,
2): 3–10. doi:10.4028/www.scientific.net/KEM.309-311.3.
[10] Bertazzo, S.; Bertran, C.A.; Camilli, J.A. (2006). "Morphological Characterization of Femur and Parietal Bone Mineral of Rats at Different
Ages". Key Engineering Materials 309–311: 11–14. doi:10.4028/www.scientific.net/KEM.309-311.11.
[11] Salentijn, L. Biology of Mineralized Tissues: Cartilage and Bone, Columbia University College of Dental Medicine post-graduate dental
lecture series, 2007
[12] Mohan, S.; Baylink, D. J. (1991). "Bone growth factors". Clinical orthopaedics and related research (263): 30–48. PMID 1993386.
[13] http:/ / www. sciencedirect. com/ science/ article/ pii/ S0140673681905262
[14] Netter, Frank H. (1987). Musculoskeletal system: anatomy, physiology, and metabolic disorders. New Jersey, Summit: Ciba-Geigy
Corporation. ISBN 0-914168-88-6 pp. 187–189.
[15] Boulpaep, Emile L.; Boron, Walter F. (2005). Medical physiology: a cellular and molecular approach. Philadelphia: Saunders.
pp. 1089–1091. ISBN 1-4160-2328-3.
[16] WHO (1994). "Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study
Group". World Health Organization technical report series 843: 1–129. PMID 7941614.
[17] Hans J. Rolf; Alfred Enderle (1999). "Hard fallow deer antler: a living bone till antler casting?". The Anatomical Record 255 (1): 69–77.
doi:10.1002/(SICI)1097-0185(19990501)255:1<69::AID-AR8>3.0.CO;2-R. PMID 10321994.

References
• Katja Hoehn; Marieb, Elaine Nicpon (2007). Human Anatomy & Physiology (7th Edition). San Francisco:
Benjamin Cummings. ISBN 0-8053-5909-5.
• Bryan H. Derrickson; Tortora, Gerard J. (2005). Principles of anatomy and physiology. New York: Wiley.
ISBN 0-471-68934-3.

External links
• Educational resource materials (including animations) by the American Society for Bone and Mineral Research
(http://depts.washington.edu/bonebio/ASBMRed/ASBMRed.html)
• Review (including references) of piezoelectricity and bone remodelling (http://silver.neep.wisc.edu/~lakes/
BoneElectr.html)
• A good basic overview of bone biology from the Science Creative Quarterly (http://www.scq.ubc.ca/?p=400)
Bone marrow 79

Bone marrow
Bone marrow

A simplified illustration of cells in bone marrow

Latin Medulla ossium

MeSH [1]
Bone+Marrow

Code [2]
TA A13.1.01.001

Bone marrow (Latin: medulla ossium) is the flexible tissue found in the interior of bones. In humans, red blood cells
are produced in the heads of long bones, in a process known as hematopoesis. On average, bone marrow constitutes
4% of the total body mass of humans; in an adult weighing 65 kilograms (unknown operator: u'strong' lb), bone
marrow accounts for approximately 2.6 kilograms (unknown operator: u'strong' lb). The hematopoietic
compartment of bone marrow produces approximately 500 billion blood cells per day, which use the bone marrow
vasculature as a conduit to the body's systemic circulation.[3] Bone marrow is also a key component of the lymphatic
system, producing the lymphocytes that support the body's immune system.[4]

Marrow types
The two types of bone marrow are medulla ossium rubra (red
marrow), which consists mainly of hematopoietic tissue, and medulla
ossium flava (yellow marrow), which is mainly made up of fat cells.
Red blood cells, platelets and most white blood cells arise in red
marrow. Both types of bone marrow contain numerous blood vessels
and capillaries. At birth, all bone marrow is red. With age, more and
more of it is converted to the yellow type; only around half of adult
bone marrow is red. Red marrow is found mainly in the flat bones,
such as the pelvis, sternum, cranium, ribs, vertebrae and scapulae, and
in the cancellous ("spongy") material at the epiphyseal ends of long
bones such as the femur and humerus. Yellow marrow is found in the
A femoral head with a cortex of cortical bone and
medullary cavity, the hollow interior of the middle portion of long medulla of trabecular bone. Both red bone
bones. In cases of severe blood loss, the body can convert yellow marrow and a focus of yellow bone marrow are
marrow back to red marrow to increase blood cell production. visible.

Stroma
The stroma of the bone marrow is all tissue not directly involved in the primary function of hematopoiesis. Yellow
bone marrow makes up the majority of bone marrow stroma, in addition to smaller concentrations of stromal cells
located in the red bone marrow. Though not as active as parenchymal red marrow, stroma is indirectly involved in
Bone marrow 80

hematopoiesis, since it provides the hematopoietic microenvironment that facilitates hematopoiesis by the
parenchymal cells. For instance, they generate colony stimulating factors, which have a significant effect on
hematopoiesis. Cells that constitute the bone marrow stroma are:
• fibroblasts (reticular connective tissue)
• macrophages
• adipocytes
• osteoblasts
• osteoclasts
• endothelial cells, which form the sinusoids. These derive from endothelial stem cells, which are also present in the
bone marrow.[5]
Macrophages contribute especially to red blood cell production, as they deliver iron for hemoglobin production.

Bone marrow barrier


The blood vessels of the bone marrow constitute a barrier, inhibiting immature blood cells from leaving the marrow.
Only mature blood cells contain the membrane proteins required to attach to and pass the blood vessel endothelium.
Hematopoietic stem cells may also cross the bone marrow barrier, and may thus be harvested from blood.

Mesenchymal stem cells


The bone marrow stroma contain mesenchymal stem cells (MSCs),[5] also known as marrow stromal cells. These are
multipotent stem cells that can differentiate into a variety of cell types. MSCs have been shown to differentiate, in
vitro or in vivo, into osteoblasts, chondrocytes, myocytes, adipocytes and beta-pancreatic islets cells. MSCs can also
transdifferentiate into neuronal cells.

Red marrow parenchyma

Types of cells

Hematopoietic precursor cells: promyelocyte in the center, two


metamyelocytes next to it and band cells from a bone marrow
aspirate.
Bone marrow 81

Cellular constitution of the red bone marrow parenchyma[6]


Group Cell type Average Reference
fraction range

Cells of Myeloblasts 0.9% 0.2-1.5


myelopoiesis
Promyelocytes 3.3% 2.1-4.1

Neutrophilic myelocytes 12.7% 8.2-15.7

Eosinophilic myelocytes 0.8% 0.2-1.3

Neutrophilic metamyelocytes 15.9% 9.6-24.6

Eosinophilic metamyelocytes 1.2% 0.4-2.2

Neutrophilic band cells 12.4% 9.5-15.3

Eosinophilic band cells 0.9% 0.2-2.4

Segmented neutrophils 7.4% 6.0-12.0

Segmented eosinophils 0.5% 0.0-1.3

Segmented basophils and mast cells 0.1% 0.0-0.2

Cells of Pronormoblasts 0.6% 0.2-1.3


erythropoiesis
Basophilic normoblasts 1.4% 0.5-2.4

Polychromatic normoblasts 21.6% 17.9-29.2

Orthochromatic normoblast 2.0% 0.4-4.6

Other cell types Megakaryocytes < 0.1% 0.0-0.4

Plasma cells 1.3% 0.4-3.9

Reticular cells 0.3% 0.0-0.9

Lymphocytes 16.2% 11.1-23.2

Monocytes 0.3% 0.0-0.8

In addition, the bone marrow contains hematopoietic stem cells, which give rise to the three classes of blood cells
that are found in the circulation: white blood cells (leukocytes), red blood cells (erythrocytes), and platelets
(thrombocytes).[5]

Compartmentalization
Biological compartmentalization is evident within the bone marrow, in that certain cell types tend to aggregate in
specific areas. For instance, erythrocytes, macrophages, and their precursors tend to gather around blood vessels,
while granulocytes gather at the borders of the bone marrow.

Lymphatic role
The red bone marrow is a key element of the lymphatic system, being one of the primary lymphoid organs that
generate lymphocytes from immature hematopoietic progenitor cells.[4] The bone marrow and thymus constitute the
primary lymphoid tissues involved in the production and early selection of lymphocytes. Furthermore, bone marrow
performs a valve-like function to prevent the backflow of lymphatic fluid in the lymphatic system.
Bone marrow 82

Diseases involving the bone marrow


The normal bone marrow architecture can be displaced by malignancies, aplastic anemia, or infections such as
tuberculosis, leading to a decrease in the production of blood cells and blood platelets. In addition, cancers of the
hematologic progenitor cells in the bone marrow can arise; these are the leukemias.
Exposure to radiation or chemotherapy will kill many of the rapidly dividing cells of the bone marrow, and will
therefore result in a depressed immune system. Many of the symptoms of radiation sickness are due to damage to the
bone marrow cells.
To diagnose diseases involving the bone marrow, a bone marrow aspiration is sometimes performed. This typically
involves using a hollow needle to acquire a sample of red bone marrow from the crest of the ilium under general or
local anesthesia.

Examination
Bone marrow examination is the pathologic analysis of samples of bone
marrow obtained via biopsy and bone marrow aspiration. Bone marrow
examination is used in the diagnosis of a number of conditions, including
leukemia, multiple myeloma, anemia, and pancytopenia. The bone marrow
produces the cellular elements of the blood, including platelets, red blood
cells and white blood cells. While much information can be gleaned by
testing the blood itself (drawn from a vein by phlebotomy), it is sometimes
necessary to examine the source of the blood cells in the bone marrow to
obtain more information on hematopoiesis; this is the role of bone marrow
aspiration and biopsy.

A Wright's-stained bone marrow aspirate


The ratio between myeloid series and erythroid cells is relevant to bone
smear from a patient with leukemia. marrow function, and also to diseases of the bone marrow and peripheral
blood, such as leukemia and anemias. The normal myeloid-to-erythroid ratio
is around 3:1; this ratio may increase in myelogenous leukemias, decrease in polycythemias, and reverse in cases of
thalassemia.

Donation and transplantation


In a bone marrow transplant, hematopoietic stem cells are removed
from a person and infused into another person (allogenic) or into the
same person at a later time (autologous). If the donor and recipient are
compatible, these infused cells will then travel to the bone marrow and
initiate blood cell production. Transplantation from one person to
another is performed in severe cases of bone marrow disease. The
patient's own marrow is first killed off with drugs or radiation, and then
the new stem cells are introduced. Before radiation therapy or
A bone marrow harvest in progress.
chemotherapy in cases of cancer, some of the patient's hematopoietic
stem cells are sometimes harvested and later infused back when the
therapy is finished to restore the immune system.
Bone marrow 83

Harvesting
The stem cells are typically harvested directly from the red marrow in the iliac crest, often under general anesthesia.
The procedure is minimally invasive and does not require stitches afterwards. Depending on the donor's health and
reaction to the procedure, the actual harvesting can be an outpatient procedure, or can require 1–2 days of recovery
in the hospital.[7]
Another option is to administer certain drugs that stimulate the release of stem cells from the bone marrow into
circulating blood.[8] An IV is inserted into the donor's arm, and the stem cells are filtered out of the blood. This
procedure is similar to donating blood or platelets. Bone marrow may also be taken from the sternum. The tibia may
seem a good source, since it is very superficial, but adult tibia bone marrow does not contain any substantial amount
of red marrow.[9] In newborns, stem cells may be retrieved from the umbilical cord.[10]

Food
Many cultures have used bone marrow as food throughout history.
Anthropologists believe that early humans were scavengers rather than
hunters in some regions of the world. Marrow would have been a
useful food source (largely due to its fat content) for tool-using
hominids, who were able to crack open the bones of carcasses left by
apex predators such as lions.[11]

European diners in the 18th century often used a marrow scoop (or
marrow spoon), often of silver and with a long, thin bowl, as a table
implement for removing marrow from a bone. Bone marrow was also
used in various preparations, such as pemmican. Bone marrow's In some parts of Germany, beef soup is served
popularity as a food is now relatively limited in the western world, but with Markklößchen (bone marrow balls).
it remains in use in some gourmet restaurants, and is popular among
food enthusiasts.[12]

In Vietnam, beef bone marrow is used as the soup base for the national staple dish, phở, while in the Philippines, the
soup bulalo is made primarily of beef stock and marrow bones, seasoned with vegetables and boiled meat; a similar
soup in the Philippines is called kansi.[13] In Indonesia, bone marrow is called sumsum and can be found especially
in Minangkabau cuisine. Sumsum is often cooked as soup or as gulai (a curry-like dish). In India and Pakistan,
slow-cooked marrow is the core ingredient of the dish nalli nihari.
In Hungary, tibia is a main ingredient of beef soup; the bone is chopped into short (10–15 cm) pieces and the ends
are covered with salt to prevent the marrow from leaking from the bone while cooking. Upon serving the soup, the
marrow is usually spread on toast.
Beef bone marrow is also the main ingredient in Italian dish ossobuco (braised veal shanks), and beef marrow bones
are often included in the French pot-au-feu broth, the cooked marrow being traditionally eaten on toasted bread with
sprinkled coarse sea salt.
In Iranian cuisine, lamb shanks are usually broken before cooking to allow diners to suck out and eat the marrow
when the dish is served. Similar practices are also common in Pakistani cuisine. Some Native Alaskans eat the bone
marrow of caribou and moose.
Bone marrow 84

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Bone+ Marrow
[2] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTA/ TAa13. html
[3] "Challenges in Cardiac Tissue Engineering"; Gordana Vunjak-Novakovic, Ph.D.,Nina Tandon, Ph.D., Amandine Godier, B.S.,1 Robert
Maidhof, M.S.,Anna Marsano, Ph.D., Timothy P. Martens, M.D., Ph.D., and Milica Radisic, Ph.D.; TISSUE ENGINEERING: Part B;
Volume 16, Number 2, 2010
[4] The Lymphatic System (http:/ / allonhealth. com/ health-news/ par-lymphatic-system. htm). Allonhealth.com. Retrieved 2011-12-05.
[5] Raphael Rubin and David S. Strayer (2007). Rubin's Pathology: Clinicopathologic Foundations of Medicine. Lippincott Williams & Wilkins.
p. 90. ISBN 0-7817-9516-8.
[6] Appendix A:IV (http:/ / www. msd. com. mx/ secure/ ebooks/ WintrobesClinicalHematology/ sid4266054. html) in: Wintrobe's clinical
hematology, 9th ed. Philadelphia: Lea & Febiger, 1993.
[7] National Marrow Donor Program Donor Guide (http:/ / www. marrow. org/ DONOR/ When_You_re_Asked_to_Donate_fo/ index. html)
[8] Mayo Clinic: Bone marrow donation: What to expect when you donate (http:/ / www. mayoclinic. com/ health/ bone-marrow/ CA00047)
[9] Semester 4 medical lectures at Uppsala University 2008 by Leif Jansson
[10] Production of stem cells with embryonic characteristics from human umbilical cord blood (http:/ / www3. interscience. wiley. com/ journal/
118705649/ abstract). Wiley Online Library, 11 August 2005. Retrieved 2012-01-29.
[11] Bruce Bower. Hunting ancient scavengers – some anthropologists say early humans were scavengers, not hunters (http:/ / findarticles. com/
p/ articles/ mi_m1200/ is_v127/ ai_3677563). Science News. March 9, 1985
[12] La Petite Bouche (Food Blog): Roasted Bone Marrow (http:/ / lapetitebouche. blogspot. com/ 2010/ 08/ roasted-bone-marrow. html). 30
August 2010. Retrieved 2011-12-05.
[13] "Kansi" (http:/ / www. flickr. com/ photos/ kamums/ 4378949248/ ) Flickr

Further reading
• Cooper, B (2011). "The origins of bone marrow as the seedbed of our blood: from antiquity to the time of Osler"
(http://baylorhealth.edu/proceedings/24_2/24_2_Cooper.pdf). Baylor University Medical Center Proceedings
24 (2): 115–8. PMC 3069519. PMID 21566758.

Carbohydrate
A carbohydrate is an organic compound
that consists only of carbon, hydrogen,
and oxygen, usually with a
hydrogen:oxygen atom ratio of 2:1 (as in
water); in other words, with the empirical
formula Cm(H2O)n. (Some exceptions
exist; for example, deoxyribose, a
component of DNA, has the empirical
formula C5H10O4.) Carbohydrates are not Lactose is a disaccharide found in milk. It consists of a molecule of D-galactose and a
technically hydrates of carbon. molecule of D-glucose bonded by beta-1-4 glycosidic linkage. It has a formula of
Structurally it is more accurate to view C12H22O11.

them as polyhydroxy aldehydes and


ketones.

The term is most common in biochemistry, where it is a synonym of saccharide. The carbohydrates (saccharides)
are divided into four chemical groupings: monosaccharides, disaccharides, oligosaccharides, and polysaccharides. In
general, the monosaccharides and disaccharides, which are smaller (lower molecular weight) carbohydrates, are
commonly referred to as sugars.[1] The word saccharide comes from the Greek word σάκχαρον (sákkharon),
meaning "sugar". While the scientific nomenclature of carbohydrates is complex, the names of the monosaccharides
Carbohydrate 85

and disaccharides very often end in the suffix -ose. For example, blood sugar is the monosaccharide glucose, table
sugar is the disaccharide sucrose, and milk sugar is the disaccharide lactose (see illustration).
Carbohydrates perform numerous roles in living organisms. Polysaccharides serve for the storage of energy (e.g.,
starch and glycogen), and as structural components (e.g., cellulose in plants and chitin in arthropods). The 5-carbon
monosaccharide ribose is an important component of coenzymes (e.g., ATP, FAD, and NAD) and the backbone of
the genetic molecule known as RNA. The related deoxyribose is a component of DNA. Saccharides and their
derivatives include many other important biomolecules that play key roles in the immune system, fertilization,
preventing pathogenesis, blood clotting, and development.[2]
In food science and in many informal contexts, the term carbohydrate often means any food that is particularly rich
in the complex carbohydrate starch (such as cereals, bread, and pasta) or simple carbohydrates, such as sugar (found
in candy, jams, and desserts).

Structure
Formerly the name "carbohydrate" was used in chemistry for any compound with the formula Cm (H2O) n. Following
this definition, some chemists considered formaldehyde (CH2O) to be the simplest carbohydrate,[3] while others
claimed that title for glycolaldehyde.[4] Today the term is generally understood in the biochemistry sense, which
excludes compounds with only one or two carbons.
Natural saccharides are generally built of simple carbohydrates called monosaccharides with general formula
(CH2O)n where n is three or more. A typical monosaccharide has the structure H-(CHOH)x(C=O)-(CHOH)y-H, that
is, an aldehyde or ketone with many hydroxyl groups added, usually one on each carbon atom that is not part of the
aldehyde or ketone functional group. Examples of monosaccharides are glucose, fructose, and glyceraldehydes.
However, some biological substances commonly called "monosaccharides" do not conform to this formula (e.g.,
uronic acids and deoxy-sugars such as fucose), and there are many chemicals that do conform to this formula but are
not considered to be monosaccharides (e.g., formaldehyde CH2O and inositol (CH2O)6).[5]
The open-chain form of a monosaccharide often coexists with a closed ring form where the aldehyde/ketone
carbonyl group carbon (C=O) and hydroxyl group (-OH) react forming a hemiacetal with a new C-O-C bridge.
Monosaccharides can be linked together into what are called polysaccharides (or oligosaccharides) in a large variety
of ways. Many carbohydrates contain one or more modified monosaccharide units that have had one or more groups
replaced or removed. For example, deoxyribose, a component of DNA, is a modified version of ribose; chitin is
composed of repeating units of N-acetyl glucosamine, a nitrogen-containing form of glucose.
Carbohydrate 86

Monosaccharides
Monosaccharides are the simplest carbohydrates in that they cannot be hydrolyzed
to smaller carbohydrates. They are aldehydes or ketones with two or more
hydroxyl groups. The general chemical formula of an unmodified monosaccharide
is (C•H2O) n, literally a "carbon hydrate." Monosaccharides are important fuel
molecules as well as building blocks for nucleic acids. The smallest
monosaccharides, for which n = 3, are dihydroxyacetone and D- and
L-glyceraldehydes.

Classification of monosaccharides

D-glucose is an aldohexose with the


formula (C·H2O)6. The red atoms
The α and β anomers of glucose. Note the position of the hydroxyl group (red or highlight the aldehyde group, and
green) on the anomeric carbon relative to the CH2OH group bound to carbon 5: the blue atoms highlight the
they are either on the opposite sides (α), or the same side (β). asymmetric center furthest from the
aldehyde; because this -OH is on
Monosaccharides are classified according to three different characteristics: the the right of the Fischer projection,
placement of its carbonyl group, the number of carbon atoms it contains, and its this is a D sugar.
chiral handedness. If the carbonyl group is an aldehyde, the monosaccharide is an
aldose; if the carbonyl group is a ketone, the monosaccharide is a ketose. Monosaccharides with three carbon atoms
are called trioses, those with four are called tetroses, five are called pentoses, six are hexoses, and so on.[6] These two
systems of classification are often combined. For example, glucose is an aldohexose (a six-carbon aldehyde), ribose
is an aldopentose (a five-carbon aldehyde), and fructose is a ketohexose (a six-carbon ketone).

Each carbon atom bearing a hydroxyl group (-OH), with the exception of the first and last carbons, are asymmetric,
making them stereo centers with two possible configurations each (R or S). Because of this asymmetry, a number of
isomers may exist for any given monosaccharide formula. The aldohexose D-glucose, for example, has the formula
(C·H2O) 6, of which all but two of its six carbons atoms are stereogenic, making D-glucose one of 24 = 16 possible
stereoisomers. In the case of glyceraldehydes, an aldotriose, there is one pair of possible stereoisomers, which are
enantiomers and epimers. 1, 3-dihydroxyacetone, the ketose corresponding to the aldose glyceraldehydes, is a
symmetric molecule with no stereo centers). The assignment of D or L is made according to the orientation of the
asymmetric carbon furthest from the carbonyl group: in a standard Fischer projection if the hydroxyl group is on the
right the molecule is a D sugar, otherwise it is an L sugar. The "D-" and "L-" prefixes should not be confused with
"d-" or "l-", which indicate the direction that the sugar rotates plane polarized light. This usage of "d-" and "l-" is no
longer followed in carbohydrate chemistry.[7]
Carbohydrate 87

Ring-straight chain isomerism


The aldehyde or ketone group of a straight-chain monosaccharide
will react reversibly with a hydroxyl group on a different carbon
atom to form a hemiacetal or hemiketal, forming a heterocyclic
ring with an oxygen bridge between two carbon atoms. Rings with
five and six atoms are called furanose and pyranose forms,
respectively, and exist in equilibrium with the straight-chain
form.[8]

During the conversion from straight-chain form to the cyclic form,


the carbon atom containing the carbonyl oxygen, called the
anomeric carbon, becomes a stereogenic center with two possible
Glucose can exist in both a straight-chain and ring
configurations: The oxygen atom may take a position either above
form.
or below the plane of the ring. The resulting possible pair of
stereoisomers is called anomers. In the α anomer, the -OH
substituent on the anomeric carbon rests on the opposite side (trans) of the ring from the CH2OH side branch. The
alternative form, in which the CH2OH substituent and the anomeric hydroxyl are on the same side (cis) of the plane
of the ring, is called the β anomer.

Use in living organisms


Monosaccharides are the major source of fuel for metabolism, being used both as an energy source (glucose being
the most important in nature) and in biosynthesis. When monosaccharides are not immediately needed by many cells
they are often converted to more space-efficient forms, often polysaccharides. In many animals, including humans,
this storage form is glycogen, especially in liver and muscle cells. In plants, starch is used for the same purpose.

Disaccharides
Two joined monosaccharides are called a disaccharide
and these are the simplest polysaccharides. Examples
include sucrose and lactose. They are composed of two
monosaccharide units bound together by a covalent
bond known as a glycosidic linkage formed via a
dehydration reaction, resulting in the loss of a hydrogen
atom from one monosaccharide and a hydroxyl group
from the other. The formula of unmodified
Sucrose, also known as table sugar, is a common disaccharide. It is
disaccharides is C12H22O11. Although there are composed of two monosaccharides: D-glucose (left) and D-fructose
numerous kinds of disaccharides, a handful of (right).
disaccharides are particularly notable.

Sucrose, pictured to the right, is the most abundant disaccharide, and the main form in which carbohydrates are
transported in plants. It is composed of one D-glucose molecule and one D-fructose molecule. The systematic name
for sucrose, O-α-D-glucopyranosyl-(1→2)-D-fructofuranoside, indicates four things:
• Its monosaccharides: glucose and fructose
• Their ring types: glucose is a pyranose, and fructose is a furanose
• How they are linked together: the oxygen on carbon number 1 (C1) of α-D-glucose is linked to the C2 of
D-fructose.
• The -oside suffix indicates that the anomeric carbon of both monosaccharides participates in the glycosidic bond.
Carbohydrate 88

Lactose, a disaccharide composed of one D-galactose molecule and one D-glucose molecule, occurs naturally in
mammalian milk. The systematic name for lactose is O-β-D-galactopyranosyl-(1→4)-D-glucopyranose. Other
notable disaccharides include maltose (two D-glucoses linked α-1,4) and cellulobiose (two D-glucoses linked β-1,4).
disaccharides can be classified into two types.They are reducing and non-reducing disaccahrides if the functional
group is present in bonding with another sugar unit it is called a reducing disaccharide or biose.

Nutrition
Foods high in carbohydrate include fruits, sweets, soft drinks, breads,
pastas, beans, potatoes, bran, rice, and cereals. Carbohydrates are a
common source of energy in living organisms; however, no
carbohydrate is an essential nutrient in humans.[9]
Carbohydrates are not necessary building blocks of other molecules,
and the body can obtain all its energy from protein and fats.[10][11] The
brain and neurons generally cannot burn fat for energy, but use glucose
or ketones. Humans can synthesize some glucose (in a set of processes
known as gluconeogenesis) from specific amino acids, from the
glycerol backbone in triglycerides and in some cases from fatty acids.
Carbohydrate and protein contain 4 kilocalories per gram, while fats
contain 9 kilocalories per gram. In the case of protein, this is somewhat
misleading as only some amino acids are usable for fuel.

Organisms typically cannot metabolize all types of carbohydrate to


yield energy. Glucose is a nearly universal and accessible source of
calories. Many organisms also have the ability to metabolize other Grain products: rich sources of carbohydrates

monosaccharides and Disaccharides, though glucose is preferred. In


Escherichia coli, for example, the lac operon will express enzymes for the digestion of lactose when it is present, but
if both lactose and glucose are present the lac operon is repressed, resulting in the glucose being used first (see:
Diauxie). Polysaccharides are also common sources of energy. Many organisms can easily break down starches into
glucose, however, most organisms cannot metabolize cellulose or other polysaccharides like chitin and
arabinoxylans. These carbohydrates types can be metabolized by some bacteria and protists. Ruminants and termites,
for example, use microorganisms to process cellulose. Even though these complex carbohydrates are not very
digestible, they may comprise important dietary elements for humans. Called dietary fiber, these carbohydrates
enhance digestion among other benefits.[12]

Based on the effects on risk of heart disease and obesity,[13] the Institute of Medicine recommends that American
and Canadian adults get between 45–65% of dietary energy from carbohydrates.[14] The Food and Agriculture
Organization and World Health Organization jointly recommend that national dietary guidelines set a goal of
55–75% of total energy from carbohydrates, but only 10% directly from sugars (their term for simple
carbohydrates).[15]

Classification
Historically nutritionists have classified carbohydrates as either simple or complex. However, the exact delineation
of these categories is ambiguous. Today, simple carbohydrate typically refers to monosaccharides and disaccharides
and complex carbohydrate means polysaccharides (and oligosaccharides). However, the term complex carbohydrate
was first used in slightly different context in the U.S. Senate Select Committee on Nutrition and Human Needs
publication Dietary Goals for the United States (1977). In this work, complex carbohydrate were defined as "fruit,
vegetables and whole-grains".[16] Some nutritionists use complex carbohydrate to refer to any sort of digestible
Carbohydrate 89

saccharide present in a whole food, where fiber, vitamins and minerals are also found (as opposed to processed
carbohydrates, which provide calories but few other nutrients).
Some simple carbohydrates (e.g. fructose) are digested very slowly, while some complex carbohydrates (starches),
especially if processed, raise blood sugar rapidly. The speed of digestion is determined by a variety of factors
including which other nutrients are consumed with the carbohydrate, how the food is prepared, individual differences
in metabolism, and the chemistry of the carbohydrate.
The USDA's Dietary Guidelines for Americans 2010 call for moderate- to high-carbohydrate consumption from a
balanced diet that includes six one-ounce servings of grain foods each day, at least half from whole grain sources and
the rest from enriched.[17]
The glycemic index (GI) and glycemic load concepts have been developed to characterize food behavior during
human digestion. They rank carbohydrate-rich foods based on the rapidity and magnitude of their effect on blood
glucose levels. Glycemic index is a measure of how quickly food glucose is absorbed, while glycemic load is a
measure of the total absorbable glucose in foods. The insulin index is a similar, more recent classification method
that ranks foods based on their effects on blood insulin levels, which are caused by glucose (or starch) and some
amino acids in food.

Metabolism

Catabolism
Catabolism is the metabolic reaction in which cells undergo to extract energy. There are two major metabolic
pathways of monosaccharide catabolism: glycolysis and the citric acid cycle.
In glycolysis, oligo/polysaccharides are cleaved first to smaller monosaccharides by enzymes called glycoside
hydrolases. The monosaccharide units can then enter into monosaccharide catabolism. In some cases, as with
humans, not all carbohydrate types are usable as the digestive and metabolic enzymes necessary are not present.

Carbohydrate chemistry
Carbohydrate chemistry is a large and economically important branch of organic chemistry. Some of the main
organic reactions that involve carbohydrates are:
• Carbohydrate acetalisation
• Cyanohydrin reaction
• Lobry-de Bruyn-van Ekenstein transformation
• Amadori rearrangement
• Nef reaction
• Wohl degradation
• Koenigs–Knorr reaction
Carbohydrate 90

References
[1] Flitsch, SL & Ulijn, RV (2003). "Sugars tied to the spot." Nature 421: 219–220 (http:/ / www. nature. com/ nature/ journal/ v421/ n6920/ pdf/
421219a. pdf).
[2] Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993).
Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. pp. 52–59. ISBN 0-13-981176-1.
[3] John Merle Coulter, Charler Reid Barnes, Henry Chandler Cowles (1930), A Textbook of Botany for Colleges and Universities (http:/ /
books. google. com. br/ books?id=WyZnVpCiTHIC& pg=PA375& dq=simplest+ carbohydrate)"
[4] Carl A. Burtis, Edward R. Ashwood, Norbert W. Tietz (2000), Tietz fundamentals of clinical chemistry (http:/ / books. google. com/
books?id=l5hqAAAAMAAJ& q=simplest+ carbohydrate)
[5] Matthews, C. E.; K. E. Van Holde; K. G. Ahern (1999) Biochemistry. 3rd edition. Benjamin Cummings. ISBN 0-8053-3066-6
[6] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[7] Pigman, Ward; Horton, D. (1972). "Chapter 1: Stereochemistry of the Monosaccharides". In Pigman and Horton. The Carbohydrates:
Chemistry and Biochemistry Vol 1A (2nd ed.). San Diego: Academic Press. pp. 1–67.
[8] Pigman, Ward; Anet, E.F.L.J. (1972). "Chapter 4: Mutarotations and Actions of Acids and Bases". In Pigman and Horton. The
Carbohydrates: Chemistry and Biochemistry Vol 1A (2nd ed.). San Diego: Academic Press. pp. 165–194.
[9] http:/ / www. ajcn. org/ content/ 75/ 5/ 951. 2. full
[10] Is dietary carbohydrate essential for human nutrition? - Westman 75 (5): 951 - American Journal of Clinical Nutrition (http:/ / www. ajcn.
org/ cgi/ content/ full/ 75/ 5/ 951-a)
[11] A High-Protein, High-Fat, Carbohydrate-Free Diet Reduces Energy Intake, Hepatic Lipogenesis, and Adiposity in Rats - Pichon et al. 136
(5): 1256 - Journal of Nutrition (http:/ / jn. nutrition. org/ cgi/ reprint/ 136/ 5/ 1256?ijkey=ebf0450b5cf21e8d83dd43f62b5559254694f65f)
[12] Dietary Fiber Intake and Mortality in the NIH-AARP Diet and Health Study - Part, et al. 171 (12): 1061 - Archives of Internal Medicine
(http:/ / archinte. ama-assn. org/ cgi/ content/ short/ archinternmed. 2011. 18)
[13] Effect of increased consumption of whole-grain foods on blood pressure and other cardiovascular risk markers in healthy middle-aged
persons: a randomized, controlled trial - Tighe, et al. 92 (4): 733 - American Journal of Clinical Nutrition (http:/ / www. ajcn. org/ content/ 92/
4/ 733. abstract?sid=f97a2937-5a29-4143-8f1a-676f100177ab)
[14] Food and Nutrition Board (2002/2005). Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein,
and Amino Acids (http:/ / newton. nap. edu/ books/ 0309085373/ html). Washington, D.C.: The National Academies Press. Page 769 (http:/ /
newton. nap. edu/ books/ 0309085373/ html/ 769. html). ISBN 0-309-08537-3.
[15] Joint WHO/FAO expert consultation (2003). Diet, Nutrition and the Prevention of Chronic Diseases (http:/ / www. who. int/ hpr/ NPH/
docs/ who_fao_expert_report. pdf) (PDF). Geneva: World Health Organization. Pages 55–56. ISBN 92-4-120916-X.
[16] Joint WHO/FAO expert consultation (1998), Carbohydrates in human nutrition, chapter 1 (http:/ / www. fao. org/ docrep/ W8079E/
w8079e07. htm). ISBN 92-5-104114-8.
[17] DHHS and USDA, Dietary Guidelines for Americans 2010, (http:/ / www. cnpp. usda. gov/ DietaryGuidelines. htm)

External links
• Carbohydrates, including interactive models and animations (http://www2.ufp.pt/~pedros/bq/carb_en.htm)
(Requires MDL Chime (http://www.mdl.com/products/framework/chime/))
• IUPAC-IUBMB Joint Commission on Biochemical Nomenclature (JCBN): Carbohydrate Nomenclature (http://
www.chem.qmw.ac.uk/iupac/2carb/)
• Carbohydrates detailed (http://www.cem.msu.edu/~reusch/VirtualText/carbhyd.htm)
• Complex And Simple Carbohydrates (http://evilcyber.com/nutrition/complex-and-simple-carbohydrates/)
Explanation of the differences
• Carbohydrates and Glycosylation - The Virtual Library of Biochemistry and Cell Biology (http://www.
biochemweb.org/carbohydrates.shtml)
• Functional Glycomics Gateway (http://www.functionalglycomics.org/), a collaboration between the
Consortium for Functional Glycomics and Nature Publishing Group
• Wine Carbohydrates (http://www.wineclubwizard.com/wine-carbohydrates.html)
Cell (biology) 91

Cell (biology)
The cell is the basic structural and
functional unit of all known living
organisms. It is the smallest unit of life
that is classified as a living thing, and
is often called the building block of
life.[1] Organisms can be classified as
unicellular (consisting of a single cell;
including most bacteria) or
multicellular (including plants and
animals). Humans contain about 10
trillion (1013) cells. Most plant and
animal cells are between 1 and 100 µm
and therefore are visible only under the
microscope.[2]
Allium cells in different phases of the cell cycle
The cell was discovered by Robert
Hooke in 1665. In 1835, before the
final cell theory was developed, Jan
Evangelista Purkyně observed small
"granules" while looking at the plant
tissue through a microscope. The cell
theory, first developed in 1839 by
Matthias Jakob Schleiden and Theodor
Schwann, states that all organisms are
composed of one or more cells, that all
cells come from preexisting cells, that The cells of eukaryotes (left) and prokaryotes (right)
vital functions of an organism occur
within cells, and that all cells contain the hereditary information necessary for regulating cell functions and for
transmitting information to the next generation of cells.[3]

The word cell comes from the Latin cella, meaning "small room". The descriptive term for the smallest living
biological structure was coined by Robert Hooke in a book he published in 1665 when he compared the cork cells he
saw through his microscope to the small rooms monks lived in.[4]

Anatomy
There are two types of cells: eukaryotic and prokaryotic. Prokaryotic cells are usually independent, while eukaryotic
cells are often found in multicellular organisms.
Cell (biology) 92

Table 1: Comparison of features of prokaryotic and eukaryotic cells


Prokaryotes Eukaryotes

Typical organisms bacteria, archaea protists, fungi, plants, animals

Typical size ~ 1–10 µm ~ 10–100 µm (sperm cells, apart from the tail, are smaller)

Type of nucleus nucleoid region; no real nucleus real nucleus with double membrane

DNA circular (usually) linear molecules (chromosomes) with histone proteins

RNA-/protein-synthesis coupled in cytoplasm RNA-synthesis inside the nucleus


protein synthesis in cytoplasm

Ribosomes 50S+30S 60S+40S

Cytoplasmatic structure very few structures highly structured by endomembranes and a cytoskeleton

Cell movement flagella made of flagellin flagella and cilia containing microtubules; lamellipodia and filopodia containing actin

Mitochondria none one to several thousand (though some lack mitochondria)

Chloroplasts none in algae and plants

Organization usually single cells single cells, colonies, higher multicellular organisms with specialized cells

Cell division Binary fission (simple division) Mitosis (fission or budding)


Meiosis

Prokaryotic cells
The prokaryote cell is simpler, and
therefore smaller, than a eukaryote
cell, lacking a nucleus and most of the
other organelles of eukaryotes. There
are two kinds of prokaryotes: bacteria
and archaea; these share a similar
structure.

Nuclear material of prokaryotic cell


consist of a single chromosome that is
in direct contact with cytoplasm. Here,
the undefined nuclear region in the
cytoplasm is called nucleoid.
A prokaryotic cell has three
architectural regions:
• On the outside, flagella and pili
project from the cell's surface.
Diagram of a typical prokaryotic cell
These are structures (not present in
all prokaryotes) made of proteins
that facilitate movement and communication between cells;
• Enclosing the cell is the cell envelope – generally consisting of a cell wall covering a plasma membrane though
some bacteria also have a further covering layer called a capsule. The envelope gives rigidity to the cell and
separates the interior of the cell from its environment, serving as a protective filter. Though most prokaryotes
have a cell wall, there are exceptions such as Mycoplasma (bacteria) and Thermoplasma (archaea). The cell wall
Cell (biology) 93

consists of peptidoglycan in bacteria, and acts as an additional barrier against exterior forces. It also prevents the
cell from expanding and finally bursting (cytolysis) from osmotic pressure against a hypotonic environment.
Some eukaryote cells (plant cells and fungi cells) also have a cell wall;
• Inside the cell is the cytoplasmic region that contains the cell genome (DNA) and ribosomes and various sorts of
inclusions. A prokaryotic chromosome is usually a circular molecule (an exception is that of the bacterium
Borrelia burgdorferi, which causes Lyme disease). Though not forming a nucleus, the DNA is condensed in a
nucleoid. Prokaryotes can carry extrachromosomal DNA elements called plasmids, which are usually circular.
Plasmids enable additional functions, such as antibiotic resistance.

Eukaryotic cells
Plants, animals, fungi, slime moulds, protozoa, and algae are all eukaryotic. These cells are about 15 times wider
than a typical prokaryote and can be as much as 1000 times greater in volume. The major difference between
prokaryotes and eukaryotes is that eukaryotic cells contain membrane-bound compartments in which specific
metabolic activities take place. Most important among these is a cell nucleus, a membrane-delineated compartment
that houses the eukaryotic cell's DNA. This nucleus gives the eukaryote its name, which means "true nucleus." Other
differences include:
• The plasma membrane resembles that of prokaryotes in function, with minor differences in the setup. Cell walls
may or may not be present.
• The eukaryotic DNA is organized in one or more linear molecules, called chromosomes, which are associated
with histone proteins. All chromosomal DNA is stored in the cell nucleus, separated from the cytoplasm by a
membrane. Some eukaryotic organelles such as mitochondria also contain some DNA.
• Many eukaryotic cells are ciliated with primary cilia. Primary cilia play important roles in chemosensation,
mechanosensation, and thermosensation. Cilia may thus be "viewed as sensory cellular antennae that coordinate a
large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively
to cell division and differentiation."[5]
• Eukaryotes can move using motile cilia or flagella. The flagella are more complex than those of prokaryotes.

Structure of a typical animal cell Structure of a typical plant cell


Cell (biology) 94

Table 2: Comparison of structures between animal and plant cells


Typical animal cell Typical plant cell

Organelles • Nucleus • Nucleus


• Nucleolus (within nucleus) • Nucleolus (within nucleus)
• Rough endoplasmic reticulum (ER) • Rough ER
• Smooth ER • Smooth ER
• Ribosomes • Ribosomes
• Cytoskeleton • Cytoskeleton
• Golgi apparatus • Golgi apparatus (dictiosomes)
• Cytoplasm • Cytoplasm
• Mitochondria • Mitochondria
• Vesicles • Plastids and its derivatives
• Lysosomes • Vacuole(s)
• Centrosome • Cell wall
• Centrioles

Subcellular components
All cells, whether prokaryotic or eukaryotic, have a membrane that envelops the cell, separates its interior from its
environment, regulates what moves in and out (selectively permeable), and maintains the electric potential of the
cell. Inside the membrane, a salty cytoplasm takes up most of the cell volume. All cells possess DNA, the hereditary
material of genes, and RNA, containing the information necessary to build various proteins such as enzymes, the
cell's primary machinery. There are also other kinds of biomolecules in cells. This article lists these primary
components of the cell, then briefly describe their function.

Membrane
The cytoplasm of a cell is surrounded by a cell membrane or plasma membrane. The plasma membrane in plants and
prokaryotes is usually covered by a cell wall. This membrane serves to separate and protect a cell from its
surrounding environment and is made mostly from a double layer of lipids (hydrophobic fat-like molecules) and
hydrophilic phosphorus molecules. Hence, the layer is called a phospholipid bilayer. It may also be called a fluid
mosaic membrane. Embedded within this membrane is a variety of protein molecules that act as channels and pumps
that move different molecules into and out of the cell. The membrane is said to be 'semi-permeable', in that it can
either let a substance (molecule or ion) pass through freely, pass through to a limited extent or not pass through at all.
Cell surface membranes also contain receptor proteins that allow cells to detect external signaling molecules such as
hormones.
Cell (biology) 95

Cytoskeleton
The cytoskeleton acts to organize and maintain the
cell's shape; anchors organelles in place; helps during
endocytosis, the uptake of external materials by a cell,
and cytokinesis, the separation of daughter cells after
cell division; and moves parts of the cell in processes of
growth and mobility. The eukaryotic cytoskeleton is
composed of microfilaments, intermediate filaments
and microtubules. There is a great number of proteins
associated with them, each controlling a cell's structure
by directing, bundling, and aligning filaments. The
prokaryotic cytoskeleton is less well-studied but is
involved in the maintenance of cell shape, polarity and
cytokinesis.[6] Bovine Pulmonary Artery Endothelial cell: nuclei stained blue,
mitochondria stained red, and F-actin, an important component in
microfilaments, stained green. Cell imaged on a fluorescent
Genetic material microscope.

Two different kinds of genetic material exist:


deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Most organisms use DNA for their long-term information
storage, but some viruses (e.g., retroviruses) have RNA as their genetic material. The biological information
contained in an organism is encoded in its DNA or RNA sequence. RNA is also used for information transport (e.g.,
mRNA) and enzymatic functions (e.g., ribosomal RNA) in organisms that use DNA for the genetic code itself.
Transfer RNA (tRNA) molecules are used to add amino acids during protein translation.

Prokaryotic genetic material is organized in a simple circular DNA molecule (the bacterial chromosome) in the
nucleoid region of the cytoplasm. Eukaryotic genetic material is divided into different, linear molecules called
chromosomes inside a discrete nucleus, usually with additional genetic material in some organelles like mitochondria
and chloroplasts (see endosymbiotic theory).
A human cell has genetic material contained in the cell nucleus (the nuclear genome) and in the mitochondria (the
mitochondrial genome). In humans the nuclear genome is divided into 23 pairs of linear DNA molecules called
chromosomes. The mitochondrial genome is a circular DNA molecule distinct from the nuclear DNA. Although the
mitochondrial DNA is very small compared to nuclear chromosomes, it codes for 13 proteins involved in
mitochondrial energy production and specific tRNAs.
Foreign genetic material (most commonly DNA) can also be artificially introduced into the cell by a process called
transfection. This can be transient, if the DNA is not inserted into the cell's genome, or stable, if it is. Certain viruses
also insert their genetic material into the genome.

Organelles
The human body contains many different organs, such as the heart, lung, and kidney, with each organ performing a
different function. Cells also have a set of "little organs," called organelles, that are adapted and/or specialized for
carrying out one or more vital functions. Both eukaryotic and prokaryotic cells have organelles but organelles in
eukaryotes are generally more complex and may be membrane bound.
There are several types of organelles in a cell. Some (such as the nucleus and golgi apparatus) are typically solitary,
while others (such as mitochondria, peroxisomes and lysosomes) can be numerous (hundreds to thousands). The
cytosol is the gelatinous fluid that fills the cell and surrounds the organelles.
Cell (biology) 96

• Cell nucleus – eukaryotes only - A cell's information center, the


cell nucleus is the most conspicuous organelle found in a eukaryotic
cell. It houses the cell's chromosomes, and is the place where almost
all DNA replication and RNA synthesis (transcription) occur. The
nucleus is spherical and separated from the cytoplasm by a double
membrane called the nuclear envelope. The nuclear envelope
isolates and protects a cell's DNA from various molecules that could
accidentally damage its structure or interfere with its processing.
During processing, DNA is transcribed, or copied into a special
RNA, called messenger RNA (mRNA). This mRNA is then
transported out of the nucleus, where it is translated into a specific
protein molecule. The nucleolus is a specialized region within the Diagram of a cell nucleus

nucleus where ribosome subunits are assembled. In prokaryotes,


DNA processing takes place in the cytoplasm.

• Mitochondria and Chloroplasts – eukaryotes only - the power generators: Mitochondria are self-replicating
organelles that occur in various numbers, shapes, and sizes in the cytoplasm of all eukaryotic cells. Mitochondria
play a critical role in generating energy in the eukaryotic cell. Mitochondria generate the cell's energy by
oxidative phosphorylation, using oxygen to release energy stored in cellular nutrients (typically pertaining to
glucose) to generate ATP. Mitochondria multiply by splitting in two. Respiration occurs in the cell mitochondria.
• Endoplasmic reticulum – eukaryotes only: The endoplasmic
reticulum (ER) is the transport network for molecules targeted for
certain modifications and specific destinations, as compared to
molecules that float freely in the cytoplasm. The ER has two forms:
the rough ER, which has ribosomes on its surface and secretes
proteins into the cytoplasm, and the smooth ER, which lacks them.
Smooth ER plays a role in calcium sequestration and release.

• Golgi apparatus – eukaryotes only : The primary function of the


Golgi apparatus is to process and package the macromolecules such
as proteins and lipids that are synthesized by the cell.
• Ribosomes: The ribosome is a large complex of RNA and protein
molecules. They each consist of two subunits, and act as an
Diagram of an endomembrane system
assembly line where RNA from the nucleus is used to synthesise
proteins from amino acids. Ribosomes can be found either floating
freely or bound to a membrane (the rough endoplasmatic reticulum in eukaryotes, or the cell membrane in
prokaryotes).[7]

• Lysosomes and Peroxisomes – eukaryotes only: Lysosomes contain digestive enzymes (acid hydrolases). They
digest excess or worn-out organelles, food particles, and engulfed viruses or bacteria. Peroxisomes have enzymes
that rid the cell of toxic peroxides. The cell could not house these destructive enzymes if they were not contained
in a membrane-bound system.
• Centrosome – the cytoskeleton organiser: The centrosome produces the microtubules of a cell – a key
component of the cytoskeleton. It directs the transport through the ER and the Golgi apparatus. Centrosomes are
composed of two centrioles, which separate during cell division and help in the formation of the mitotic spindle.
A single centrosome is present in the animal cells. They are also found in some fungi and algae cells.
• Vacuoles: Vacuoles store food and waste. Some vacuoles store extra water. They are often described as liquid
filled space and are surrounded by a membrane. Some cells, most notably Amoeba, have contractile vacuoles,
Cell (biology) 97

which can pump water out of the cell if there is too much water. The vacuoles of eukaryotic cells are usually
larger in those of plants than animals.

Structures outside the cell membrane


Many cells also have structures which exist wholly or partially outside the cell membrane. These structures are
notable because they are not protected from the external environment by the impermeable cell membrane. In order to
assemble these structures export processes to carry macromolecules across the cell membrane must be used.

Cell wall
Many types of prokaryotic and eukaryotic cell have a cell wall. The cell wall acts to protect the cell mechanically
and chemically from its environment, and is an additional layer of protection to the cell membrane. Different types
of cell have cell walls made up of different materials; plant cell walls are primarily made up of pectin, fungi cell
walls are made up of chitin and bacteria cell walls are made up of peptidoglycan.

Prokaryotic

Capsule
A gelatinous capsule is present in some bacteria outside the cell membrane and cell wall. The capsule may be
polysaccharide as in pneumococci, meningococci or polypeptide as Bacillus anthracis or hyaluronic acid as in
streptococci. Capsules are not marked by normal staining protocols and can be detected by special stain.

Flagella
Flagella are organelles for cellular mobility. The bacterial flagellum stretches from cytoplasm through the cell
membrane(s) and extrudes through the cell wall. They are long and thick thread-like appendages, protein in nature.
Are most commonly found in bacteria cells but are found in animal cells as well.

Fimbriae (pili)
They are short and thin hair like filaments, formed of protein called pilin (antigenic). Fimbriae are responsible for
attachment of bacteria to specific receptors of human cell (adherence). There are special types of pili called (sex pili)
involved in conjunction.

Functions

Growth and metabolism


Between successive cell divisions, cells grow through the functioning of cellular metabolism. Cell metabolism is the
process by which individual cells process nutrient molecules. Metabolism has two distinct divisions: catabolism, in
which the cell breaks down complex molecules to produce energy and reducing power, and anabolism, in which the
cell uses energy and reducing power to construct complex molecules and perform other biological functions.
Complex sugars consumed by the organism can be broken down into a less chemically complex sugar molecule
called glucose. Once inside the cell, glucose is broken down to make adenosine triphosphate (ATP), a form of
energy, through two different pathways.
The first pathway, glycolysis, requires no oxygen and is referred to as anaerobic metabolism. Each reaction is
designed to produce some hydrogen ions that can then be used to make energy packets (ATP). In prokaryotes,
glycolysis is the only method used for converting energy.
The second pathway, called the Krebs cycle, or citric acid cycle, occurs inside the mitochondria and can generate
enough ATP to run all the cell functions.
Cell (biology) 98

Creation
Cell division involves a single cell (called a mother cell) dividing into two daughter
cells. This leads to growth in multicellular organisms (the growth of tissue) and to
procreation (vegetative reproduction) in unicellular organisms.
Prokaryotic cells divide by binary fission. Eukaryotic cells usually undergo a process of
nuclear division, called mitosis, followed by division of the cell, called cytokinesis. A
diploid cell may also undergo meiosis to produce haploid cells, usually four. Haploid
cells serve as gametes in multicellular organisms, fusing to form new diploid cells.
DNA replication, or the process of duplicating a cell's genome, is required every time a
cell divides. Replication, like all cellular activities, requires specialized proteins for An overview of protein
carrying out the job. synthesis.Within the
nucleus of the cell (light
blue), genes (DNA, dark
Protein synthesis blue) are transcribed into
RNA. This RNA is then
Cells are capable of synthesizing new proteins, which are essential for the modulation
subject to
and maintenance of cellular activities. This process involves the formation of new post-transcriptional
protein molecules from amino acid building blocks based on information encoded in modification and control,
DNA/RNA. Protein synthesis generally consists of two major steps: transcription and resulting in a mature
mRNA (red) that is then
translation.
transported out of the
Transcription is the process where genetic information in DNA is used to produce a nucleus and into the
complementary RNA strand. This RNA strand is then processed to give messenger RNA cytoplasm (peach), where
it undergoes translation
(mRNA), which is free to migrate through the cell. mRNA molecules bind to
into a protein. mRNA is
protein-RNA complexes called ribosomes located in the cytosol, where they are translated by ribosomes
translated into polypeptide sequences. The ribosome mediates the formation of a (purple) that match the
polypeptide sequence based on the mRNA sequence. The mRNA sequence directly three-base codons of the
mRNA to the three-base
relates to the polypeptide sequence by binding to transfer RNA (tRNA) adapter
anti-codons of the
molecules in binding pockets within the ribosome. The new polypeptide then folds into a appropriate tRNA. Newly
functional three-dimensional protein molecule. synthesized proteins
(black) are often further
modified, such as by
Movement or motility binding to an effector
molecule (orange), to
Cells can move during many processes: such as wound healing, the immune response become fully active.
and cancer metastasis. For wound healing to occur, white blood cells and cells that ingest
bacteria move to the wound site to kill the microorganisms that cause infection.
At the same time fibroblasts (connective tissue cells) move there to remodel damaged structures. In the case of tumor
development, cells from a primary tumor move away and spread to other parts of the body. Cell motility involves
many receptors, crosslinking, bundling, binding, adhesion, motor and other proteins.[8] The process is divided into
three steps – protrusion of the leading edge of the cell, adhesion of the leading edge and de-adhesion at the cell body
and rear, and cytoskeletal contraction to pull the cell forward. Each step is driven by physical forces generated by
unique segments of the cytoskeleton.[9][10]
Cell (biology) 99

Origins
The origin of cells has to do with the origin of life, which began the history of life on Earth.

Origin of the first cell


There are several theories about the origin of small molecules that could lead to life in an early Earth. One is that
they came from meteorites (see Murchison meteorite). Another is that they were created at deep-sea vents. A third is
that they were synthesized by lightning in a reducing atmosphere (see Miller–Urey experiment); although it is not
clear if Earth had such an atmosphere. There are essentially no experimental data defining what the first
self-replicating forms were. RNA is generally assumed the earliest self-replicating molecule, as it is capable of both
storing genetic information and catalyzing chemical reactions (see RNA world hypothesis). But some other entity
with the potential to self-replicate could have preceded RNA, like clay or peptide nucleic acid.[11]
Cells emerged at least 4.0–4.3 billion years ago. The current belief is that these cells were heterotrophs. An
important characteristic of cells is the cell membrane, composed of a bilayer of lipids. The early cell membranes
were probably more simple and permeable than modern ones, with only a single fatty acid chain per lipid. Lipids are
known to spontaneously form bilayered vesicles in water, and could have preceded RNA, but the first cell
membranes could also have been produced by catalytic RNA, or even have required structural proteins before they
could form.[12]

Origin of eukaryotic cells


The eukaryotic cell seems to have evolved from a symbiotic community of prokaryotic cells. DNA-bearing
organelles like the mitochondria and the chloroplasts are almost certainly what remains of ancient symbiotic
oxygen-breathing proteobacteria and cyanobacteria, respectively, where the rest of the cell appears derived from an
ancestral archaean prokaryote cell—an idea called the endosymbiotic theory.
There is still considerable debate about whether organelles like the hydrogenosome predated the origin of
mitochondria, or viceversa: see the hydrogen hypothesis for the origin of eukaryotic cells.
Sex, as the stereotyped choreography of meiosis and syngamy that persists in nearly all extant eukaryotes, may have
played a role in the transition from prokaryotes to eukaryotes. An 'origin of sex as vaccination' theory suggests that
the eukaryote genome accreted from prokaryan parasite genomes in numerous rounds of lateral gene transfer.
Sex-as-syngamy (fusion sex) arose when infected hosts began swapping nuclearized genomes containing co-evolved,
vertically transmitted symbionts that conveyed protection against horizontal infection by more virulent
symbionts.[13]

History of research
• 1632–1723: Antonie van Leeuwenhoek teaches himself to grind lenses, builds a microscope and draws protozoa,
such as Vorticella from rain water, and bacteria from his own mouth.
• 1665: Robert Hooke discovers cells in cork, then in living plant tissue using an early microscope.[4]
• 1839: Theodor Schwann and Matthias Jakob Schleiden elucidate the principle that plants and animals are made of
cells, concluding that cells are a common unit of structure and development, and thus founding the cell theory.
• The belief that life forms can occur spontaneously (generatio spontanea) is contradicted by Louis Pasteur
(1822–1895) (although Francesco Redi had performed an experiment in 1668 that suggested the same
conclusion).
• 1855: Rudolf Virchow states that cells always emerge from cell divisions (omnis cellula ex cellula).
• 1931: Ernst Ruska builds first transmission electron microscope (TEM) at the University of Berlin. By 1935, he
has built an EM with twice the resolution of a light microscope, revealing previously unresolvable organelles.
• 1953: Watson and Crick made their first announcement on the double-helix structure for DNA on February 28.
Cell (biology) 100

• 1981: Lynn Margulis published Symbiosis in Cell Evolution detailing the endosymbiotic theory.

References
[1] Cell Movements and the Shaping of the Vertebrate Body (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search& db=books&
doptcmdl=GenBookHL& term=Cell+ Movements+ and+ the+ Shaping+ of+ the+ Vertebrate+ Body+ AND+ mboc4[book]+ AND+
374635[uid]& rid=mboc4. section. 3919) in Chapter 21 of Molecular Biology of the Cell (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query.
fcgi?cmd=Search& db=books& doptcmdl=GenBookHL& term=cell+ biology+ AND+ mboc4[book]+ AND+ 373693[uid]& rid=mboc4)
fourth edition, edited by Bruce Alberts (2002) published by Garland Science.
The Alberts text discusses how the "cellular building blocks" move to shape developing embryos. It is also common to describe small
molecules such as amino acids as " molecular building blocks (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?cmd=Search&
db=books& doptcmdl=GenBookHL& term="all+ cells"+ AND+ mboc4[book]+ AND+ 372023[uid]& rid=mboc4. section. 4#23)".
[2] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[3] Maton, Anthea; Hopkins, Jean Johnson, Susan LaHart, David Quon Warner, Maryanna Wright, Jill D (1997). Cells Building Blocks of Life.
New Jersey: Prentice Hall. ISBN 0-13-423476-6.
[4] "... I could exceedingly plainly perceive it to be all perforated and porous, much like a Honey-comb, but that the pores of it were not regular
[..] these pores, or cells, [..] were indeed the first microscopical pores I ever saw, and perhaps, that were ever seen, for I had not met with any
Writer or Person, that had made any mention of them before this. . ." – Hooke describing his observations on a thin slice of cork. Robert
Hooke (http:/ / www. ucmp. berkeley. edu/ history/ hooke. html)
[5] Satir, P; Christensen, ST; Søren T. Christensen (2008-03-26). "Structure and function of mammalian cilia" (http:/ / www. springerlink. com/
content/ x5051hq648t3152q/ ). Histochemistry and Cell Biology (Springer Berlin / Heidelberg) 129 (6): 687–693.
doi:10.1007/s00418-008-0416-9. PMC 2386530. PMID 18365235. 1432-119X. . Retrieved 2009-09-12.
[6] Michie K, Löwe J (2006). "Dynamic filaments of the bacterial cytoskeleton". Annu Rev Biochem 75: 467–92.
doi:10.1146/annurev.biochem.75.103004.142452. PMID 16756499.
[7] Ménétret JF, Schaletzky J, Clemons WM, et al., CW; Akey (December 2007). "Ribosome binding of a single copy of the SecY complex:
implications for protein translocation". Mol. Cell 28 (6): 1083–92. doi:10.1016/j.molcel.2007.10.034. PMID 18158904.
[8] Revathi Ananthakrishnan1 *, Allen Ehrlicher2 ✉. "The Forces Behind Cell Movement" (http:/ / www. biolsci. org/ v03p0303. htm).
Biolsci.org. . Retrieved 2009-04-17.
[9] Alberts B, Johnson A, Lewis J. et al. Molecular Biology of the Cell, 4e. Garland Science. 2002
[10] Ananthakrishnan R, Ehrlicher A. The Forces Behind Cell Movement. Int J Biol Sci 2007; 3:303–317. http:/ / www. biolsci. org/ v03p0303.
htm
[11] Orgel LE (1998). "The origin of life--a review of facts and speculations". Trends Biochem Sci 23 (12): 491–5.
doi:10.1016/S0968-0004(98)01300-0. PMID 9868373.
[12] Griffiths G (December 2007). "Cell evolution and the problem of membrane topology". Nature reviews. Molecular cell biology 8 (12):
1018–24. doi:10.1038/nrm2287. PMID 17971839.
[13] Sterrer W (2002). "On the origin of sex as vaccination". Journal of Theoretical Biology 216: 387–396. doi:10.1006/jtbi.2002.3008.
PMID 12151256.

•  This article incorporates public domain material from the NCBI document "Science Primer" (http://www.
ncbi.nlm.nih.gov/About/primer/index.html).

External links
• Inside the Cell (http://publications.nigms.nih.gov/insidethecell/)
• Virtual Cell's Educational Animations (http://vcell.ndsu.nodak.edu/animations/)
• The Inner Life of A Cell (http://www.studiodaily.com/main/searchlist/6850.html), a flash video showing
what happens inside of a cell. Daniel Reda of Singularity University narrates (beginning at 22:24) (http://www.
youtube.com/watch?v=It83JKAxejM)
• The Virtual Cell (http://www.ibiblio.org/virtualcell/tour/cell/cell.htm)
• Cells Alive! (http://www.cellsalive.com/)
• Journal of Cell Biology (http://www.jcb.org/)
• The Biology Project > Cell Biology (http://www.biology.arizona.edu/cell_bio/cell_bio.html)
• Centre of the Cell online (http://www.centreofthecell.org/)
• The Image & Video Library of The American Society for Cell Biology (http://cellimages.ascb.org/), a
collection of peer-reviewed still images, video clips and digital books that illustrate the structure, function and
Cell (biology) 101

biology of the cell.


• HighMag Blog (http://highmagblog.blogspot.com/), still images of cells from recent research articles.
• New Microscope Produces Dazzling 3D Movies of Live Cells (http://www.hhmi.org/news/betzig20110304.
html), March 4, 2011 - Howard Hughes Medical Institute.
• WormWeb.org: Interactive Visualization of the C. elegans Cell lineage (http://wormweb.org/celllineage) -
Visualize the entire cell lineage tree of the nematode C. elegans

Textbooks
• Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). Molecular Biology of the Cell (http://www.
ncbi.nlm.nih.gov/books/bv.fcgi?rid=mboc4.TOC&depth=2) (4th ed.). Garland. ISBN 0-8153-3218-1.
• Lodish H, Berk A, Matsudaira P, Kaiser CA, Krieger M, Scott MP, Zipurksy SL, Darnell J (2004). Molecular
Cell Biology (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mcb.TOC) (5th ed.). WH Freeman: New
York, NY. ISBN 978-0-7167-4366-8.
• Cooper GM (2000). The cell: a molecular approach (http://www.ncbi.nlm.nih.gov/books/bv.
fcgi?rid=cooper.TOC&depth=2) (2nd ed.). Washington, D.C: ASM Press. ISBN 0-87893-102-3.

Cell biology
Cell biology (formerly cytology, from the Greek kytos, "contain") is a scientific discipline that studies cells – their
physiological properties, their structure, the organelles they contain, interactions with their environment, their life
cycle, division and death. This is done both on a microscopic and molecular level. Cell biology research
encompasses both the great diversity of single-celled organisms like bacteria and protozoa, as well as the many
specialized cells in multicellular organisms such as humans.
Knowing the components of cells and how cells work is fundamental to all biological sciences. Appreciating the
similarities and differences between cell types is particularly important to the fields of cell and molecular biology as
well as to biomedical fields such as cancer research and developmental biology. These fundamental similarities and
differences provide a unifying theme, sometimes allowing the principles learned from studying one cell type to be
extrapolated and generalized to other cell types. Therefore, research in cell biology is closely related to genetics,
biochemistry, molecular biology, immunology, and developmental biology.
Cell biology 102

Processes

Understanding cells in terms of their molecular components.

Movement of proteins
Each type of protein is usually sent to a particular part of the cell. An
important part of cell biology is the investigation of molecular
mechanisms by which proteins are moved to different places inside
cells or secreted from cells.
Most proteins are synthesized by ribosomes in the rough endoplasmic
reticulum.Ribosomes contain the nucleic acid RNA, which assembles
and joins amino acids to make proteins. They can be found alone or in
groups within the cytoplasm as well as on the RER. This process is
known as protein biosynthesis. Biosynthesis (also called biogenesis) is
an enzyme-catalyzed process in cells of living organisms by which
substrates are converted to more complex products (also simply known
Endothelial cells under the microscope. Nuclei as protein translation). Some proteins, such as those to be incorporated
are stained blue with DAPI, microtubles are in membranes (known as membrane proteins), are transported into the
marked green by an antibody and actin filaments
"rough" endoplasmic reticulum (ER) during synthesis. This process
are labelled red with phalloidin.
can be followed by transportation and processing in the Golgi
apparatus. The Golgi apparatus is a large organelle that processes
proteins and prepares them for use both inside and outside the cell. The Golgi apparatus is somewhat like a post
office. It receives items (proteins from the ER), packages and labels them, and then sends them on to their
destinations (to different parts of the cell or to the cell membrane for transport out of the cell).[1] From the Golgi,
membrane proteins can move to the plasma membrane, to other sub-cellular compartments, or they can be secreted
from the cell. The ER and Golgi can be thought of as the "membrane protein synthesis compartment" and the
"membrane protein processing compartment", respectively. There is a semi-constant flux of proteins through these
compartments. ER and Golgi-resident proteins associate with other proteins but remain in their respective
compartments. Other proteins "flow" through the ER and Golgi to the plasma membrane. Motor proteins transport
membrane protein-containing vesicles along cytoskeletal tracks to distant parts of cells such as axon terminals.
Cell biology 103

Some proteins that are made in the cytoplasm contain structural features that target them for transport into
mitochondria or the nucleus. Some mitochondrial proteins are made inside mitochondria and are coded for by
mitochondrial DNA. In plants, chloroplasts also make some cell proteins.
Extracellular and cell surface proteins destined to be degraded can move back into intracellular compartments upon
being incorporated into endocytosed vesicles some of which fuse with lysosomes where the proteins are broken
down to their individual amino acids. The degradation of some membrane proteins begins while still at the cell
surface when they are separated by secretases. Proteins that function in the cytoplasm are often degraded by
proteasomes.

Other cellular processes


• Active transport and Passive transport - Movement of molecules into and out of cells.
• Autophagy - The process whereby cells "eat" their own internal components or microbial invaders.
• Adhesion - Holding together cells and tissues.
• Reproduction - Made possible by the combination of sperm made in the testiculi (contained in some male cells'
nuclei) and the egg made in the ovary (contained in the nucleus of a female cell). When the sperm breaks through
the hard outer shell of the egg a new cell embryo is formed, which, in humans, grows to full size in 9 months.
• Cell movement: Chemotaxis, Contraction, cilia and flagella.
• Cell signaling - Regulation of cell behavior by signals from outside.
• DNA repair and Cell death
• Metabolism: Glycolysis, respiration, Photosynthesis
• Transcription and mRNA splicing - gene expression.

Internal cellular structures


• Chloroplast - key organelle for photosynthesis (only found in plant
cells)
• Cilium - motile microtubule-containing structure of eukaryotes
• Cytoplasm - contents of the main fluid-filled space inside cells
• Cytoskeleton - protein filaments inside cells
• Endoplasmic reticulum - major site of membrane protein synthesis
• Flagellum - motile structure of bacteria, archaea and eukaryotes
• Golgi apparatus - site of protein glycosylation in the endomembrane
system
• Lipid bilayer - fundamental organizational structure of cell membranes
• Lysosome - break down cellular waste products and debris into simple Electron micrograph.
compounds (only found in animal cells)
• Membrane lipid and protein barrier
• Mitochondrion - major energy-producing organelle by releasing it in the form of ATP
• Nucleus - holds most of the DNA of eukaryotic cells and controls all cellular activities
• Organelle - term used for major subcellular structures
• Ribosome - RNA and protein complex required for protein synthesis in cells
• Vesicle - small membrane-bounded spheres inside cells
Cell biology 104

Techniques used to study cells


Cells may be observed under the microscope. This includes
the Optical Microscope, Transmission Electron Microscope,
Scanning Electron Microscope, Fluorescence Microscope, and
by Confocal Microscopy.
Several different techniques exist to study cells are
• Cell culture is the basic technique of growing cells in a
laboratory independent of an organism.
• Immunostaining, also known as immunohistochemistry, is
a specialized histological method used to localize proteins
in cells or tissue slices. Unlike regular histology, which
uses stains to identify cells, cellular components or protein
classes, immunostaining requires the reaction of an
antibody directed against the protein of interest within the
tissue or cell. Through the use of proper controls and published protocols (need to add reference links here),
specificity of the antibody-antigen reaction can be achieved. Once this complex is formed, it is identified via
either a "tag" attached directly to the antibody, or added in an additional technical step. Commonly used "tags"
include fluorophores or enzymes. In the case of the former, detection of the location of the "immuno-stained"
protein occurs via fluorescence microscopy. With an enzymatic tag, such as horse radish peroxidase, a chemical
reaction is carried out that results in a dark color in the location of the protein of interest. This darkened pattern is
then detected using light microscopy.
• Computational genomics is used to find patterns in genomic information [2]
• DNA microarrays identify changes in transcript levels between different experimental conditions.
• Gene knockdown mutates a selected gene.
• In situ hybridization shows which cells are expressing a particular RNA transcript.
• PCR can be used to determine how many copies of a gene are present in a cell.
• Transfection introduces a new gene into a cell, usually an expression construct
Purification of cells and their parts Purification may be performed using the following methods:
• Cell fractionation
• Release of cellular organelles by disruption of cells.
• Separation of different organelles by centrifugation.
• Flow cytometry
• Immunoprecipitation
• Proteins extracted from cell membranes by detergents and salts or other kinds of chemicals.
Cell biology 105

References
• Cell and Molecular Biology by Karp 5th Ed., ISBN 0-471-46580-1
•  This article incorporates public domain material from the NCBI document "Science Primer" [3].
[1] Open Content Flexbook- Cellular Structure & functions(for ribosomes and Golgi body info) (http:/ / www. ck12. org/ flexbook/ chapter/
8485)
[2] Cristianini, N. and Hahn, M. Introduction to Computational Genomics (http:/ / www. computational-genomics. net/ ), Cambridge University
Press, 2006. (ISBN 9780521671910 | ISBN 0-521-67191-4)
[3] http:/ / www. ncbi. nlm. nih. gov/ About/ primer/ index. html

• Aging Cell (http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1474-9726)

External links
• Cell Centered Database (http://ccdb.ucsd.edu/sand/main?event=showMPByType&typeid=0&start=1&pl=y)
• Cell Biology (http://www.dmoz.org/Science/Biology/Cell_Biology/) at the Open Directory Project

Cell membrane
The cell membrane or plasma
membrane is a biological membrane that
separates the interior of all cells from the
outside environment.[1] The cell
membrane is selectively permeable to
ions and organic molecules and controls
the movement of substances in and out of
cells.[2] It basically protects the cell from
outside forces. It consists of the lipid
bilayer with embedded proteins. Cell
membranes are involved in a variety of
cellular processes such as cell adhesion,
ion conductivity and cell signaling and
serve as the attachment surface for
several extracellular structures, including
the cell wall, glycocalyx, and
intracellular cytoskeleton. Cell
membranes can be artificially
reassembled.[3][4][5]

Function
The cell membrane surrounds the Illustration of a Eukaryotic cell membrane
cytoplasm of a cell and, in animal cells,
physically separates the intracellular components from the extracellular environment. Fungi, bacteria and plants also
have the cell wall which provides a mechanical support for the cell and precludes the passage of larger molecules.
The cell membrane also plays a role in anchoring the cytoskeleton to provide shape to the cell, and in attaching to the
extracellular matrix and other cells to help group cells together to form tissues.
Cell membrane 106

The membrane is selectively permeable and able to regulate what enters and exits the cell, thus facilitating the
transport of materials needed for survival. The movement of substances across the membrane can be either "passive",
occurring without the input of cellular energy, or active, requiring the cell to expend energy in transporting it. The
membrane also maintains the cell potential. The cell membrane thus works as a selective filter that allows only
certain things to come inside or go outside the cell. Cell employs a number of transport mechanisms that involve
biological membranes:
1. Passive diffusion and osmosis: Some substances (small molecules, ions) such as carbon dioxide (CO2), oxygen
(O2), and water, can move across the plasma membrane by diffusion, which is a passive transport process. Because
the membrane acts as a barrier for certain molecules and ions, they can occur in different concentrations on the two
sides of the membrane. Such a concentration gradient across a semipermeable membrane sets up an osmotic flow for
the water.
2. Transmembrane protein channels and transporters: Nutrients, such as sugars or amino acids, must enter the cell,
and certain products of metabolism must leave the cell. Such molecules are pumped across the membrane by
transmembrane transporters or diffuse through protein channels. These proteins, also called permeases, are usually
quite specific, recognizing and transporting only a limited group of chemical substances, often even only a single
substance.
3. Endocytosis: Endocytosis is the process in which cells absorb molecules by engulfing them. The plasma
membrane creates a small deformation inward, called an invagination, in which the substance to be transported is
captured. The deformation then pinches off from the membrane on the inside of the cell, creating a vesicle
containing the captured substance. Endocytosis is a pathway for internalizing solid particles (cell eating or
phagocytosis), small molecules and ions (cell drinking or pinocytosis), and macromolecules. Endocytosis requires
energy and is thus a form of active transport.
4. Exocytosis: Just as material can be brought into the cell by invagination and formation of a vesicle, the membrane
of a vesicle can be fused with the plasma membrane, extruding its contents to the surrounding medium. This is the
process of exocytosis. Exocytosis occurs in various cells to remove undigested residues of substances brought in by
endocytosis, to secrete substances such as hormones and enzymes, and to transport a substance completely across a
cellular barrier. In the process of exocytosis, the undigested waste-containing food vacuole or the secretory vesicle
budded from Golgi apparatus, is first moved by cytoskeleton from the interior of the cell to the surface. The vesicle
membrane comes in contact with the plasma membrane. The lipid molecules of the two bilayers rearrange
themselves and the two membranes are, thus, fused. A passage is formed in the fused membrane and the vesicles
discharges its contents outside the cell.

Prokaryotes
Gram-negative bacteria have a plasma membrane and an outer membrane separated by a periplasmic space. Other
prokaryotic species have only a plasma membrane. Prokaryotic cells are also surrounded by a cell wall composed of
peptidoglycan (amino acid and sugar). Some eukaryotic cells also have cells walls, but none that are made of
peptidoglycan.

Structure

Fluid mosaic model


According to the fluid mosaic model of S.J. Singer and G.L. Nicolson (1972), which replaced the earlier model of
Davson and Danielli, biological membranes can be considered as a two-dimensional liquid in which lipid and protein
molecules diffuse more or less easily.[6] Although the lipid bilayers that form the basis of the membranes do indeed
form two-dimensional liquids by themselves, the plasma membrane also contains a large quantity of proteins, which
provide more structure. Examples of such structures are protein-protein complexes, pickets and fences formed by the
Cell membrane 107

actin-based cytoskeleton, and potentially lipid rafts.

Lipid bilayer
Lipid bilayers form through the process of self-assembly. The cell
membrane consists primarily of a thin layer of amphipathic
phospholipids which spontaneously arrange so that the
hydrophobic "tail" regions are isolated from the surrounding polar
fluid, causing the more hydrophilic "head" regions to associate
with the intracellular (cytosolic) and extracellular faces of the
resulting bilayer. This forms a continuous, spherical lipid bilayer.
Forces such as van der Waals, electrostatic, hydrogen bonds, and Diagram of the arrangement of amphipathic lipid
noncovalent interactions, are all forces that contribute to the molecules to form a lipid bilayer. The yellow polar
head groups separate the grey hydrophobic tails from
formation of the lipid bilayer. Overall, hydrophobic interactions
the aqueous cytosolic and extracellular environments.
are the major driving force in the formation of lipid bilayers.

Lipid bilayers are generally impermeable to ions and polar molecules. The arrangement of hydrophilic heads and
hydrophobic tails of the lipid bilayer prevent polar solutes (e.g. amino acids, nucleic acids, carbohydrates, proteins,
and ions) from diffusing across the membrane, but generally allows for the passive diffusion of hydrophobic
molecules. This affords the cell the ability to control the movement of these substances via transmembrane protein
complexes such as pores, channels and gates.
Flippases and scramblases concentrate phosphatidyl serine, which carries a negative charge, on the inner membrane.
Along with NANA, this creates an extra barrier to charged moieties moving through the membrane.
Membranes serve diverse functions in eukaryotic and prokaryotic cells. One important role is to regulate the
movement of materials into and out of cells. The phospholipid bilayer structure (fluid mosaic model) with specific
membrane proteins accounts for the selective permeability of the membrane and passive and active transport
mechanisms. In addition, membranes in prokaryotes and in the mitochondria and chloroplasts of eukaryotes facilitate
the synthesis of ATP through chemiosmosis.

Membrane polarity
The apical membrane of a polarized cell is
the surface of the plasma membrane that
faces the lumen. This is particularly evident
in epithelial and endothelial cells, but also
describes other polarized cells, such as
neurons. The basolateral membrane of a
polarized cell is the surface of the plasma
membrane that forms its basal and lateral
surfaces. It faces outwards, towards the
interstitium, and away from the lumen.
Basolateral membrane is a compound phrase
referring to the terms "basal (base)
membrane" and "lateral (side) membrane",
which, especially in epithelial cells, are
identical in composition and activity. Alpha intercalated cell
Cell membrane 108

Proteins (such as ion channels and pumps) are free to move from the basal to the lateral surface of the cell or vice
versa in accordance with the fluid mosaic model. Tight junctions join epithelial cells near their apical surface to
prevent the migration of proteins from the basolateral membrane to the apical membrane. The basal and lateral
surfaces thus remain roughly equivalent to one another, yet distinct from the apical surface.

Membrane structures
Cell membrane can form different types of "supramembrane" structures such as caveola, postsynaptic density,
podosome, invadopodium, focal adhesion, and different types of cell junctions. These structures are usually
responsible for cell adhesion, communication, endocytosis and exocytosis. They can be visualized by electron
microscopy or fluorescence microscopy. They are composed of specific proteins, such as integrins and cadherins.

Cytoskeleton
The cytoskeleton is found underlying the cell membrane in the cytoplasm and provides a scaffolding for membrane
proteins to anchor to, as well as forming organelles that extend from the cell. Indeed, cytoskeletal elements interact
extensively and intimately with the cell membrane.[7] Anchoring proteins restricts them to a particular cell surface —
for example, the apical surface of epithelial cells that line the vertebrate gut — and limits how far they may diffuse
within the bilayer. The cytoskeleton is able to form appendage-like organelles, such as cilia, which are
microtubule-based extensions covered by the cell membrane, and filopodia, which are actin-based extensions. These
extensions are ensheathed in membrane and project from the surface of the cell in order to sense the external
environment and/or make contact with the substrate or other cells. The apical surfaces of epithelial cells are dense
with actin-based finger-like projections known as microvilli, which increase cell surface area and thereby increase
the absorption rate of nutrients. Localized decoupling of the cytoskeleton and cell membrane results in formation of
a bleb.

Composition
Cell membranes contain a variety of biological molecules, notably lipids and proteins. Material is incorporated into
the membrane, or deleted from it, by a variety of mechanisms:
• Fusion of intracellular vesicles with the membrane (exocytosis) not only excretes the contents of the vesicle but
also incorporates the vesicle membrane's components into the cell membrane. The membrane may form blebs
around extracellular material that pinch off to become vesicles (endocytosis).
• If a membrane is continuous with a tubular structure made of membrane material, then material from the tube can
be drawn into the membrane continuously.
• Although the concentration of membrane components in the aqueous phase is low (stable membrane components
have low solubility in water), there is an exchange of molecules between the lipid and aqueous phases.
Cell membrane 109

Lipids
The cell membrane consists of three
classes of amphipathic lipids:
phospholipids, glycolipids, and
cholesterols. The amount of each depends
upon the type of cell, but in the majority
of cases phospholipids are the most
abundant.[8] In RBC studies, 30% of the
plasma membrane is lipid.

The fatty chains in phospholipids and


glycolipids usually contain an even
number of carbon atoms, typically
between 16 and 20. The 16- and
18-carbon fatty acids are the most
common. Fatty acids may be saturated or
unsaturated, with the configuration of the
double bonds nearly always "cis". The
length and the degree of unsaturation of
fatty acid chains have a profound effect
on membrane fluidity[9] as unsaturated
lipids create a kink, preventing the fatty
Examples of the major membrane phospholipids and glycolipids: phosphatidylcholine
acids from packing together as tightly,
(PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns),
thus decreasing the melting temperature phosphatidylserine (PtdSer).
(increasing the fluidity) of the membrane.
The ability of some organisms to regulate the fluidity of their cell membranes by altering lipid composition is called
homeoviscous adaptation.

The entire membrane is held together via non-covalent interaction of hydrophobic tails, however the structure is
quite fluid and not fixed rigidly in place. Under physiological conditions phospholipid molecules in the cell
membrane are in the liquid crystalline state. It means the lipid molecules are free to diffuse and exhibit rapid lateral
diffusion along the layer in which they are present. However, the exchange of phospholipid molecules between
intracellular and extracellular leaflets of the bilayer is a very slow process. Lipid rafts and caveolae are examples of
cholesterol-enriched microdomains in the cell membrane.

In animal cells cholesterol is normally found dispersed in varying degrees throughout cell membranes, in the
irregular spaces between the hydrophobic tails of the membrane lipids, where it confers a stiffening and
strengthening effect on the membrane.[2]

Phospholipids forming lipid vesicles


Lipid vesicles or liposomes are circular pockets that are enclosed by a lipid bilayer. These structures are used in
laboratories to study the effects of chemicals in cells by delivering these chemicals directly to the cell, as well as
getting more insight into cell membrane permeability. Lipid vesicles and liposomes are formed by first suspending a
lipid in an aqueous solution then agitating the mixture through sonication, resulting in a vesicle. By measuring the
rate of efflux from that of the inside of the vesicle to the ambient solution, allows researcher to better understand
membrane permeability. Vesicles can be formed with molecules and ions inside the vesicle by forming the vesicle
with the desired molecule or ion present in the solution. Proteins can also be embedded into the membrane through
solubilizing the desired proteins in the presence of detergents and attaching them to the phospholipids in which the
Cell membrane 110

liposome is formed. These provide researchers with a tool to examine various membrane protein functions.

Carbohydrates
Plasma membranes also contain carbohydrates, predominantly glycoproteins, but with some glycolipids
(cerebrosides and gangliosides). For the most part, no glycosylation occurs on membranes within the cell; rather
generally glycosylation occurs on the extracellular surface of the plasma membrane. The glycocalyx is an important
feature in all cells, especially epithelia with microvilli. Recent data suggest the glycocalyx participates in cell
adhesion, lymphocyte homing, and many others. The penultimate sugar is galactose and the terminal sugar is sialic
acid, as the sugar backbone is modified in the golgi apparatus. Sialic acid carries a negative charge, providing an
external barrier to charged particles.

Proteins

Type Description Examples

Integral proteins Span the membrane and have a hydrophilic cytosolic domain, which interacts with internal Ion channels, proton
or molecules, a hydrophobic membrane-spanning domain that anchors it within the cell pumps, G
transmembrane membrane, and a hydrophilic extracellular domain that interacts with external molecules. The protein-coupled
proteins hydrophobic domain consists of one, multiple, or a combination of α-helices and β sheet receptor
protein motifs.

Lipid anchored Covalently bound to single or multiple lipid molecules; hydrophobically insert into the cell G proteins
proteins membrane and anchor the protein. The protein itself is not in contact with the membrane.

Peripheral Attached to integral membrane proteins, or associated with peripheral regions of the lipid Some enzymes, some
proteins bilayer. These proteins tend to have only temporary interactions with biological membranes, hormones
and, once reacted the molecule, dissociates to carry on its work in the cytoplasm.

The cell membrane has large content of proteins, typically around 50% of membrane volume[9] These proteins are
important for cell because they are responsible for various biological activities. Approximately a third of the genes in
yeast code specifically for them, and this number is even higher in multicellular organisms.[8]
The cell membrane, being exposed to the outside environment, is an important site of cell-cell communication. As
such, a large variety of protein receptors and identification proteins, such as antigens, are present on the surface of
the membrane. Functions of membrane proteins can also include cell-cell contact, surface recognition, cytoskeleton
contact, signaling, enzymatic activity, or transporting substances across the membrane.
Most membrane proteins must be inserted in some way into the membrane. For this to occur, an N-terminus "signal
sequence" of amino acids directs proteins to the endoplasmic reticulum, which inserts the proteins into a lipid
bilayer. Once inserted, the proteins are then transported to their final destination in vesicles, where the vesicle fuses
with the target membrane.

Variation
The cell membrane has different lipid and protein compositions in distinct types of cells and may have therefore
specific names for certain cell types:
• Sarcolemma in myocytes
• Oolemma in oocytes
• Axolemma in neuronal processes - axons
• Historically, the plasma membrane was also referred to as the plasmalemma
Cell membrane 111

Permeability
The permeability of a membrane is the rate of passive diffusion of molecules through the membrane. These
molecules are known as permeant molecules. Permeability depends mainly on the electric charge and polarity of the
molecule and to a lesser extent the molar mass of the molecule. Due to the cell membrane's hydrophobic nature,
small electrically neutral molecules pass through the membrane easier than charged, large ones. The inability of
charged molecules to pass through the cell membrane results in pH partition of substances throughout the fluid
compartments of the body.

References
[1] Kimball's Biology Pages (http:/ / users. rcn. com/ jkimball. ma. ultranet/ BiologyPages/ C/ CellMembranes. html), Cell Membranes
[2] Alberts B, Johnson A, Lewis J, et al. (2002). Molecular Biology of the Cell (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=mboc4.
section. 1864) (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1. .
[3] Budin, Itay; Devaraj, Neal K. (December 29, 2011). "Membrane Assembly Driven by a Biomimetic Coupling Reaction" (http:/ / pubs. acs.
org/ doi/ abs/ 10. 1021/ ja2076873). Journal of the American Chemical Society 134 (2): 751–753. doi:10.1021/ja2076873. . Retrieved
February 18, 2012.
[4] Staff (January 25, 2012). "Chemists Synthesize Artificial Cell Membrane" (http:/ / www. sciencedaily. com/ releases/ 2012/ 01/
120125132822. htm). ScienceDaily. . Retrieved February 18, 2012.
[5] Staff (January 26, 2012). "Chemists create artificial cell membrane" (http:/ / www. kurzweilai. net/ chemists-create-artificial-cell-membrane).
kurzweilai.net. . Retrieved February 18, 2012.
[6] Singer SJ, Nicolson GL (Feb 1972). "The fluid mosaic model of the structure of cell membranes" (http:/ / www. sciencemag. org/ cgi/
content/ abstract/ 175/ 4023/ 720). Science 175 (4023): 720–31. doi:10.1126/science.175.4023.720. PMID 4333397. .
[7] Doherty GJ and McMahon HT (2008). "Mediation, Modulation and Consequences of Membrane-Cytoskeleton Interactions" (http:/ /
arjournals. annualreviews. org/ doi/ abs/ 10. 1146/ annurev. biophys. 37. 032807. 125912). Annual Review of Biophysics 37: 65–95.
doi:10.1146/annurev.biophys.37.032807.125912. PMID 18573073. .
[8] Lodish H, Berk A, Zipursky LS, et al. (2004). Molecular Cell Biology (4th ed.). New York: Scientific American Books.
ISBN 0-7167-3136-3.
[9] Jesse Gray, Shana Groeschler, Tony Le, Zara Gonzalez (2002). "Membrane Structure" (http:/ / www. bio. davidson. edu/ people/
macampbell/ 111/ memb-swf/ membranes. swf) (SWF). Davidson College. . Retrieved 2007-01-11.

External links
• Lipids, Membranes and Vesicle Trafficking - The Virtual Library of Biochemistry and Cell Biology (http://
www.biochemweb.org/lipids_membranes.shtml)
• Cell membrane protein extraction protocol (http://www.westernblotting.org/protocol membrane extraction.
htm)
• Membrane homeostasis, tension regulation, mechanosensitive membrane exchange and membrane traffic (http://
www.phys.unsw.edu.au/~jw/tension.html)
• 3D structures of proteins associated with plasma membrane of eukaryotic cells (http://opm.phar.umich.edu/
localization.php?localization=Eukaryotic plasma membrane)
• Lipid composition and proteins of some eukariotic membranes (http://opm.phar.umich.edu/atlas.
php?membrane=Eukaryotic plasma membrane)
• (http://www.etap.org/demo/biology1/instruction3tutor.html)
Cell nucleus 112

Cell nucleus
In cell biology, the nucleus (pl. nuclei;
from Latin nucleus or nuculeus,
meaning kernel) is a
membrane-enclosed organelle found in
eukaryotic cells. It contains most of the
cell's genetic material, organized as
multiple long linear DNA molecules in
complex with a large variety of
proteins, such as histones, to form
chromosomes. The genes within these
chromosomes are the cell's nuclear
genome. The function of the nucleus is
to maintain the integrity of these genes
and to control the activities of the cell
by regulating gene expression — the
nucleus is, therefore, the control center HeLa cells stained for the cell nucleus DNA with the Blue Hoechst dye. The central and
of the cell. The main structures making rightmost cell are in interphase, thus their entire nuclei are labeled. On the left, a cell is
up the nucleus are the nuclear going through mitosis and its DNA has condensed ready for division.

envelope, a double membrane that


encloses the entire organelle and
unifies its contents from the cellular
cytoplasm, and the nucleoskeleton
(which includes nuclear lamina), a
meshwork within the nucleus that adds
mechanical support, much like the
cytoskeleton, which supports the cell
as a whole. Because the nuclear
membrane is impermeable to large
molecules, nuclear pores are required
to allow movement of molecules
across the envelope. These pores cross
both of the membranes, providing a
Schematic of typical animal cell, showing subcellular components. Organelles: (1)
channel that allows free movement of
Nucleolus (2) Nucleus (3) Ribosomes (little dots) (4) Vesicle (5) Rough endoplasmic
small molecules and ions. The reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) Smooth ER (9) Mitochondria
movement of larger molecules such as (10) Vacuole (11) Cytosol (12) Lysosome (13) Centrioles within Centrosome
proteins is carefully controlled, and
requires active transport regulated by carrier proteins. Nuclear transport is crucial to cell function, as movement
through the pores is required for both gene expression and chromosomal maintenance. The interior of the nucleus
does not contain any membrane-bound subcompartments, its contents are not uniform, and a number of subnuclear
bodies exist, made up of unique proteins, RNA molecules, and particular parts of the chromosomes. The best-known
of these is the nucleolus, which is mainly involved in the assembly of ribosomes. After being produced in the
nucleolus, ribosomes are exported to the cytoplasm where they translate mRNA.
Cell nucleus 113

History
The nucleus was the first organelle to be
discovered. What is most likely the oldest
preserved drawing dates back to the early
microscopist Antonie van Leeuwenhoek (1632 –
1723). He observed a "Lumen", the nucleus, in the
red blood cells of salmon.[1] Unlike mammalian
Oldest known depiction of cells and their nuclei by Antonie van red blood cells, those of other vertebrates still
Leeuwenhoek, 1719. possess nuclei. The nucleus was also described by
Franz Bauer in 1804[2] and in more detail in 1831
by Scottish botanist Robert Brown in a talk at the
Linnean Society of London. Brown was studying
orchids under microscope when he observed an
opaque area, which he called the areola or nucleus,
in the cells of the flower's outer layer.[3] He did not
suggest a potential function. In 1838, Matthias
Schleiden proposed that the nucleus plays a role in
generating cells, thus he introduced the name
"Cytoblast" (cell builder). He believed that he had
observed new cells assembling around
"cytoblasts". Franz Meyen was a strong opponent
of this view, having already described cells
Drawing of a Chironomus salivary gland cell multiplying by division and believing that many
published by Walther Flemming in 1882. The
cells would have no nuclei. The idea that cells can
nucleus contains Polytene chromosomes.
be generated de novo, by the "cytoblast" or
otherwise, contradicted work by Robert Remak
(1852) and Rudolf Virchow (1855) who decisively propagated the new paradigm that cells are generated solely by
cells ("Omnis cellula e cellula"). The function of the nucleus remained unclear.[4]

Between 1877 and 1878, Oscar Hertwig published several studies on the fertilization of sea urchin eggs, showing
that the nucleus of the sperm enters the oocyte and fuses with its nucleus. This was the first time it was suggested
that an individual develops from a (single) nucleated cell. This was in contradiction to Ernst Haeckel's theory that the
complete phylogeny of a species would be repeated during embryonic development, including generation of the first
nucleated cell from a "Monerula", a structureless mass of primordial mucus ("Urschleim"). Therefore, the necessity
of the sperm nucleus for fertilization was discussed for quite some time. However, Hertwig confirmed his
observation in other animal groups, e.g., amphibians and molluscs. Eduard Strasburger produced the same results for
plants (1884). This paved the way to assign the nucleus an important role in heredity. In 1873, August Weismann
postulated the equivalence of the maternal and paternal germ cells for heredity. The function of the nucleus as carrier
of genetic information became clear only later, after mitosis was discovered and the Mendelian rules were
rediscovered at the beginning of the 20th century; the chromosome theory of heredity was developed.[4]
Cell nucleus 114

Structures
The nucleus is the largest cellular organelle in animals.[5] In mammalian cells, the average diameter of the nucleus is
approximately 6 micrometers (μm), which occupies about 10% of the total cell volume.[6] The viscous liquid within
it is called nucleoplasm, and is similar in composition to the cytosol found outside the nucleus.[7] It appears as a
dense, roughly spherical organelle.

Nuclear envelope and pores

The eukaryotic cell nucleus. Visible in this diagram are the A cross section of a nuclear pore on the surface of the nuclear
ribosome-studded double membranes of the nuclear envelope, the envelope (1). Other diagram labels show (2) the outer ring, (3)
DNA (complexed as chromatin), and the nucleolus. Within the cell spokes, (4) basket, and (5) filaments.
nucleus is a viscous liquid called nucleoplasm, similar to the
cytoplasm found outside the nucleus.

The outer envelope, otherwise known as nuclear membrane, consists of two cellular membranes, an inner and an
outer membrane, arranged parallel to one another and separated by 10 to 50 nanometers (nm). The nuclear envelope
completely encloses the nucleus and separates the cell's genetic material from the surrounding cytoplasm, serving as
a barrier to prevent macromolecules from diffusing freely between the nucleoplasm and the cytoplasm.[8] The outer
nuclear membrane is continuous with the membrane of the rough endoplasmic reticulum (RER), and is similarly
studded with ribosomes.[8] The space between the membranes is called the perinuclear space and is continuous with
the RER lumen.
Nuclear pores, which provide aqueous channels through the envelope, are composed of multiple proteins,
collectively referred to as nucleoporins. The pores are about 125 million daltons in molecular weight and consist of
around 50 (in yeast) to 100 proteins (in vertebrates).[5] The pores are 100 nm in total diameter; however, the gap
through which molecules freely diffuse is only about 9 nm wide, due to the presence of regulatory systems within the
center of the pore. This size allows the not-free passage of small water-soluble molecules while preventing larger
molecules, such as nucleic acids and larger proteins, from inappropriately entering or exiting the nucleus. These
large molecules must be actively transported into the nucleus instead. The nucleus of a typical mammalian cell will
have about 3000 to 4000 pores throughout its envelope,[9] each of which contains a donut-shaped,
eightfold-symmetric ring-shaped structure at a position where the inner and outer membranes fuse.[10] Attached to
the ring is a structure called the nuclear basket that extends into the nucleoplasm, and a series of filamentous
extensions that reach into the cytoplasm. Both structures serve to mediate binding to nuclear transport proteins.[5]
Most proteins, ribosomal subunits, and some DNAs are transported through the pore complexes in a process
mediated by a family of transport factors known as karyopherins. Those karyopherins that mediate movement into
Cell nucleus 115

the nucleus are also called importins, whereas those that mediate movement out of the nucleus are called exportins.
Most karyopherins interact directly with their cargo, although some use adaptor proteins.[11] Steroid hormones such
as cortisol and aldosterone, as well as other small lipid-soluble molecules involved in intercellular signaling, can
diffuse through the cell membrane and into the cytoplasm, where they bind nuclear receptor proteins that are
trafficked into the nucleus. There they serve as transcription factors when bound to their ligand; in the absence of
ligand, many such receptors function as histone deacetylases that repress gene expression.[5]

Nuclear lamina
In animal cells, two networks of intermediate filaments provide the nucleus with mechanical support: The nuclear
lamina forms an organized meshwork on the internal face of the envelope, while less organized support is provided
on the cytosolic face of the envelope. Both systems provide structural support for the nuclear envelope and
anchoring sites for chromosomes and nuclear pores.[6]
The nuclear lamina is composed mostly of lamin proteins. Like all proteins, lamins are synthesized in the cytoplasm
and later transported into the nucleus interior, where they are assembled before being incorporated into the existing
network of nuclear lamina.[12][13] Lamins found on the cytosolic face of the membrane, such as emerin and nesprin,
bind to the cytoskeleton to provide structural support. Lamins are also found inside the nucleoplasm where they form
another regular structure, known as the nucleoplasmic veil,[14] that is visible using fluorescence microscopy. The
actual function of the veil is not clear, although it is excluded from the nucleolus and is present during interphase.[15]
Lamin structures that make up the veil, such as LEM3, bind chromatin and disrupting their structure inhibits
transcription of protein-coding genes.[16]
Like the components of other intermediate filaments, the lamin monomer contains an alpha-helical domain used by
two monomers to coil around each other, forming a dimer structure called a coiled coil. Two of these dimer
structures then join side by side, in an antiparallel arrangement, to form a tetramer called a protofilament. Eight of
these protofilaments form a lateral arrangement that is twisted to form a ropelike filament. These filaments can be
assembled or disassembled in a dynamic manner, meaning that changes in the length of the filament depend on the
competing rates of filament addition and removal.[6]
Mutations in lamin genes leading to defects in filament assembly are known as laminopathies. The most notable
laminopathy is the family of diseases known as progeria, which causes the appearance of premature aging in its
sufferers. The exact mechanism by which the associated biochemical changes give rise to the aged phenotype is not
well understood.[17]
Cell nucleus 116

Chromosomes
The cell nucleus contains the majority of the cell's genetic material
in the form of multiple linear DNA molecules organized into
structures called chromosomes. Each human cell contains 2m of
DNA. During most of the cell cycle these are organized in a
DNA-protein complex known as chromatin, and during cell
division the chromatin can be seen to form the well-defined
chromosomes familiar from a karyotype. A small fraction of the
cell's genes are located instead in the mitochondria.

There are two types of chromatin. Euchromatin is the less compact


DNA form, and contains genes that are frequently expressed by
the cell.[18] The other type, heterochromatin, is the more compact
form, and contains DNA that are infrequently transcribed. This
structure is further categorized into facultative heterochromatin, A mouse fibroblast nucleus in which DNA is stained
consisting of genes that are organized as heterochromatin only in blue. The distinct chromosome territories of
chromosome 2 (red) and chromosome 9 (green) are
certain cell types or at certain stages of development, and
stained with fluorescent in situ hybridization.
constitutive heterochromatin that consists of chromosome
structural components such as telomeres and centromeres.[19]
During interphase the chromatin organizes itself into discrete individual patches,[20] called chromosome
territories.[21] Active genes, which are generally found in the euchromatic region of the chromosome, tend to be
located towards the chromosome's territory boundary.[22]

Antibodies to certain types of chromatin organization, in particular, nucleosomes, have been associated with a
number of autoimmune diseases, such as systemic lupus erythematosus.[23] These are known as anti-nuclear
antibodies (ANA) and have also been observed in concert with multiple sclerosis as part of general immune system
dysfunction.[24] As in the case of progeria, the role played by the antibodies in inducing the symptoms of
autoimmune diseases is not obvious.

Nucleolus
The nucleolus is a discrete densely stained structure found in the
nucleus. It is not surrounded by a membrane, and is sometimes
called a suborganelle. It forms around tandem repeats of rDNA,
DNA coding for ribosomal RNA (rRNA). These regions are called
nucleolar organizer regions (NOR). The main roles of the
nucleolus are to synthesize rRNA and assemble ribosomes. The
structural cohesion of the nucleolus depends on its activity, as
ribosomal assembly in the nucleolus results in the transient
association of nucleolar components, facilitating further ribosomal
assembly, and hence further association. This model is supported
by observations that inactivation of rDNA results in intermingling
of nucleolar structures.[25]

An electron micrograph of a cell nucleus, showing the In the first step of ribosome assembly, a protein called RNA
darkly stained nucleolus. polymerase I transcribes rDNA, which forms a large pre-rRNA
precursor. This is cleaved into the subunits 5.8S, 18S, and 28S
Cell nucleus 117

rRNA.[26] The transcription, post-transcriptional processing, and assembly of rRNA occurs in the nucleolus, aided
by small nucleolar RNA (snoRNA) molecules, some of which are derived from spliced introns from messenger
RNAs encoding genes related to ribosomal function. The assembled ribosomal subunits are the largest structures
passed through the nuclear pores.[5]
When observed under the electron microscope, the nucleolus can be seen to consist of three distinguishable regions:
the innermost fibrillar centers (FCs), surrounded by the dense fibrillar component (DFC), which in turn is bordered
by the granular component (GC). Transcription of the rDNA occurs either in the FC or at the FC-DFC boundary,
and, therefore, when rDNA transcription in the cell is increased, more FCs are detected. Most of the cleavage and
modification of rRNAs occurs in the DFC, while the latter steps involving protein assembly onto the ribosomal
subunits occur in the GC.[21]

Other subnuclear bodies

Structure name Structure diameter


Cajal bodies 0.2–2.0 µm [27]

PIKA 5 µm [28]

PML bodies 0.2–1.0 µm [29]

Paraspeckles 0.2–1.0 µm [30]

Speckles 20–25 nm [28]

|+ Subnuclear structure sizes Besides the nucleolus, the nucleus contains a number of other
non-membrane-delineated bodies. These include Cajal bodies, Gemini of coiled bodies, polymorphic interphase
karyosomal association (PIKA), promyelocytic leukaemia (PML) bodies, paraspeckles, and splicing speckles.
Although little is known about a number of these domains, they are significant in that they show that the
nucleoplasm is not uniform mixture, but rather contains organized functional subdomains.[29]
Other subnuclear structures appear as part of abnormal disease processes. For example, the presence of small
intranuclear rods has been reported in some cases of nemaline myopathy. This condition typically results from
mutations in actin, and the rods themselves consist of mutant actin as well as other cytoskeletal proteins.[31]

Cajal bodies and gems


A nucleus typically contains between 1 and 10 compact structures called Cajal bodies or coiled bodies (CB), whose
diameter measures between 0.2 µm and 2.0 µm depending on the cell type and species.[27] When seen under an
electron microscope, they resemble balls of tangled thread[28] and are dense foci of distribution for the protein
coilin.[32] CBs are involved in a number of different roles relating to RNA processing, specifically small nucleolar
RNA (snoRNA) and small nuclear RNA (snRNA) maturation, and histone mRNA modification.[27]
Similar to Cajal bodies are Gemini of coiled bodies, or gems, whose name is derived from the Gemini constellation
in reference to their close "twin" relationship with CBs. Gems are similar in size and shape to CBs, and in fact are
virtually indistinguishable under the microscope.[32] Unlike CBs, gems do not contain small nuclear
ribonucleoproteins (snRNPs), but do contain a protein called survivor of motor neurons (SMN) whose function
relates to snRNP biogenesis. Gems are believed to assist CBs in snRNP biogenesis,[33] though it has also been
suggested from microscopy evidence that CBs and gems are different manifestations of the same structure.[32]
Cell nucleus 118

RAFA and PTF domains


RAFA domains, or polymorphic interphase karyosomal associations, were first described in microscopy studies in
1991. Their function was and remains unclear, though they were not thought to be associated with active DNA
replication, transcription, or RNA processing.[34] They have been found to often associate with discrete domains
defined by dense localization of the transcription factor PTF, which promotes transcription of snRNA.[35]

PML bodies
Promyelocytic leukaemia bodies (PML bodies) are spherical bodies found scattered throughout the nucleoplasm,
measuring around 0.2–1.0 µm. They are known by a number of other names, including nuclear domain 10 (ND10),
Kremer bodies, and PML oncogenic domains. They are often seen in the nucleus in association with Cajal bodies
and cleavage bodies. It has been suggested that they play a role in regulating transcription.[29]

Paraspeckles
Discovered by Fox et al. in 2002, paraspeckles are irregularly shaped compartments in the nucleus' interchromatin
space.[36] First documented in HeLa cells, where there are generally 10–30 per nucleus,[37] paraspeckles are now
known to also exist in all human primary cells, transformed cell lines, and tissue sections.[38] Their name is derived
from their distribution in the nucleus; the "para" is short for parallel and the "speckles" refers to the splicing speckles
to which they are always in close proximity.[37]
Paraspeckles are dynamic structures that are altered in response to changes in cellular metabolic activity. They are
transcription dependent[36] and in the absence of RNA Pol II transcription, the paraspeckle disappears and all of its
associated protein components (PSP1, p54nrb, PSP2, CFI(m)68, and PSF) form a crescent shaped perinucleolar cap
in the nucleolus. This phenomenon is demonstrated during the cell cycle. In the cell cycle, paraspeckles are present
during interphase and during all of mitosis except for telophase. During telophase, when the two daughter nuclei are
formed, there is no RNA Pol II transcription so the protein components instead form a perinucleolar cap.[38]

Splicing speckles
Speckles are subnuclear structures that are enriched in pre-messenger RNA splicing factors and are located in the
interchromatin regions of the nucleoplasm of mammalian cells. At the fluorescence-microscope level they appear as
irregular, punctate structures, which vary in size and shape, and when examined by electron microscopy they are
seen as clusters of interchromatin granules. Speckles are dynamic structures, and both their protein and RNA-protein
components can cycle continuously between speckles and other nuclear locations, including active transcription
sites. Studies on the composition, structure and behaviour of speckles have provided a model for understanding the
functional compartmentalization of the nucleus and the organization of the gene-expression machinery.[39]
Sometimes referred to as interchromatin granule clusters or as splicing-factor compartments, speckles are rich in
splicing snRNPs[40][41] and other splicing proteins necessary for pre-mRNA processing.[42] Because of a cell's
changing requirements, the composition and location of these bodies changes according to mRNA transcription and
regulation via phosphorylation of specific proteins.[43]
Cell nucleus 119

Function
The main function of the cell nucleus is to control gene expression and mediate the replication of DNA during the
cell cycle. The nucleus provides a site for genetic transcription that is segregated from the location of translation in
the cytoplasm, allowing levels of gene regulation that are not available to prokaryotes.

Cell compartmentalization
The nuclear envelope allows the nucleus to control its contents, and separate them from the rest of the cytoplasm
where necessary. This is important for controlling processes on either side of the nuclear membrane. In most cases
where a cytoplasmic process needs to be restricted, a key participant is removed to the nucleus, where it interacts
with transcription factors to downregulate the production of certain enzymes in the pathway. This regulatory
mechanism occurs in the case of glycolysis, a cellular pathway for breaking down glucose to produce energy.
Hexokinase is an enzyme responsible for the first the step of glycolysis, forming glucose-6-phosphate from glucose.
At high concentrations of fructose-6-phosphate, a molecule made later from glucose-6-phosphate, a regulator protein
removes hexokinase to the nucleus,[44] where it forms a transcriptional repressor complex with nuclear proteins to
reduce the expression of genes involved in glycolysis.[45]
In order to control which genes are being transcribed, the cell separates some transcription factor proteins
responsible for regulating gene expression from physical access to the DNA until they are activated by other
signaling pathways. This prevents even low levels of inappropriate gene expression. For example, in the case of
NF-κB-controlled genes, which are involved in most inflammatory responses, transcription is induced in response to
a signal pathway such as that initiated by the signaling molecule TNF-α, binds to a cell membrane receptor, resulting
in the recruitment of signalling proteins, and eventually activating the transcription factor NF-κB. A nuclear
localisation signal on the NF-κB protein allows it to be transported through the nuclear pore and into the nucleus,
where it stimulates the transcription of the target genes.[6]
The compartmentalization allows the cell to prevent translation of unspliced mRNA.[46] Eukaryotic mRNA contains
introns that must be removed before being translated to produce functional proteins. The splicing is done inside the
nucleus before the mRNA can be accessed by ribosomes for translation. Without the nucleus, ribosomes would
translate newly transcribed (unprocessed) mRNA, resulting in misformed and nonfunctional proteins.
Cell nucleus 120

Gene expression
Gene expression first involves transcription, in which DNA is used
as a template to produce RNA. In the case of genes encoding
proteins, that RNA produced from this process is messenger RNA
(mRNA), which then needs to be translated by ribosomes to form
a protein. As ribosomes are located outside the nucleus, mRNA
produced needs to be exported.[47]

Since the nucleus is the site of transcription, it also contains a


variety of proteins that either directly mediate transcription or are
involved in regulating the process. These proteins include
helicases, which unwind the double-stranded DNA molecule to
facilitate access to it, RNA polymerases, which synthesize the
growing RNA molecule, topoisomerases, which change the
amount of supercoiling in DNA, helping it wind and unwind, as
well as a large variety of transcription factors that regulate
expression.[48]
A micrograph of ongoing gene transcription of
ribosomal RNA illustrating the growing primary
transcripts. "Begin" indicates the 5' end of the DNA, Processing of pre-mRNA
where new RNA synthesis begins; "end" indicates the
Newly synthesized mRNA molecules are known as primary
3' end, where the primary transcripts are almost
complete. transcripts or pre-mRNA. They must undergo post-transcriptional
modification in the nucleus before being exported to the
cytoplasm; mRNA that appears in the cytoplasm without these modifications is degraded rather than used for protein
translation. The three main modifications are 5' capping, 3' polyadenylation, and RNA splicing. While in the nucleus,
pre-mRNA is associated with a variety of proteins in complexes known as heterogeneous ribonucleoprotein particles
(hnRNPs). Addition of the 5' cap occurs co-transcriptionally and is the first step in post-transcriptional modification.
The 3' poly-adenine tail is only added after transcription is complete.

RNA splicing, carried out by a complex called the spliceosome, is the process by which introns, or regions of DNA
that do not code for protein, are removed from the pre-mRNA and the remaining exons connected to re-form a single
continuous molecule. This process normally occurs after 5' capping and 3' polyadenylation but can begin before
synthesis is complete in transcripts with many exons.[5] Many pre-mRNAs, including those encoding antibodies, can
be spliced in multiple ways to produce different mature mRNAs that encode different protein sequences. This
process is known as alternative splicing, and allows production of a large variety of proteins from a limited amount
of DNA.
Cell nucleus 121

Dynamics and regulation

Nuclear transport
The entry and exit of large molecules
from the nucleus is tightly controlled
by the nuclear pore complexes.
Although small molecules can enter
the nucleus without regulation,[49]
macromolecules such as RNA and
proteins require association
karyopherins called importins to enter
the nucleus and exportins to exit.
"Cargo" proteins that must be
translocated from the cytoplasm to the
nucleus contain short amino acid
sequences known as nuclear
localization signals, which are bound
Macromolecules, such as RNA and proteins, are actively transported across the nuclear
by importins, while those transported
membrane in a process called the Ran-GTP nuclear transport cycle.
from the nucleus to the cytoplasm
carry nuclear export signals bound by
exportins. The ability of importins and exportins to transport their cargo is regulated by GTPases, enzymes that
hydrolyze the molecule guanosine triphosphate to release energy. The key GTPase in nuclear transport is Ran, which
can bind either GTP or GDP (guanosine diphosphate), depending on whether it is located in the nucleus or the
cytoplasm. Whereas importins depend on RanGTP to dissociate from their cargo, exportins require RanGTP in order
to bind to their cargo.[11]

Nuclear import depends on the importin binding its cargo in the cytoplasm and carrying it through the nuclear pore
into the nucleus. Inside the nucleus, RanGTP acts to separate the cargo from the importin, allowing the importin to
exit the nucleus and be reused. Nuclear export is similar, as the exportin binds the cargo inside the nucleus in a
process facilitated by RanGTP, exits through the nuclear pore, and separates from its cargo in the cytoplasm.
Specialized export proteins exist for translocation of mature mRNA and tRNA to the cytoplasm after
post-transcriptional modification is complete. This quality-control mechanism is important due to these molecules'
central role in protein translation; mis-expression of a protein due to incomplete excision of exons or
mis-incorporation of amino acids could have negative consequences for the cell; thus, incompletely modified RNA
that reaches the cytoplasm is degraded rather than used in translation.[5]
Cell nucleus 122

Assembly and disassembly


During its lifetime, a nucleus may be broken down, either in
the process of cell division or as a consequence of
apoptosis, a regulated form of cell death. During these
events, the structural components of the nucleus — the
envelope and lamina — can be systematically degraded. In
most cells, the disassembly of the nuclear envelope marks
the end of the prophase of mitosis. However, this
disassembly of the nucleus is not a universal feature of
mitosis and does not occur in all cells. Some unicellular
eukaryotes (e.g., yeasts) undergo so-called closed mitosis,
in which the nuclear envelope remains intact. In closed
mitosis, the daughter chromosomes migrate to opposite
poles of the nucleus, which then divides in two. The cells of
An image of a newt lung cell stained with fluorescent dyes
higher eukaryotes, however, usually undergo open mitosis,
during metaphase. The mitotic spindle can be seen, stained
green, attached to the two sets of chromosomes, stained light which is characterized by breakdown of the nuclear
blue. All chromosomes but one are already at the metaphase envelope. The daughter chromosomes then migrate to
plate. opposite poles of the mitotic spindle, and new nuclei
reassemble around them

At a certain point during the cell cycle in open mitosis, the cell divides to form two cells. In order for this process to
be possible, each of the new daughter cells must have a full set of genes, a process requiring replication of the
chromosomes as well as segregation of the separate sets. This occurs by the replicated chromosomes, the sister
chromatids, attaching to microtubules, which in turn are attached to different centrosomes. The sister chromatids can
then be pulled to separate locations in the cell. In many cells, the centrosome is located in the cytoplasm, outside the
nucleus; the microtubules would be unable to attach to the chromatids in the presence of the nuclear envelope.[50]
Therefore the early stages in the cell cycle, beginning in prophase and until around prometaphase, the nuclear
membrane is dismantled.[14] Likewise, during the same period, the nuclear lamina is also disassembled, a process
regulated by phosphorylation of the lamins by protein kinases such as the CDC2 protein kinase.[51] Towards the end
of the cell cycle, the nuclear membrane is reformed, and around the same time, the nuclear lamina are reassembled
by dephosphorylating the lamins.[51]

However, in dinoflagellates, the nuclear envelope remains intact, the centrosomes are located in the cytoplasm, and
the microtubules come in contact with chromosomes, whose centromeric regions are incorporated into the nuclear
envelope (the so-called closed mitosis with extranuclear spindle). In many other protists (e.g., ciliates, sporozoans)
and fungi, the centrosomes are intranuclear, and their nuclear envelope also does not disassemle during cell division.
Apoptosis is a controlled process in which the cell's structural components are destroyed, resulting in death of the
cell. Changes associated with apoptosis directly affect the nucleus and its contents, for example, in the condensation
of chromatin and the disintegration of the nuclear envelope and lamina. The destruction of the lamin networks is
controlled by specialized apoptotic proteases called caspases, which cleave the lamin proteins and, thus, degrade the
nucleus' structural integrity. Lamin cleavage is sometimes used as a laboratory indicator of caspase activity in assays
for early apoptotic activity.[14] Cells that express mutant caspase-resistant lamins are deficient in nuclear changes
related to apoptosis, suggesting that lamins play a role in initiating the events that lead to apoptotic degradation of
the nucleus.[14] Inhibition of lamin assembly itself is an inducer of apoptosis.[52]
The nuclear envelope acts as a barrier that prevents both DNA and RNA viruses from entering the nucleus. Some
viruses require access to proteins inside the nucleus in order to replicate and/or assemble. DNA viruses, such as
herpesvirus replicate and assemble in the cell nucleus, and exit by budding through the inner nuclear membrane. This
Cell nucleus 123

process is accompanied by disassembly of the lamina on the nuclear face of the inner membrane.[14]

Anucleated and multinucleated cells


Although most cells have a single nucleus, some eukaryotic cell types have
no nucleus, and others have many nuclei. This can be a normal process, as in
the maturation of mammalian red blood cells, or a result of faulty cell
division.
Anucleated cells contain no nucleus and are, therefore, incapable of dividing
to produce daughter cells. The best-known anucleated cell is the mammalian
red blood cell, or erythrocyte, which also lacks other organelles such as
mitochondria, and serves primarily as a transport vessel to ferry oxygen from
the lungs to the body's tissues. Erythrocytes mature through erythropoiesis in
the bone marrow, where they lose their nuclei, organelles, and ribosomes.
The nucleus is expelled during the process of differentiation from an
erythroblast to a reticulocyte, which is the immediate precursor of the mature Human red blood cells, like those of other

erythrocyte.[53] The presence of mutagens may induce the release of some mammals, lack nuclei. This occurs as a
normal part of the cells' development.
immature "micronucleated" erythrocytes into the bloodstream.[54][55]
Anucleated cells can also arise from flawed cell division in which one
daughter lacks a nucleus and the other has two nuclei.

Multinucleated cells contain multiple nuclei. Most acantharean species of protozoa[56] and some fungi in
mycorrhizae[57] have naturally multinucleated cells. Other examples include the intestinal parasites in the genus
Giardia, which have two nuclei per cell.[58] In humans, skeletal muscle cells, called myocytes and syncytium,
become multinucleated during development; the resulting arrangement of nuclei near the periphery of the cells
allows maximal intracellular space for myofibrils.[5] Multinucleated and binucleated cells can also be abnormal in
humans; for example, cells arising from the fusion of monocytes and macrophages, known as giant multinucleated
cells, sometimes accompany inflammation[59] and are also implicated in tumor formation.[60]

Evolution
As the major defining characteristic of the eukaryotic cell, the nucleus' evolutionary origin has been the subject of
much speculation. Four major theories have been proposed to explain the existence of the nucleus, although none
have yet earned widespread support.[61]
The theory known as the "syntrophic model" proposes that a symbiotic relationship between the archaea and bacteria
created the nucleus-containing eukaryotic cell. (Organisms of the Archaea and Bacteria domain have no cell
nucleus.[62]) It is hypothesized that the symbiosis originated when ancient archaea, similar to modern methanogenic
archaea, invaded and lived within bacteria similar to modern myxobacteria, eventually forming the early nucleus.
This theory is analogous to the accepted theory for the origin of eukaryotic mitochondria and chloroplasts, which are
thought to have developed from a similar endosymbiotic relationship between proto-eukaryotes and aerobic
bacteria.[63] The archaeal origin of the nucleus is supported by observations that archaea and eukarya have similar
genes for certain proteins, including histones. Observations that myxobacteria are motile, can form multicellular
complexes, and possess kinases and G proteins similar to eukarya, support a bacterial origin for the eukaryotic
cell.[64]
A second model proposes that proto-eukaryotic cells evolved from bacteria without an endosymbiotic stage. This
model is based on the existence of modern planctomycetes bacteria that possess a nuclear structure with primitive
pores and other compartmentalized membrane structures.[65] A similar proposal states that a eukaryote-like cell, the
chronocyte, evolved first and phagocytosed archaea and bacteria to generate the nucleus and the eukaryotic cell.[66]
Cell nucleus 124

The most controversial model, known as viral eukaryogenesis, posits that the membrane-bound nucleus, along with
other eukaryotic features, originated from the infection of a prokaryote by a virus. The suggestion is based on
similarities between eukaryotes and viruses such as linear DNA strands, mRNA capping, and tight binding to
proteins (analogizing histones to viral envelopes). One version of the proposal suggests that the nucleus evolved in
concert with phagocytosis to form an early cellular "predator".[67] Another variant proposes that eukaryotes
originated from early archaea infected by poxviruses, on the basis of observed similarity between the DNA
polymerases in modern poxviruses and eukaryotes.[68][69] It has been suggested that the unresolved question of the
evolution of sex could be related to the viral eukaryogenesis hypothesis.[70]
A very recent proposal suggests that traditional variants of the endosymbiont theory are insufficiently powerful to
explain the origin of the eukaryotic nucleus. This model, termed the exomembrane hypothesis, suggests that the
nucleus instead originated from a single ancestral cell that evolved a second exterior cell membrane; the interior
membrane enclosing the original cell then became the nuclear membrane and evolved increasingly elaborate pore
structures for passage of internally synthesized cellular components such as ribosomal subunits.[71]

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[43] Handwerger, Korie E.; Joseph G. Gall (January 2006). "Subnuclear organelles: new insights into form and function". TRENDS in Cell
Biology 16 (1): 19–26. doi:10.1016/j.tcb.2005.11.005. PMID 16325406.
[44] Lehninger, Albert L.; David L. Nelson, Michael M. Cox. (2000). Lehninger principles of biochemistry (3rd ed.). New York: Worth
Publishers. ISBN 1-57259-931-6.
[45] Moreno F, Ahuatzi D, Riera A, Palomino CA, Herrero P. (2005). "Glucose sensing through the Hxk2-dependent signalling pathway.".
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[46] Görlich, Dirk; Ulrike Kutay (1999). "Transport between the cell nucleus and the cytoplasm". Ann. Rev. Cell Dev. Biol. 15 (1): 607–660.
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Further reading
• Goldman, Robert D.; Gruenbaum, Y; Moir, RD; Shumaker, DK; Spann, TP (2002). "Nuclear lamins: building
blocks of nuclear architecture". Genes & Dev. 16 (5): 533–547. doi:10.1101/gad.960502. PMID 11877373.
A review article about nuclear lamins, explaining their structure and various roles
• Görlich, Dirk; Kutay, U (1999). "Transport between the cell nucleus and the cytoplasm". Ann. Rev. Cell Dev.
Biol. 15: 607–660. doi:10.1146/annurev.cellbio.15.1.607. PMID 10611974.
A review article about nuclear transport, explains the principles of the mechanism, and the various transport
pathways
Cell nucleus 127

• Lamond, Angus I.; Earnshaw, WC (1998-04-24). "Structure and Function in the Nucleus". Science 280 (5363):
547–553. doi:10.1126/science.280.5363.547. PMID 9554838.
A review article about the nucleus, explaining the structure of chromosomes within the organelle, and
describing the nucleolus and other subnuclear bodies
• Pennisi E. (2004). "Evolutionary biology. The birth of the nucleus". Science 305 (5685): 766–768.
doi:10.1126/science.305.5685.766. PMID 15297641.
A review article about the evolution of the nucleus, explaining a number of different theories
• Pollard, Thomas D.; William C. Earnshaw (2004). Cell Biology. Philadelphia: Saunders. ISBN 0-7216-3360-9.
A university level textbook focusing on cell biology. Contains information on nucleus structure and function,
including nuclear transport, and subnuclear domains

External links
• cellnucleus.com (http://www.cellnucleus.com/education_main.htm) Website covering structure and function
of the nucleus from the Department of Oncology at the University of Alberta.
• http://npd.hgu.mrc.ac.uk/user/?page=compartment The Nuclear Protein Database] Information on nuclear
components.
• The Nucleus Collection (http://cellimages.ascb.org/cdm4/browse.php?CISOROOT=/p4041coll6) in the
Image & Video Library (http://cellimages.ascb.org/) of The American Society for Cell Biology (http://www.
ascb.org/) contains peer-reviewed still images and video clips that illustrate the nucleus.
• Nuclear Envelope and Nuclear Import Section (http://cellimages.ascb.org/u?/p4041coll11,62) from Landmark
Papers in Cell Biology (http://cellimages.ascb.org/cdm4/browse.php?CISOROOT=/p4041coll11), Joseph G.
Gall, J. Richard McIntosh, eds., contains digitized commentaries and links to seminal research papers on the
nucleus. Published online in the Image & Video Library (http://cellimages.ascb.org/) of The American Society
for Cell Biology (http://www.ascb.org/)
• Cytoplasmic patterns generated by human antibodies (http://www.antibodypatterns.com/cytoplasmic.php)

Gallery

Comparison of human and chimpanzee Mouse 24 chromosome


chromosomes. chromosome territories in
territories in human cells.
different cell
types.
Cell wall 128

Cell wall
The cell wall is the tough, usually flexible but sometimes fairly rigid layer that surrounds some types of cells. It is
located outside the cell membrane and provides these cells with structural support and protection, in addition to
acting as a filtering mechanism. A major function of the cell wall is to act as a pressure vessel, preventing
over-expansion when water enters the cell. Cell walls are found in plants, bacteria, fungi, algae, and some archaea.
Animals and protozoa do not have cell walls.
The material in the cell wall varies between species, and can also differ depending on cell type and developmental
stage. In bacteria, peptidoglycan forms the cell wall. Archaean cell walls have various compositions, and may be
formed of glycoprotein S-layers, pseudopeptidoglycan, or polysaccharides. Fungi possess cell walls made of the
glucosamine polymer chitin, and algae typically possess walls made of glycoproteins and polysaccharides.
Unusually, diatoms have a cell wall composed of biogenic silica. Often, other accessory molecules are found
anchored to the cell wall.

Properties
The cell wall serves a similar purpose in those
organisms that possess them. The wall gives cells
rigidity and strength, offering protection against
mechanical stress. In multicellular organisms, it permits
the organism to build and hold its shape
(morphogenesis). The cell wall also limits the entry of
large molecules that may be toxic to the cell. It further
permits the creation of a stable osmotic environment by
preventing osmotic lysis and helping to retain water.
The composition, properties, and form of the cell wall
may change during the cell cycle and depend on growth
conditions.
Diagram of the plant cell, with the cell wall in green.

Rigidity of cell walls


The rigidity of the cell walls is often over-estimated. In most cells, the cell wall is flexible, meaning that it will bend
rather than holding a fixed shape, but has considerable tensile strength. The apparent rigidity of primary plant tissues
is enabled by cell walls, but not due to the walls' stiffness. Hydraulic turgor pressure creates this rigidity, along with
the wall structure. The flexibility of the cell walls is seen when plants wilt, so that the stems and leaves begin to
droop, or in seaweeds that bend in water currents. As John Howland states it:
Think of the cell wall as a wicker basket in which a balloon has been inflated so that it exerts pressure from the
inside. Such a basket is very rigid and resistant to mechanical damage. Thus does the prokaryote cell (and
eukaryotic cell that possesses a cell wall) gain strength from a flexible plasma membrane pressing against a
rigid cell wall.[1]
The rigidity of the cell wall thus results in part from inflation of the cell contained. This inflation is a result of the
passive uptake of water.
In plants, a secondary cell wall is a thicker additional layer of cellulose which increases wall rigidity. Additional
layers may be formed containing lignin in xylem cell walls, or containing suberin in cork cell walls. These
compounds are rigid and waterproof, making the secondary wall stiff. Both wood and bark cells of trees have
secondary walls. Other parts of plants such as the leaf stalk may acquire similar reinforcement to resist the strain of
Cell wall 129

physical forces.
Certain single-cell protists and algae also produce a rigid wall. Diatoms build a frustule from silica extracted from
the surrounding water; radiolarians also produce a test from minerals. Many green algae, such as the Dasycladales
encase their cells in a secreted skeleton of calcium carbonate. In each case, the wall is rigid and essentially inorganic.

Permeability
The primary cell wall of most plant cells is semi-permeable and permits the passage of small molecules and small
proteins, with size exclusion estimated to be 30-60 kDa. Key nutrients, especially water and carbon dioxide, are
distributed throughout the plant from cell wall to cell wall in apoplastic flow. The pH is an important factor
governing the transport of molecules through cell walls.[2]

Plant cell walls


Many plant cells have walls that are strong enough to withstand the osmotic pressure from the difference in solute
concentration between the cell interior and distilled water.[3] Plant cell walls vary from 1/10 to several µm thick.[4]

Layers
Up to three strata or layers may be found in plant cell
walls:[5]
• The middle lamella, a layer rich in pectins. This
outermost layer forms the interface between
adjacent plant cells and glues them together.
• The primary cell wall, generally a thin, flexible and
extensible layer formed while the cell is growing.
• The secondary cell wall, a thick layer formed inside
the primary cell wall after the cell is fully grown. It
is not found in all cell types. Some cells, such as the Molecular structure of the primary cell wall in plants.

conducting cells in xylem, possess a secondary wall


containing lignin, which strengthens and waterproofs the wall.

Composition
In the primary (growing) plant cell wall, the major carbohydrates are cellulose, hemicellulose and pectin. The
cellulose microfibrils are linked via hemicellulosic tethers to form the cellulose-hemicellulose network, which is
embedded in the pectin matrix. The most common hemicellulose in the primary cell wall is xyloglucan. In grass cell
walls, xyloglucan and pectin are reduced in abundance and partially replaced by glucuronarabinoxylan, a
hemicellulose. Primary cell walls characteristically extend (grow) by a mechanism called acid growth, which
involves turgor-driven movement of the strong cellulose microfibrils within the weaker hemicellulose/pectin matrix,
catalyzed by expansin proteins. The outer part of the primary cell wall of the plant epidermis is usually impregnated
with cutin and wax, forming a permeability barrier known as the plant cuticle.
Secondary cell walls contain a wide range of additional compounds that modify their mechanical properties and
permeability. The major polymers that make up wood (largely secondary cell walls) include:
• cellulose, 35-50%
• xylan, 20-35%, a type of hemicellulose
• lignin, 10-25%, a complex phenolic polymer that penetrates the spaces in the cell wall between cellulose,
hemicellulose and pectin components, driving out water and strengthening the wall.
Cell wall 130

Additionally, structural proteins (1-5%) are found in most plant cell walls; they are classified as hydroxyproline-rich
glycoproteins (HRGP), arabinogalactan proteins (AGP), glycine-rich proteins (GRPs), and proline-rich proteins
(PRPs). Each class of glycoprotein is defined by a characteristic, highly repetitive protein sequence. Most are
glycosylated, contain hydroxyproline (Hyp) and become cross-linked in the cell wall. These proteins are often
concentrated in specialized cells and in cell corners. Cell walls of the epidermis and endodermis may also contain
suberin or cutin, two polyester-like polymers that protect the cell from herbivores.[6] The relative composition of
carbohydrates, secondary compounds and protein varies between plants and between the cell type and age.
Plant cells walls also contain numerous enzymes, such as hydrolases, esterases, peroxidases, and transglycosylases,
that cut, trim and cross-link wall polymers.
The walls of cork cells in the bark of trees are impregnated with suberin, and suberin also forms the permeability
barrier in primary roots known as the Casparian strip. Secondary walls - especially in grasses - may also contain
microscopic silica crystals, which may strengthen the wall and protect it from herbivores.
Cell walls in some plant tissues also function as storage depots for carbohydrates that can be broken down and
resorbed to supply the metabolic and growth needs of the plant. For example, endosperm cell walls in the seeds of
cereal grasses, nasturtium, and other species, are rich in glucans and other polysaccharides that are readily digested
by enzymes during seed germination to form simple sugars that nourish the growing embryo. Cellulose microfibrils
are not readily digested by plants, however.

Formation
The middle lamella is laid down first, formed from the cell plate during cytokinesis, and the primary cell wall is then
deposited inside the middle lamella. The actual structure of the cell wall is not clearly defined and several models
exist - the covalently linked cross model, the tether model, the diffuse layer model and the stratified layer model.
However, the primary cell wall, can be defined as composed of cellulose microfibrils aligned at all angles.
Microfibrils are held together by hydrogen bonds to provide a high tensile strength. The cells are held together and
share the gelatinous membrane called the middle lamella, which contains magnesium and calcium pectates (salts of
pectic acid). Cells interact though plasmodesma(ta), which are inter-connecting channels of cytoplasm that connect
to the protoplasts of adjacent cells across the cell wall.
In some plants and cell types, after a maximum size or point in development has been reached, a secondary wall is
constructed between the plasma membrane and primary wall.[7] Unlike the primary wall, the microfibrils are aligned
mostly in the same direction, and with each additional layer the orientation changes slightly. Cells with secondary
cell walls are rigid. Cell to cell communication is possible through pits in the secondary cell wall that allow
plasmodesma to connect cells through the secondary cell walls.
Cell wall 131

Algal cell walls


Like plants, algae have cell walls.[8] Algal cell walls
contain either polysaccharides (such as cellulose (a
glucan)) or a variety of glycoproteins (Volvocales) or
both. The inclusion of additional polysaccharides in
algal cells walls is used as a feature for algal taxonomy.
• Mannans: They form microfibrils in the cell walls of
a number of marine green algae including those
from the genera, Codium, Dasycladus, and
Acetabularia as well as in the walls of some red
algae, like Porphyra and Bangia.
• Xylans:
• Alginic acid: It is a common polysaccharide in the
cell walls of brown algae. Scanning electron micrographs of diatoms showing the external
• Sulfonated polysaccharides: They occur in the cell appearance of the cell wall
walls of most algae; those common in red algae
include agarose, carrageenan, porphyran, furcelleran and funoran.
Other compounds that may accumulate in algal cell walls include sporopollenin and calcium ions.
The group of algae known as the diatoms synthesize their cell walls (also known as frustules or valves) from silicic
acid (specifically orthosilicic acid, H4SiO4). The acid is polymerised intra-cellularly, then the wall is extruded to
protect the cell. Significantly, relative to the organic cell walls produced by other groups, silica frustules require less
energy to synthesize (approximately 8%), potentially a major saving on the overall cell energy budget[9] and possibly
an explanation for higher growth rates in diatoms.[10]

Fungal cell walls


There are several groups of organisms that may be called "fungi".
Some of these groups have been transferred out of the Kingdom Fungi,
in part because of fundamental biochemical differences in the
composition of the cell wall. Most true fungi have a cell wall
consisting largely of chitin and other polysaccharides.[11] True fungi do
not have cellulose in their cell walls, but some fungus-like organisms
do.

True fungi Chemical structure of a unit from a chitin


polymer chain.
Not all species of fungi have cell walls but in those that do, the plasma
membrane is followed by three layers of cell wall material. From inside out these are:
• a chitin layer (polymer consisting mainly of unbranched chains of N-acetyl-D-glucosamine)
• a layer of β-1,3-glucan (zymosan)
• a layer of mannoproteins (mannose-containing glycoproteins) which are heavily glycosylated at the outside of the
cell.
Cell wall 132

Fungus-like protists
The group Oomycetes, also known as water molds, are saprotrophic plant pathogens like fungi. Until recently they
were widely believed to be fungi, but structural and molecular evidence[12] has led to their reclassification as
heterokonts, related to autotrophic brown algae and diatoms. Unlike fungi, oomycetes typically possess cell walls of
cellulose and glucans rather than chitin, although some genera (such as Achlya and Saprolegnia) do have chitin in
their walls.[13] The fraction of cellulose in the walls is no more than 4 to 20%, far less than the fraction comprised by
glucans.[13] Oomycete cell walls also contain the amino acid hydroxyproline, which is not found in fungal cell walls.
The dictyostelids are another group formerly classified among the fungi. They are slime molds that feed as
unicellular amoebae, but aggregate into a reproductive stalk and sporangium under certain conditions. Cells of the
reproductive stalk, as well as the spores formed at the apex, possess a cellulose wall.[14] The spore wall has been
shown to possess three layers, the middle of which is composed primarily of cellulose, and the innermost is sensitive
to cellulase and pronase.[14]

Prokaryotic cell walls

Bacterial cell walls


Around the outside of the cell membrane is
the bacterial cell wall. Bacterial cell walls
are made of peptidoglycan (also called
murein), which is made from polysaccharide
chains cross-linked by unusual peptides
containing D-amino acids.[15] Bacterial cell
walls are different from the cell walls of
plants and fungi which are made of cellulose
and chitin, respectively.[16] The cell wall of
bacteria is also distinct from that of
Archaea, which do not contain
peptidoglycan. The cell wall is essential to
the survival of many bacteria, although
L-form bacteria can be produced in the
laboratory that lack a cell wall.[17] The
antibiotic penicillin is able to kill bacteria by Diagram of a typical gram-negative bacterium, with the thin cell wall sandwiched
preventing the cross-linking of between the red outer membrane and the thin green plasma membrane
peptidoglycan and this causes the cell wall
to weaken and lyse.[16] The lysozyme enzyme can also damage bacterial cell walls.

There are broadly speaking two different types of cell wall in bacteria, called Gram-positive and Gram-negative. The
names originate from the reaction of cells to the Gram stain, a test long-employed for the classification of bacterial
species.[18]
Cell wall 133

Gram-positive bacteria possess a thick cell wall containing many layers


of peptidoglycan and teichoic acids. In contrast, Gram-negative
bacteria have a relatively thin cell wall consisting of a few layers of
peptidoglycan surrounded by a second lipid membrane containing
lipopolysaccharides and lipoproteins. Most bacteria have the
Gram-negative cell wall and only the Firmicutes and Actinobacteria
(previously known as the low G+C and high G+C Gram-positive
bacteria, respectively) have the alternative Gram-positive
arrangement.[19] These differences in structure can produce differences
in antibiotic susceptibility, for instance vancomycin can kill only Schematic of typical gram-positive cell wall
Gram-positive bacteria and is ineffective against Gram-negative showing arrangement of N-Acetylglucosamine
and N-Acetlymuramic acid
pathogens, such as Haemophilus influenzae or Pseudomonas
aeruginosa.[20]

Archaeal cell walls


Although not truly unique, the cell walls of Archaea are unusual. Whereas peptidoglycan is a standard component of
all bacterial cell walls, all archaeal cell walls lack peptidoglycan,[21] with the exception of one group of
methanogens.[1] In that group, the peptidoglycan is a modified form very different from the kind found in
bacteria.[21] There are four types of cell wall currently known among the Archaea.
One type of archaeal cell wall is that composed of pseudopeptidoglycan (also called pseudomurein). This type of
wall is found in some methanogens, such as Methanobacterium and Methanothermus.[22] While the overall structure
of archaeal pseudopeptidoglycan superficially resembles that of bacterial peptidoglycan, there are a number of
significant chemical differences. Like the peptidoglycan found in bacterial cell walls, pseudopeptidoglycan consists
of polymer chains of glycan cross-linked by short peptide connections. However, unlike peptidoglycan, the sugar
N-acetylmuramic acid is replaced by N-acetyltalosaminuronic acid,[21] and the two sugars are bonded with a β,1-3
glycosidic linkage instead of β,1-4. Additionally, the cross-linking peptides are L-amino acids rather than D-amino
acids as they are in bacteria.[22]
A second type of archaeal cell wall is found in Methanosarcina and Halococcus. This type of cell wall is composed
entirely of a thick layer of polysaccharides, which may be sulfated in the case of Halococcus.[22] Structure in this
type of wall is complex and as yet is not fully investigated.
A third type of wall among the Archaea consists of glycoprotein, and occurs in the hyperthermophiles,
Halobacterium, and some methanogens. In Halobacterium, the proteins in the wall have a high content of acidic
amino acids, giving the wall an overall negative charge. The result is an unstable structure that is stabilized by the
presence of large quantities of positive sodium ions that neutralize the charge.[22] Consequently, Halobacterium
thrives only under conditions with high salinity.
In other Archaea, such as Methanomicrobium and Desulfurococcus, the wall may be composed only of surface-layer
proteins,[1] known as an S-layer. S-layers are common in bacteria, where they serve as either the sole cell-wall
component or an outer layer in conjunction with polysaccharides. Most Archaea are Gram-negative, though at least
one Gram-positive member is known.[1]
Cell wall 134

References
[1] Howland, John L. (2000). The Surprising Archaea: Discovering Another Domain of Life. Oxford: Oxford University Press. pp. 69–71.
ISBN 0-19-511183-4.
[2] C.Michael Hogan. 2010. Abiotic factor. Encyclopedia of Earth. eds Emily Monosson and C. Cleveland. National Council for Science and the
Environment (http:/ / www. eoearth. org/ article/ Abiotic_factor?topic=49461). Washington DC
[3] http:/ / www. madsci. org/ posts/ archives/ 2006-11/ 1164842041. Cb. r. html
[4] Campbell, Neil A.; Reece, Jane B.; Urry, Lisa A.; Cain, Michael L.; Wasserman, Steven A.; Minorsky, Peter V.; Jackson, Robert B. (2008).
Biology (8th ed.). p. 118. ISBN 978-0-8053-6844-4.
[5] Buchanan; Gruissem, Jones (2000). Biochemistry & molecular biology of plants (1st ed.). American society of plant physiology.
ISBN 0-943088-39-9.
[6] Laurence Moire, Alain Schmutz, Antony Buchala, Bin Yan, Ruth E. Stark, and Ulrich Ryser (1999). "Glycerol Is a Suberin Monomer. New
Experimental Evidence for an Old Hypothesis" (http:/ / www. plantphysiol. org/ cgi/ content/ full/ 119/ 3/ 1137). Plant Physiol 119 (3):
1137–1146. doi:10.1104/pp.119.3.1137. PMC 32096. PMID 10069853. .
[7] Campbell, Neil A.; Reece, Jane B.; Urry, Lisa A.; Cain, Michael L.; Wasserman, Steven A.; Minorsky, Peter V.; Jackson, Robert B. (2008).
Biology (8th ed.). p. 119. ISBN 978-0-8053-6844-4.
[8] Sendbusch, Peter V. (2003-07-31). " Cell Walls of Algae (http:/ / www. biologie. uni-hamburg. de/ b-online/ e26/ 26d. htm)". Botany Online.
Retrieved on 2007-10-29.
[9] Raven, J. A. (1983). "The transport and function of silicon in plants". Biol. Rev. 58 (2): 179–207. doi:10.1111/j.1469-185X.1983.tb00385.x.
[10] Furnas, M. J. (1990). "In situ growth rates of marine phytoplankton : Approaches to measurement, community and species growth rates". J.
Plankton Res. 12 (6): 1117–1151. doi:10.1093/plankt/12.6.1117.
[11] Hudler, George W. (1998). Magical Mushrooms, Mischievous Molds. Princeton, NJ: Princeton University Press, 7. ISBN 0-691-02873-7.
[12] Sengbusch, Peter V. (2003-07-31). " Interactions between Plants and Fungi: the Evolution of their Parasitic and Symbiotic Relations (http:/ /
www. biologie. uni-hamburg. de/ b-online/ e33/ 33. htm)". biologie.uni-hamburg.de. Retrieved on 2007-10-29.
[13] Alexopoulos, C. J., C. W. Mims, & M. Blackwell (1996). Introductory Mycology 4. New York: John Wiley & Sons, 687-688. ISBN
0-471-52229-5.
[14] Raper, Kenneth B. (1984). The Dictyostelids. Princeton, NJ: Princeton University Press, 99-100. ISBN 0-691-08345-2.
[15] van Heijenoort J (2001). "Formation of the glycan chains in the synthesis of bacterial peptidoglycan" (http:/ / glycob. oxfordjournals. org/
cgi/ content/ full/ 11/ 3/ 25R). Glycobiology 11 (3): 25R – 36R. doi:10.1093/glycob/11.3.25R. PMID 11320055. .
[16] Koch A (2003). "Bacterial wall as target for attack: past, present, and future research" (http:/ / cmr. asm. org/ cgi/ content/ full/ 16/ 4/
673?view=long& pmid=14557293). Clin Microbiol Rev 16 (4): 673–87. doi:10.1128/CMR.16.4.673-687.2003. PMC 207114.
PMID 14557293. .
[17] Joseleau-Petit D, Liébart JC, Ayala JA, D'Ari R (September 2007). "Unstable Escherichia coli L forms revisited: growth requires
peptidoglycan synthesis" (http:/ / jb. asm. org/ cgi/ pmidlookup?view=long& pmid=17586646). J. Bacteriol. 189 (18): 6512–20.
doi:10.1128/JB.00273-07. PMC 2045188. PMID 17586646. .
[18] Gram, HC (1884). "Über die isolierte Färbung der Schizomyceten in Schnitt- und Trockenpräparaten". Fortschr. Med. 2: 185–189.
[19] Hugenholtz P; Rogozin, Igor B; Grishin, Nick V; Tatusov, Roman L; Koonin, Eugene V (2002). "Exploring prokaryotic diversity in the
genomic era". Genome Biol 3 (2): REVIEWS0003. doi:10.1186/gb-2002-3-2-reviews0003. PMC 139013. PMID 11864374.
[20] Walsh F, Amyes S (2004). "Microbiology and drug resistance mechanisms of fully resistant pathogens.". Curr Opin Microbiol 7 (5):
439–44. doi:10.1016/j.mib.2004.08.007. PMID 15451497.
[21] White, David. (1995) The Physiology and Biochemistry of Prokaryotes, pages 6, 12-21. (Oxford: Oxford University Press). ISBN
0-19-508439-X.
[22] Brock, Thomas D., Michael T. Madigan, John M. Martinko, & Jack Parker. (1994) Biology of Microorganisms, 7th ed., pages 818-819, 824
(Englewood Cliffs, NJ: Prentice Hall). ISBN 0-13-042169-3.

External links
• Cell wall ultrastructure (http://micro.magnet.fsu.edu/cells/plants/cellwall.html)
• The Cell Wall (http://www.palaeos.com/Fungi/FPieces/CellWall.html)
Cellular microbiology 135

Cellular microbiology
Cellular microbiology is a discipline that
bridges microbiology and cell biology.
The term "cellular microbiology" was
coined in 1996 [1] in a Science article.
Cooperation and mutual dependency
between microbiology and cell biology had
been increasing in the years before that, and
the emergence of a new discipline had been
suggested and discussed in several scientific
conferences.

Cellular microbiology attempts to use


pathogenic microbes as tools for
cell-biology research, and to employ
cell-biology methods to understand the
pathogenicity of microbes. Toxins and
virulence factors from microbes have been Salmonella bacteria (red) invade cultured human cells

used for decades to influence processes in


eukaryotic cells and to study them. It has increasingly appeared that applying a purified toxin on a cell does not
always provide the complete picture, and that understanding the role of the toxin in pathogenicity, the way the toxin
promotes the microbe, the way the toxin is produced and the co-evolution of the toxin and its host-cell counterparts,
is crucial.

Numerous eukaryotic cellular processes have been clarified using microbial "tools". A major subject in this category
is the cytoskeleton. Many microbes modify and influence the synthesis or degradation of the host-cell cytoskeleton,
in particular the actin network[2]. Intracellular microbes, such as the bacteria Salmonella and Shigella, elicit actin
polymerization in host cells that otherwise do not internalize microbes (non-phagocytes). This causes the formation
of projections that eventually engulf the bacteria. Bacteria such as Yersinia inhibit actin polymerization in
phagocytes, thereby preventing their uptake. Cellular microbiology tries to understand these processes and how they
promote infection. Other eukaryotic processes that microbes influence and that are researched using microbes are
signal transduction, metabolism, vesicle trafficking, cell cycle and transcriptional regulation, to name but a few.
Recently, the field of Cellular Microbiology has been expanded to incorporate investigation of the cell biology of
microbes themselves [3][4]. "The field of cellular microbiology is a coalescence of two fields: molecular
microbiology and cell biology," said Professor Jacek Hawiger, Chair of Microbiology and Immunology at
Vanderbuilt University [4]. Particularly in the case of bacterial cells, new technology is starting to be used to reveal a
high level of organization within the bacterial cells themselves. For example, high-resolution fluorescence
microscopy [5] and atomic force microscopy [6] are both being used to show just how sophisticated bacterial cells are.
Cellular microbiology 136

References
[1] Cossart P, Boquet P, Normark S, Rappuoli R (1996). "Cellular microbiology emerging". Science 271 (5247): 315–317.
doi:10.1126/science.271.5247.315.
[2] Dramsi S and Cossart P (1998). "Intracellular pathogens and the actin cytoskeleton". Annu Rev Cell Dev Biol 14 (1): 137–166.
doi:10.1146/annurev.cellbio.14.1.137. PMID 9891781.
[3] NHMRC Program in Cellular Microbiology (http:/ / med. monash. edu/ biochem/ nhmrc/ )
[4] NIH Cellular and Molecular Microbiology (CMM) training program (http:/ / www. mc. vanderbilt. edu/ reporter/ index. html?ID=988)
[5] Ebersbach G, Jacobs-Wagner C. “Exploration into the spatial and temporal mechanisms of bacterial polarity.”Trends Microbiol. 2007
Mar;15(3):101-8
[6] Dufrêne YF. “Towards nanomicrobiology using atomic force microscopy.” Nat Rev Microbiol. 2008 Sep;6(9):674-80

Collagen
Collagen (  /ˈkɒlədʒɪn/) is a group of naturally occurring proteins found in animals,
especially in the flesh and connective tissues of mammals.[1] It is the main component of
connective tissue, and is the most abundant protein in mammals,[2] making up about 25% to
35% of the whole-body protein content. Collagen, in the form of elongated fibrils, is mostly
found in fibrous tissues such as tendon, ligament and skin, and is also abundant in cornea,
cartilage, bone, blood vessels, the gut, and intervertebral disc. The fibroblast is the most
common cell which creates collagen.

In muscle tissue, it serves as a major component of the endomysium. Collagen constitutes one
to two percent of muscle tissue, and accounts for 6% of the weight of strong, tendinous
muscles.[3] Gelatin, which is used in food and industry, is collagen that has been irreversibly
hydrolyzed.

History and background


The molecular and packing structures of collagen have eluded scientists over decades of
research. The first evidence that it possesses a regular structure at the molecular level was
presented in the mid-1930s.[4][5] Since that time, many prominent scholars, including Nobel
laureates Crick, Pauling, Rich and Yonath, and others, including Brodsky, Berman, and
Ramachandran, concentrated on the conformation of the collagen monomer. Several
competing models, although correctly dealing with the conformation of each individual peptide
chain, gave way to the triple-helical "Madras" model, which provided an essentially correct
model of the molecule's quaternary structure[6][7][8] although this model still required some
refinement.[9][10][11][12] The packing structure of collagen has not been defined to the same Tropocollagen triple
degree outside of the fibrillar collagen types, although it has been long known to be hexagonal helix
[13][14][15]
or quasi-hexagonal. As with its monomeric structure, several conflicting models
alleged that either the packing arrangement of collagen molecules is 'sheet-like' or microfibrillar.[16][17] The
microfibrillar structure of collagen fibrils in tendon, cornea and cartilage has been directly imaged by electron
microscopy.[18][19][20] In 2006, the microfibrillar structure of adult tendon, as described by Fraser, Miller, and Wess
(amongst others), was confirmed as being closest to the observed structure, although it oversimplified the topological
progression of neighboring collagen molecules, and hence did not predict the correct conformation of the
discontinuous D-periodic pentameric arrangement termed simply: the microfibril.[21] Various cross linking agents
like dopaquinone, embelin, potassium embelate and 5-O-methyl embelin could be developed as potential
cross-linking/stabilization agent of collagen preparation and its application as wound dressing sheet in clinical
applications is enhanced.[22]
Collagen 137

Chemistry of Collagen
Collagen is a composed of a triple helix, which generally consists of two identical chains (α1) and an additional
chain that differs slightly in its chemical composition (α2).[23] The amino acid composition of collagen is atypical for
proteins, particularly with respect to its high hydroxyproline content. The most common motifs in the amino acid
sequence of collagen are Glycine-Proline-X and Glycine-X-Hydroxyproline, where X is any amino acid other than
glycine, proline or hydroxyproline. The average amino acid composition for fish and mammal skin is given.[23]

Amino Acid Abundance in Mammal Skin (Residues/1000) Abundance in Fish Skin (Residues/1000)

Asp 47 47

Hyp 95 67

Thr 19 26

Ser 36 46

Glu 74 76

Pro 126 108

Gly 329 339

Ala 109 114

Val 22 21

Met 6 13

Ile 11 11

Leu 24 23

Tyr 3 3

Phe 13 14

Hyl 6 8

Lys 29 26

His 5 7

Arg 49 52

Synthesis
First, a three dimensional stranded structure is assembled, with the amino acids glycine and proline as its principal
components. This is not yet collagen but its precursor, procollagen. A recent study shows that vitamin C must have
an important role in its synthesis. Prolonged exposure of cultures of human connective-tissue cells to ascorbate
induced an eight-fold increase in the synthesis of collagen with no increase in the rate of synthesis of other proteins
(Murad et al., 1981). Since the production of procollagen must precede the production of collagen, vitamin C must
have a role in this step. The conversion involves a reaction that substitutes a hydroxyl group, OH, for a hydrogen
atom, H, in the proline residues at certain points in the polypeptide chains, converting those residues to
hydroxyproline. This hydroxylation reaction secures the chains in the triple helix of collagen. The hydroxylation,
next, of the residues of the amino acid lysine, transforming them to hydroxylysine, is then needed to permit the
cross-linking of the triple helices into the fibers and networks of the tissues.
These hydroxylation reactions are catalyzed by two different enzymes: prolyl-4-hydroxylase and lysyl-hydroxylase.
Vitamin C also serves with them in inducing these reactions. It has recently been shown by Myllyla and his
colleagues that, in this service, one molecule of vitamin C is destroyed for each H replaced by OH. [24] The synthesis
of collagen occurs inside and outside of the cell. The formation of collagen which results in fibrillary collagen (most
Collagen 138

common form) is discussed here. Meshwork collagen, which is often involved in the formation of filtration systems
is the other form of collagen. It should be noted that all types of collagens are triple helixes, and the differences lie in
the make-up of the alpha peptides created in step 2.
1. Transcription of mRNA: There are approximately 34 genes associated with collagen formation, each coding for
a specific mRNA sequence, and typically have the "COL" prefix. The beginning of collagen synthesis begins with
turning on genes which are associated with the formation of a particular alpha peptide (typically alpha 1, 2 or 3).
2. Pre-pro-peptide Formation: Once the final mRNA exits from the cell nucleus and enters into the cytoplasm it
links with the ribosomal subunits and the process of translation occurs. The early/first part of the new peptide is
known as the signal sequence. The signal sequence on the N-terminal of the peptide is recognized by a signal
recognition particle on the endoplasmic reticulum, which will be responsible for directing the pre-pro-peptide into
the endoplasmic reticulum. Therefore, once the synthesis of new peptide is finished, it goes directly into the
endoplasmic reticulum for post-translational processing. Note that it is now known as pre-pro-collagen.
3. Alpha Peptide to Procollagen: Three modifications of the pre-pro-peptide occurs leading to the formation of the
alpha peptide. Secondly, the triple helix known as procollagen is formed before being transported in a transport
vesicle to the golgi apparatus. 1) The signal peptide on the N-terminal is dissolved, and the molecule is now
known as propeptide (not procollagen). 2) Hydroxylation of lysines and prolines on propeptide by the enzymes
prolyl hydroxylase and lysyl hydroxylase (to produce hydroxyproline and hydroxylysine) occurs to aid
crosslinking of the alpha peptides. It is this enzymatic step that requires vitamin C as a cofactor. In scurvy, the
lack of hydroxylation of prolines and lysines causes a looser triple helix (which is formed by 3 alpha peptides). 3)
Glycosylation occurs by adding either glucose or galactose monomers onto the hydroxy groups that were placed
onto lysines, but not on prolines. From here the hydroxylated and glycosylated propeptide twists towards the left
very tightly and then three propeptides will form a triple helix. It is important to remember that this molecule,
now known as procollagen (not propeptide) is composed of a twisted portion (center) and two loose ends on
either end. At this point the procollagen is packaged into a transfer vesicle destined for the golgi apparatus.
4. Golgi Apparatus Modification: In the golgi apparatus, the procollagen goes through one last post-translational
modification before being secreted out of the cell. In this step oligosaccharides (not monosaccharides like in step
3) are added, and then the procollagen is packaged into a secretory vesicle destined for the extracellular space.
5. Formation of Tropocollagen: Once outside the cell, membrane bound enzymes known as collagen peptidases,
remove the "loose ends" of the procollagen molecule. What is left is known as tropocollagen. Defect in this step
produces one of the many collagenopathies known as Ehlers-Danlos syndrome. This step is absent when
synthesizing type III, a type of fibrilar collagen.
6. Formation of the Collagen Fibril: Lysyl oxidase and extracellular enzyme produces the final step in the collagen
synthesis pathway. This enzyme acts on lysines and hydroxylysines producing aldehyde groups, which will
eventually undergo covalent bonding between tropocollagen molecules. This polymer of tropocollogen is known
as a collagen fibril.

Molecular structure
The tropocollagen or collagen molecule is a subunit of larger collagen aggregates such as fibrils. At approximately
300 nm long and 1.5 nm in diameter, it is made up of three polypeptide strands (called alpha peptides, see step 2),
each possessing the conformation of a left-handed helix (its name is not to be confused with the commonly occurring
alpha helix, a right-handed structure). These three left-handed helices are twisted together into a right-handed coiled
coil, a triple helix or "super helix", a cooperative quaternary structure stabilized by numerous hydrogen bonds. With
type I collagen and possibly all fibrillar collagens if not all collagens, each triple-helix associates into a right-handed
super-super-coil referred to as the collagen microfibril. Each microfibril is interdigitated with its neighboring
microfibrils to a degree that might suggest they are individually unstable, although within collagen fibrils, they are so
well ordered as to be crystalline.
Collagen 139

A distinctive feature of collagen is the regular arrangement of amino acids in each of the three chains of these
collagen subunits. The sequence often follows the pattern Gly-Pro-X or Gly-X-Hyp, where X may be any of various
other amino acid residues.[23] Proline or hydroxyproline constitute about 1/6 of the total sequence. With glycine
accounting for the 1/3 of the sequence, this means approximately half of the collagen sequence is not glycine, proline
or hydroxyproline, a fact often missed due to the distraction of the unusual GX1X2 character of collagen
alpha-peptides. The high glycine content of collagen is important with respect to stabilization of the collagen helix as
this allows the very close association of the collagen fibers within the molecule, facilitating hydrogen bonding and
the formation of intermolecular cross-links.[23] This kind of regular repetition and high glycine content is found in
only a few other fibrous proteins, such as silk fibroin. About 75-80% of silk is (approximately) -Gly-Ala-Gly-Ala-
with 10% serine, and elastin is rich in glycine, proline, and alanine (Ala), whose side group is a small, inert methyl
group. Such high glycine and regular repetitions are never found in globular proteins save for very short sections of
their sequence. Chemically-reactive side groups are not needed in structural proteins, as they are in enzymes and
transport proteins; however, collagen is not quite just a structural protein. Due to its key role in the determination of
cell phenotype, cell adhesion, tissue regulation and infrastructure, many sections of its nonproline-rich regions have
cell or matrix association / regulation roles. The relatively high content of proline and hydroxyproline rings, with
their geometrically constrained carboxyl and (secondary) amino groups, along with the rich abundance of glycine,
accounts for the tendency of the individual polypeptide strands to form left-handed helices spontaneously, without
any intrachain hydrogen bonding.
Because glycine is the smallest amino acid with no side chain, it plays a unique role in fibrous structural proteins. In
collagen, Gly is required at every third position because the assembly of the triple helix puts this residue at the
interior (axis) of the helix, where there is no space for a larger side group than glycine’s single hydrogen atom. For
the same reason, the rings of the Pro and Hyp must point outward. These two amino acids help stabilize the triple
helix—Hyp even more so than Pro; a lower concentration of them is required in animals such as fish, whose body
temperatures are lower than most warm-blooded animals. Lower proline and hydroxyproline contents are
characteristic of cold-water, but not warm-water fish; the latter tend to have similar proline and hydroxyproline
contents to mammals.[23] The lower proline and hydroxproline contents of cold-water fish and other poikilotherm
animals leads to their collagen having a lower thermal stability than mammalian collagen.[23] This lower thermal
stability means that gelatin derived from fish collagen is not suitable for many Gelatin.
The tropocollagen subunits spontaneously self-assemble, with regularly staggered ends, into even larger arrays in the
extracellular spaces of tissues.[25][26] In the fibrillar collagens, the molecules are staggered from each other by about
67 nm (a unit that is referred to as ‘D’ and changes depending upon the hydration state of the aggregate). Each
D-period contains four plus a fraction collagen molecules, because 300 nm divided by 67 nm does not give an
integer (the length of the collagen molecule divided by the stagger distance D). Therefore, in each D-period repeat of
the microfibril, there is a part containing five molecules in cross-section, called the “overlap”, and a part containing
only four molecules, called the "gap".[21] The triple-helices are also arranged in a hexagonal or quasihexagonal array
in cross-section, in both the gap and overlap regions.[13][21]
There is some covalent crosslinking within the triple helices, and a variable amount of covalent crosslinking between
tropocollagen helices forming well organized aggregates (such as fibrils).[27] Larger fibrillar bundles are formed with
the aid of several different classes of proteins (including different collagen types), glycoproteins and proteoglycans
to form the different types of mature tissues from alternate combinations of the same key players.[26] Collagen's
insolubility was a barrier to the study of monomeric collagen until it was found that tropocollagen from young
animals can be extracted because it is not yet fully crosslinked. However, advances in microscopy techniques
electron microscopy (EM) and atomic force microscopy (AFM)) and X-ray diffraction have enabled researchers to
obtain increasingly detailed images of collagen structure in situ. These later advances are particularly important to
better understanding the way in which collagen structure affects cell-cell and cell-matrix communication, and how
tissues are constructed in growth and repair, and changed in development and disease.[28][29] For example using
AFM –based nanoindentation it has been shown that a single collagen fibril is a heterogeneous material along its
Collagen 140

axial direction with significantly different mechanical properties in its gap and overlap regions, correlating with its
different molecular organizations in these two regions.[30]
Collagen fibrils are semicrystalline aggregates of collagen molecules. Collagen fibers are bundles of fibrils.
Collagen fibrils/aggregates are arranged in different combinations and concentrations in various tissues to provide
varying tissue properties. In bone, entire collagen triple helices lie in a parallel, staggered array. 40 nm gaps between
the ends of the tropocollagen subunits (approximately equal to the gap region) probably serve as nucleation sites for
the deposition of long, hard, fine crystals of the mineral component, which is (approximately) C6H12O6 with some
phosphate. It is in this way that certain kinds of cartilage turn into bone. Type I collagen gives bone its tensile
strength.

Types and associated disorders


Collagen occurs in many places throughout the body. Over 90% of the collagen in the body, however, is of type
one.[31]
So far, 28 types of collagen have been identified and described. The five most common types are:
• Collagen I: skin, tendon, vascular ligature, organs, bone (main component of the organic part of bone)
• Collagen II: cartilage (main component of cartilage)
• Collagen III: reticulate (main component of reticular fibers), commonly found alongside type I.
• Collagen IV: forms bases of cell basement membrane
• Collagen V: cell surfaces, hair and placenta
Collagen-related diseases most commonly arise from genetic defects or nutritional deficiencies that affect the
biosynthesis, assembly, postranslational modification, secretion, or other processes involved in normal collagen
production.

Type Notes Gene(s) Disorders

I This is the most abundant collagen of the human body. It is present in scar COL1A1, COL1A2 Osteogenesis imperfecta,
tissue, the end product when tissue heals by repair. It is found in tendons, Ehlers–Danlos syndrome, Infantile
skin, artery walls, cornea, the endomysium of myofibrils, fibrocartilage, cortical hyperostosis aka Caffey's
and the organic part of bones and teeth. disease

II Hyaline cartilage, makes up 50% of all cartilage protein. Vitreous humour COL2A1 Collagenopathy, types II and XI
of the eye.

III This is the collagen of granulation tissue, and is produced quickly by young COL3A1 Ehlers–Danlos syndrome,
fibroblasts before the tougher type I collagen is synthesized. Reticular Dupuytren's contracture
fiber. Also found in artery walls, skin, intestines and the uterus

IV Basal lamina; eye lens. Also serves as part of the filtration system in COL4A1, COL4A2, Alport syndrome, Goodpasture's
capillaries and the glomeruli of nephron in the kidney. COL4A3, COL4A4, syndrome
COL4A5, COL4A6

V Most interstitial tissue, assoc. with type I, associated with placenta COL5A1, COL5A2, Ehlers–Danlos syndrome
COL5A3 (Classical)

VI Most interstitial tissue, assoc. with type I COL6A1, COL6A2, Ulrich myopathy, Bethlem
COL6A3, COL6A5 [32]
myopathy, Atopic dermatitis

VII Forms anchoring fibrils in dermoepidermal junctions COL7A1 Epidermolysis bullosa dystrophica

VIII Some endothelial cells COL8A1, COL8A2 Posterior polymorphous corneal


dystrophy 2

IX FACIT collagen, cartilage, assoc. with type II and XI fibrils COL9A1, COL9A2, EDM2 and EDM3
COL9A3

X Hypertrophic and mineralizing cartilage COL10A1 Schmid metaphyseal dysplasia


Collagen 141

XI Cartilage COL11A1, COL11A2 Collagenopathy, types II and XI

XII FACIT collagen, interacts with type I containing fibrils, decorin and COL12A1 –
glycosaminoglycans

XIII Transmembrane collagen, interacts with integrin a1b1, fibronectin and COL13A1 –
components of basement membranes like nidogen and perlecan.

XIV FACIT collagen COL14A1 –

XV – COL15A1 –

XVI – COL16A1 –

XVII Transmembrane collagen, also known as BP180, a 180 kDa protein COL17A1 Bullous pemphigoid and certain
forms of junctional epidermolysis
bullosa

XVIII Source of endostatin COL18A1 –

XIX FACIT collagen COL19A1 –

XX – COL20A1 –

XXI FACIT collagen COL21A1 –

XXII – COL22A1 –

XXIII MACIT collagen COL23A1 –

XXIV – COL24A1 –

XXV – COL25A1 –

XXVI – EMID2 –

XXVII – COL27A1 –

XXVIII – COL28A1 –

In addition to the above mentioned disorders, excessive deposition of collagen occurs in scleroderma.
Collagen 142

Staining
In histology, collagen is brightly eosinophilic (pink) in standard H&E slides. The dye methyl violet may be used to
stain the collagen in tissue samples.
The dye methyl blue can also be used to stain collagen and immunohistochemical stains are available if required.
The best stain for use in differentiating collagen from other fibers is Masson's trichrome stain.

Synthesis

Amino acids
Collagen has an unusual amino acid composition and sequence:
• Glycine (Gly) is found at almost every third residue
• Proline (Pro) makes up about 17% of collagen
• Collagen contains two uncommon derivative amino acids not
directly inserted during translation. These amino acids are found at
specific locations relative to glycine and are modified
post-translationally by different enzymes, both of which require
vitamin C as a cofactor.
• Hydroxyproline (Hyp), derived from proline.
• Hydroxylysine (Hyl), derived from lysine (Lys). Depending on
the type of collagen, varying numbers of hydroxylysines are
glycosylated (mostly having disaccharides attached).
Cortisol stimulates degradation of (skin) collagen into amino acids.[33]

Collagen I formation
Most collagen forms in a similar manner, but the following process is
typical for type I:
1. Inside the cell Action of lysyl oxidase
1. Two types of peptide chains are formed during translation on
ribosomes along the rough endoplasmic reticulum (RER): alpha-1 and alpha-2 chains. These peptide chains
(known as preprocollagen) have registration peptides on each end and a signal peptide.
2. Polypeptide chains are released into the lumen of the RER.
3. Signal peptides are cleaved inside the RER and the chains are now known as pro-alpha chains.
4. Hydroxylation of lysine and proline amino acids occurs inside the lumen. This process is dependent on
ascorbic acid (Vitamin C) as a cofactor.
5. Glycosylation of specific hydroxylysine residues occurs.
6. Triple helical structure is formed inside the endoplasmic reticulum from each two alpha-1 chains and one
alpha-2 chain.
7. Procollagen is shipped to the Golgi apparatus, where it is packaged and secreted by exocytosis.
2. Outside the cell
1. Registration peptides are cleaved and tropocollagen is formed by procollagen peptidase.
2. Multiple tropocollagen molecules form collagen fibrils, via covalent cross-linking (aldol reaction) by lysyl
oxidase which links hydroxylysine and lysine residues. Multiple collagen fibrils form into collagen fibers.
3. Collagen may be attached to cell membranes via several types of protein, including fibronectin and integrin.
Collagen 143

Synthetic pathogenesis
Vitamin C deficiency causes scurvy, a serious and painful disease in which defective collagen prevents the formation
of strong connective tissue. Gums deteriorate and bleed, with loss of teeth; skin discolors, and wounds do not heal.
Prior to the eighteenth century, this condition was notorious among long duration military, particularly naval,
expeditions during which participants were deprived of foods containing Vitamin C.
An autoimmune disease such as lupus erythematosus or rheumatoid arthritis[34] may attack healthy collagen fibers.
Many bacteria and viruses have virulence factors which destroy collagen or interfere with its production.

Characteristics
Collagen is one of the long, fibrous structural proteins whose functions are quite different from those of globular
proteins such as enzymes. Tough bundles of collagen called collagen fibers are a major component of the
extracellular matrix that supports most tissues and gives cells structure from the outside, but collagen is also found
inside certain cells. Collagen has great tensile strength, and is the main component of fascia, cartilage, ligaments,
tendons, bone and skin.[35][36] Along with soft keratin, it is responsible for skin strength and elasticity, and its
degradation leads to wrinkles that accompany aging.[37][38] It strengthens blood vessels and plays a role in tissue
development. It is present in the cornea and lens of the eye in crystalline form.

Uses
Collagen has a wide variety of applications, from food to medical. For instance, it is used in cosmetic surgery and
burns surgery. It is widely used in the form of collagen casings for sausages.
If collagen is sufficiently denatured, e.g. by heating, the three tropocollagen strands separate partially or completely
into globular domains, containing a different secondary structure to the normal collagen polyproline II (PPII), e.g.
random coils. This process describes the formation of gelatin, which is used in many foods, including flavored
gelatin desserts. Besides food, gelatin has been used in pharmaceutical, cosmetic, and photography industries.[39]
From a nutritional point of view, collagen and gelatin are a poor-quality sole source of protein since they do not
contain all the essential amino acids in the proportions that the human body requires—they are not 'complete
proteins' (as defined by food science, not that they are partially structured). Manufacturers of collagen-based dietary
supplements claim that their products can improve skin and fingernail quality as well as joint health. However,
mainstream scientific research has not shown strong evidence to support these claims. Individuals with problems in
these areas are more likely to be suffering from some other underlying condition (such as normal aging, dry skin,
arthritis etc.) rather than just a protein deficiency.
From the Greek for glue, kolla, the word collagen means "glue producer" and refers to the early process of boiling
the skin and sinews of horses and other animals to obtain glue. Collagen adhesive was used by Egyptians about
4,000 years ago, and Native Americans used it in bows about 1,500 years ago. The oldest glue in the world,
carbon-dated as more than 8,000 years old, was found to be collagen—used as a protective lining on rope baskets
and embroidered fabrics, and to hold utensils together; also in crisscross decorations on human skulls.[40] Collagen
normally converts to gelatin, but survived due to the dry conditions. Animal glues are thermoplastic, softening again
upon reheating, and so they are still used in making musical instruments such as fine violins and guitars, which may
have to be reopened for repairs—an application incompatible with tough, synthetic plastic adhesives, which are
permanent. Animal sinews and skins, including leather, have been used to make useful articles for millennia.
Gelatin-resorcinol-formaldehyde glue (and with formaldehyde replaced by less-toxic pentanedial and ethanedial) has
been used to repair experimental incisions in rabbit lungs.[41]
Collagen 144

Medical uses

Cardiac applications
The four dense collagen valve rings, the central body of the heart and the cardiac skeleton of the heart are
histologically bound to the myocardium. Collagen contribution to heart performance summarily represents an
essential, unique and moving solid anchor opposed to the fluid mechanics of blood within the heart. This structure is
an impermeable firewall that excludes both blood and electrical influence (except through anatomical channels) from
the upper to the lower chambers of the heart. As proof, one could posit that atrial fibrillation almost never
deteriorates to ventricular fibrillation. Individual valvular leaflets are held in sail shape by collagen under variable
pressure. Calcium deposition within collagen occurs as a natural consequence of aging. Calcium rich fixed points in
an otherwise moving display of blood and muscle enable current cardiac imaging technology to arrive at ratios
essentially stating blood in cardiac input and blood out cardiac output. Specified imaging such as calcium scoring
illustrates the utility of this methodology, especially in an aging patient subject to pathology of the collagen
underpinning.

Type II Collagen and Rheumatoid Arthritis


According to a study[42] published in the journal Science, oral administration of type II collagen improves symptoms
of rheumatoid arthritis. The authors conducted a randomized, double-blind trial involving 60 patients with severe,
active rheumatoid arthritis. A decrease in the number of swollen joints and tender joints occurred in subjects fed with
chicken type II collagen for 3 months, but not in those that received a placebo. Four patients in the collagen group
had complete remission of the disease. No side effects were evident.

Cosmetic surgery
Collagen has been widely used in cosmetic surgery, as a healing aid for burn patients for reconstruction of bone and
a wide variety of dental, orthopedic and surgical purposes. Both human and bovine collagen is widely used as dermal
fillers for treatment of wrinkles and skin aging.[38] Some points of interest are:
1. when used cosmetically, there is a chance of allergic reactions causing prolonged redness; however, this can be
virtually eliminated by simple and inconspicuous patch testing prior to cosmetic use, and
2. most medical collagen is derived from young beef cattle (bovine) from certified BSE (bovine spongiform
encephalopathy) free animals. Most manufacturers use donor animals from either "closed herds", or from
countries which have never had a reported case of BSE such as Australia, Brazil and New Zealand.
3. porcine (pig) tissue is also widely used for producing collagen sheet for a variety of surgical purposes.
4. alternatives using the patient's own fat, hyaluronic acid or polyacrylamide gels which are readily available.

Reconstructive surgical uses


Collagens are widely employed in the construction of artificial skin substitutes used in the management of severe
burns. These collagens may be derived from bovine, equine or porcine, and even human sources and are sometimes
used in combination with silicones, glycosaminoglycans, fibroblasts, growth factors and other substances.
Collagen is also sold as a pill commercially as a joint mobility supplement with poor references.[43] Because proteins
are broken down into amino acids before absorption, there is no reason for orally ingested collagen to affect
connective tissue in the body, except through the effect of individual amino acid supplementation.
Although it cannot be absorbed through the skin, collagen is now being used as a main ingredient for some cosmetic
makeup.[44]
Collagen is also frequently used in scientific research applications for cell culture, studying cell behavior and cellular
interactions with the extracellular environment.[45] Suppliers such as Trevigen [46] manufacture rat and bovine
Collagen 145

Collagen I and mouse Collagen IV.

Wound care management uses


Collagen is one of the body’s key natural resources and a component of skin tissue that can benefit all stages of the
wound healing process. When collagen is made available to the wound bed, closure can occur. Wound deterioration,
followed sometimes by procedures such as amputation, can thus be avoided.
Throughout the 4 phases of wound healing, collagen performs the following functions in wound healing: • Guiding
Function: Collagen fibers serve to guide fibroblasts. Fibroblasts migrate along a connective tissue matrix. •
Chemotactic Properties: The large surface area available on collagen fibers can attract fibrogenic cells which help in
healing. • Nucleation: Collagen, in the presence of certain neutral salt molecules can act as a nucleating agent
causing formation of fibrillar structures. A collagen wound dressing might serve as a guide for orienting new
collagen deposition and capillary growth. • Hemostatic properties: Blood platelets interact with the collagen to make
a hemostatic plug.
Suppliers such as Human BioSciences [47] manufacture bovine type 1 collagen into wound care bandages.

Paleontology and Archaeology


Because the synthesis of collagen requires a high level of atmospheric oxygen, complex animals may not have been
able to evolve until the atmosphere was oxygenic enough for collagen synthesis.[48] The origin of collagen may have
allowed cuticle, shell and muscle formation. However, the preservation of collagen in the fossil record is very
scarce.[49] There is mounting evidence—which remains controversial—that collagen has been preserved in dinosaur
specimens dated as long ago as 80 [50] million years ago.[51]
Also worth noting are the actinofibrils, collagen fibers present on the wings of pterosaurs.
Collagen is regularly extracted from the bones of prehistoric animals for use in radiocarbon dating and stable isotope
analysis. The integrity of the molecule can be assessed with a number of measurements (collagen yield, C:N ratio,
%C and %N).[23] With respect to radiometric dating, extracted collagen produces a 'more pure' form of carbon that
can be dated than does bulk bone, which contains a high amount of carbonated apatite, which is prone to exchange
with environmental sources of carbon, causing contamination. Stable isotope analysis of carbon and nitrogen are
commonly used to study diet in past populations of humans, as well as to reconstruct ecological conditions.

Art
Using the atomic coordinates deposited in the Protein Data Bank,
German-American artist Julian Voss-Andreae has created sculptures
based on the structure of collagen and other proteins.[52] In Unraveling
Collagen the triangular cut-outs reveal the dominant force lines,
reminiscent of contemporary steel construction.[53][54]

References
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Antonio, James D. (2002). "Mapping the Ligand-binding Sites and
Collagen (2005), stainless steel, height 11 ft 3 in
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its proteolysis". PNAS 105 (8): 2824–2829. doi:10.1073/pnas.0710588105. PMC 2268544. PMID 18287018.
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Matrix Interaction Domains on the Collagen Fibril, the Predominant Protein of Vertebrates". J Biol Chem 283 (30): 21187–21197.
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[29] Twardowski, T.; et al., A.; Orgel, J. P.R.O.; San Antonio, J. D. (2007). "Type I collagen and collagen mimetics as angiogenesis promoting
superpolymers" (http:/ / www. ingentaconnect. com/ content/ ben/ cpd/ 2007/ 00000013/ 00000035/ art00009). Curr Pharm Des 13 (35):
3608–3621. doi:10.2174/138161207782794176. .
[30] M. Minary-Jolandan and M.-F. Yu, "Nanomechanical Heterogeneity in the Gap and Overlap Regions of Type I Collagen Fibrils with
Implications for Bone Heterogeneity", Biomacromolecules 10, 2565 (2009)
[31] Sabiston textbook of surgery board review, 7th edition. Chapter 5 wound healing, question 14
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[32] Söderhäll, C.; Marenholz, I.; Kerscher, T.; Rüschendorf, F; Rüschendorf, F.; Esparza-Gordillo, J.; et al., C; Mayr, G et al. (2007). "Variants
in a Novel Epidermal Collagen Gene (COL29A1) Are Associated with Atopic Dermatitis". PLoS Biology 5 (9): e242.
doi:10.1371/journal.pbio.0050242. PMC 1971127. PMID 17850181.
[33] Houck, J. C.; Sharma, V. K.; Patel, Y. M.; Gladner, J. A. (1968). "Induction of Collagenolytic and Proteolytic Activities by
AntiInflammatory Drugs in the Skin and Fibroblasts". Biochemical Pharmacology 17 (10): 2081–2090. doi:10.1016/0006-2952(68)90182-2.
PMID 4301453.
[34] Al-Hadithy, H.; et al., DA; Addison, IE; Goldstone, AH; Snaith, ML (1982). "Neutrophil function in systemic lupus erythematosus and
other collagen diseases". Ann Rheum Dis 41 (1): 33–38. doi:10.1136/ard.41.1.33. PMC 1000860. PMID 7065727.
[35] Fratzl, P. (2008). Collagen: Structure and Mechanics. New York: Springer. ISBN 0-387-73905-X.
[36] Buehler, M. J. (2006). "Nature designs tough collagen: Explaining the nanostructure of collagen fibrils". PNAS 103 (33): 12285–12290.
doi:10.1073/pnas.0603216103. PMC 1567872. PMID 16895989.
[37] Structure of Skin | The Aging Skin (http:/ / pharmaxchange. info/ press/ 2011/ 03/ the-aging-skin-part-1-structure-of-skin-and-introduction/ )
[38] Dermal Fillers | The Ageing Skin (http:/ / pharmaxchange. info/ press/ 2011/ 03/ the-ageing-skin-part-4e-dermal-fillers/ )
[39] "Gelatin's Advantages: Health, Nutrition and Safety" (http:/ / www. gmap-gelatin. com/ gelatin_adv. html). .
[40] Walker, Amélie A. (May 21, 1998). "Oldest Glue Discovered" (http:/ / www. archaeology. org/ online/ news/ glue. html). Archaeology. .
[41] Ennker, I. C.; et al., JüRgen; Schoon, Doris; Schoon, Heinz Adolf; Rimpler, Manfred; Hetzer, Roland (1994). "Formaldehyde-free collagen
glue in experimental lung gluing" (http:/ / ats. ctsnetjournals. org/ cgi/ content/ abstract/ 57/ 6/ 1622). Ann Thorac Surg. 57 (6): 1622–1627.
doi:10.1016/0003-4975(94)90136-8. PMID 8010812. .
[42] Trentham, D.; Dynesius-Trentham, R.; Orav, J.; Combitchi, D.; Lorenzo, C.; Sewell, K.; Hafler, D. & Weiner, H. (1993). "Effects of Oral
Administration of Type II Collagen on Rheumatoid Arthritis". Science 261 (5119): 1727–1730. doi:10.1126/science.8378772.
[43] "Hydrolyzed Collagen pills usages" (http:/ / www. articlecat. com/ Article/ Hydrolyzed-Collagen--Protein-Hydrate/ 21273). .
[44] "www.articlesbase.com" (http:/ / www. articlesbase. com/ skin-care-articles/
can-collagen-be-absorbed-into-the-skin-or-is-it-all-just-one-big-hoax-674325. html). .
[45] Blow, Nathan (2009). "Cell culture: building a better matrix". Nature Methods 6 (8): 619–622. doi:10.1038/nmeth0809-619.
[46] http:/ / www. trevigen. com/ angiocell/ cultrex. php
[47] http:/ / www. humanbiosciences. com
[48] http:/ / facstaff. gpc. edu/ ~pgore/ geology/ geo102/ cambrian. htm
[49] We, K. M. T. O. (1996). "Fossil preservation in the Burgess Shale". Lethaia 29 (1): 107–108. doi:10.1111/j.1502-3931.1996.tb01844.x.
[50] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=80
[51] Schweitzer, H. .; Zheng, W. .; Organ, L. .; Avci, R. .; Suo, Z. .; Freimark, M. .; Lebleu, S. .; Duncan, B. . et al.; Wenxia Zheng,1 Chris L.
Organ,3 Recep Avci,4 Zhiyong Suo,4 Lisa M. Freimark,5 Valerie S. Lebleu,6,7 Michael B. Duncan,6,7 Matthew G. Vander Heiden,8 John M.
Neveu,9 William S. Lane,9 John S. Cottrell,10 John R. Horner,11 Lewis C. Cantley,5,12 Raghu Kalluri,6,7,13 John M. Asara5,14,* (May
2009). "Biomolecular Characterization and Protein Sequences of the Campanian Hadrosaur B. Canadensis". Science 324 (5927): 626–631.
Bibcode 2009Sci...324..626S. doi:10.1126/science.1165069. ISSN 0036-8075. PMID 19407199.
[52] "PDB Community Focus: Julian Voss-Andreae, Protein Sculptor" (ftp:/ / ftp. wwpdb. org/ pub/ pdb/ doc/ newsletters/ rcsb_pdb/
news32_jan07. pdf). Protein Data Bank Newsletter (32). Winter 2007. .
[53] Ward, Barbara (April 2006). "'Unraveling Collagen' structure to be installed in Orange Memorial Park Sculpture Garden" (http:/ / www.
future-drugs. com/ doi/ pdf/ 10. 1586/ 14789450. 3. 2. 169). Expert Rev. Proteomics 3 (2) (2): 174. doi:10.1586/14789450.3.2.169. .
[54] Interview with J. Voss-Andreae "Seeing Below the Surface" in Seed Magazine (http:/ / seedmagazine. com/ news/ 2006/ 05/
seeing_below_the_surface. php)

External links
• The Collagen Protein (http://macromoleculeinsights.com/collagen.php)
• Variant Collagen Products Range (http://sstwo-mall.com)
• collagen 6000mg (http://www.collypink.net/ข้à¸à¸¡à¸¹à¸¥-collypink.html)
• 12 types of collagen (http://themedicalbiochemistrypage.org/extracellularmatrix.html)
• Database of type I and type III collagen mutations (http://www.le.ac.uk/genetics/collagen/)
• Science.dirbix Collagen (http://science.dirbix.com/biology/collagen)
• Collagen Stability Calculator (http://compbio.cs.princeton.edu/csc/)
• Computer-generated animations of the assembly of Type I and Type IV Collagens (http://www.mc.vanderbilt.
edu/cmb/collagen/)
• Integrin-Collagen interface, PMAP (http://www.youtube.com/watch?v=_a8q2OWrdvM) (The Proteolysis
Map)—animation
• Integrin-Collagen binding model, PMAP (http://www.youtube.com/watch?v=8BMFqRmbbes) (The
Proteolysis Map)—animation
Collagen 148

• Collagen-Integrin atomic detail, PMAP (http://www.youtube.com/watch?v=8L3a7oqQPRY) (The Proteolysis


Map)—animation

Connective tissue
"Connective tissue" is a fibrous and most diverse tissue.[1] It is one of the four traditional classes of tissues (the
others being epithelial, muscle and nervous tissue). Connective Tissue (CT) is found throughout the body. In fact the
whole framework of the skeleton and the different specialized connective tissues from the crown of the head to the
toes determine the form of the body and act as an entity. CT has 3 main components: cells, fibers, and extracellular
matrix, all embedded in the body fluids. Fibroblasts are the cells responsible for the production of connective tissue.
The interaction of the fibers, the extracellular matrix and the water, together, form the pliable connective tissue as a
whole. Connective tissue makes up a variety of physical structures including tendons and the connective framework
of fibers in muscles, capsules and ligaments around joints, cartilage, bone, adipose tissue, blood and lymphatic
tissue. CT is classified into three subtypes; Embryonic CT, Proper CT, and Special CT. The Proper CT subtype
includes dense regular CT, dense irregular CT, and loose CT. The Special CT subtype includes cartilage, bone,
adipose tissue, blood, hematopoietic tissue (tissue that makes blood cells) and lymphatic tissue. as well as the most
abundant protein in mammals, Type-I collagen, making up about 25% of the total protein content.[2]

Functions of connective tissue


• Storage of energy
• Protection of organs
• Providing structural framework for the body
• Connection of body tissues

Fiber types and characteristics of the connective tissue


Not to be confused with muscle fibers.
Characteristics of connective tissue:
• Cells are spread through an extracellular fluid.
• Ground Substance - A clear, colorless, and viscous fluid containing glycosaminoglycans and proteoglycans to fix
the bodywater and the collagen fibers in the intercellular spaces. Ground substance slows the spread of pathogens.
• Fibers. Not all types of connective tissues are fibrous though. Examples are adipose tissue and blood. Adipose
tissue gives "mechanical cushioning" to our body. Although there is no dense collagen network in adipose tissue,
groups of adipose cells are kept together by collagen fibers and collagen sheets in order to keep fat tissue under
compression in place (for example the sole of the foot). The matrix of blood is plasma.
• Both the ground substance and proteins(fibers) create the matrix for connective tissue.
Connective tissue 149

Tissue Purpose Components Location

Collagenous - Alpha polypeptide chains tendon, ligament, skin, cornea, cartilage, bone, blood vessels, gut, and intervertebral
fibers disc.

Elastic fibers - elastic microfibrill & extracellular matrix


elastin

Reticular fibers - - liver, bone marrow, lymphatic organs

Disorders of connective tissue


Various connective tissue conditions have been identified; these can be both inherited and environmental.
• Marfan syndrome - a genetic disease causing abnormal fibrillin.
• Scurvy - caused by a dietary deficiency in vitamin C, leading to abnormal collagen.
• Ehlers-Danlos syndrome - deficient type III collagen- a genetic disease causing progressive deterioration of
collagens, with different EDS types affecting different sites in the body, such as joints, heart valves, organ walls,
arterial walls, etc.
• Loeys-Dietz syndrome - a genetic disease related to Marfan syndrome, with an emphasis on vascular
deterioration.
• Pseudoxanthoma elasticum - an autosomal recessive hereditary disease, caused by calcification and fragmentation
of elastic fibres, affecting the skin, the eyes and the cardiovascular system.
• Systemic lupus erythematosus - a chronic, multisystem, inflammatory disorder of probable autoimmune etiology,
occurring predominantly in young women.
• Osteogenesis imperfecta (brittle bone disease) - caused by insufficient production of good quality collagen to
produce healthy, strong bones.
• Fibrodysplasia ossificans progressiva - disease of the connective tissue, caused by a defective gene which turns
connective tissue into bone.
• Spontaneous pneumothorax - collapsed lung, believed to be related to subtle abnormalities in connective tissue.
• Sarcoma - a neoplastic process originating within connective tissue.
• Hemangiopericytoma - a neoplastic process

Staining of connective tissue


For microscopic viewing the majority of the connective tissue staining techniques color tissue fibers in contrasting
shades. Collagen may be differentially stained by any of the following techniques:
• Van Gieson's stain
• Masson's Trichrome stain
• Mallory's Aniline Blue stain
• Azocarmine stain
• Krajian's Aniline Blue stain
• Eosin
Connective tissue 150

References
[1] " connective tissue (http:/ / web. archive. org/ web/ 20090616022448/ http:/ / www. mercksource. com/ pp/ us/ cns/ cns_hl_dorlands_split.
jsp?pg=/ ppdocs/ us/ common/ dorlands/ dorland/ eight/ 000109061. htm)" at Dorland's Medical Dictionary
[2] Di Lullo, G. A. (2002). "Mapping the Ligand-binding Sites and Disease-associated Mutations on the Most Abundant Protein in the Human,
Type I Collagen" (http:/ / www. jbc. org/ cgi/ content/ abstract/ 277/ 6/ 4223). Journal of Biological Chemistry 277 (6): 4223–31.
doi:10.1074/jbc.M110709200. PMID 11704682. .

External links
• connective+tissue (http://www.emedicinehealth.com/script/main/srchcont_dict.asp?src=connective+tissue)
at eMedicine Dictionary
• Encyclopaedia Britannica, Connective Tissue (http://www.britannica.com/eb/article-9110162/
connective-tissue)
• Overview at kumc.edu (http://www.kumc.edu/instruction/medicine/anatomy/histoweb/ct/ct.htm)
• UIUC Histology Subject 230 (https://histo.life.illinois.edu/histo/atlas/oimages.php?oid=230)
• Connective tissue atlas at uiowa.edu (http://www.medicine.uiowa.edu/anatomy/dental/genhisto/GHWIN/
unit3/index.html)

Copolymer
A heteropolymer or copolymer is a polymer derived from two (or more) monomeric
species, as opposed to a homopolymer where only one monomer is used.[1]
Copolymerization refers to methods used to chemically synthesize a copolymer.
Commercially relevant copolymers include ABS plastic, SBR, Nitrile rubber,
styrene-acrylonitrile, styrene-isoprene-styrene (SIS) and ethylene-vinyl acetate.

Vinyl Copolymer Milk


Copolymer 151

Types of copolymers
Since a copolymer consists of at least
two types of constituent units (also
structural units), copolymers can be
classified based on how these units are
arranged along the chain.[2] These
include:

• Alternating copolymers with


regular alternating A and B units (2)
• Periodic copolymers with A and B
units arranged in a repeating
sequence (e.g.
(A-B-A-B-B-A-A-A-A-B-B-B)n) Different types of copolymers
• Statistical copolymers are
copolymers in which the sequence of monomer residues follows a statistical rule. If the probability of finding a
given type monomer residue at a particular point in the chain is equal to the mole fraction of that monomer
residue in the chain, then the polymer may be referred to as a truly random copolymer[3] (3).
• Block copolymers comprise two or more homopolymer subunits linked by covalent bonds (4). The union of the
homopolymer subunits may require an intermediate non-repeating subunit, known as a junction block. Block
copolymers with two or three distinct blocks are called diblock copolymers and triblock copolymers,
respectively.
Copolymers may also be described in terms of the existence of or arrangement of branches in the polymer structure.
Linear copolymers consist of a single main chain whereas branched copolymers consist of a single main chain
with one or more polymeric side chains.
Other special types of branched copolymers include star copolymers, brush copolymers, and comb copolymers. In
gradient copolymers the monomer composition changes gradually along the chain.
A terpolymer is a copolymer consisting of three distinct monomers. The term is derived from ter (Latin), meaning
thrice, and polymer.
• Stereoblock copolymers
A special structure can be formed from one monomer where now the
distinguishing feature is the tacticity of each block.

Graft copolymers
Graft copolymers are a special type of branched copolymer in which the side chains are structurally distinct from
the main chain. The illustration (5) depicts a special case where the main chain and side chains are composed of
distinct homopolymers. However, the individual chains of a graft copolymer may be homopolymers or copolymers.
Note that different copolymer sequencing is sufficient to define a structural difference, thus an A-B diblock
copolymer with A-B alternating copolymer side chains is properly called a graft copolymer.
For example, suppose we perform a free-radical polymerization of styrene in the presence of polybutadiene, a
synthetic rubber, which retains one reactive C=C double bond per residue. We get polystyrene chains growing out in
either direction from some of the places where there were double bonds, with a one-carbon rearrangement. Or to
look at it the other way around, the result is a polystyrene backbone with polybutadiene chains growing out of it in
Copolymer 152

both directions. This is an interesting copolymer variant in that one of the ingredients was a polymer to begin with.
As with block copolymers, the quasi-composite product has properties of both "components". In the example cited,
the rubbery chains absorb energy when the substance is hit, so it is much less brittle than ordinary polystyrene. The
product is called high-impact polystyrene, or HIPS.

Block copolymers
A special kind of copolymer is called a "block copolymer". Block copolymers are made up of blocks of different
polymerized monomers.[4] For example, PS-b-PMMA is short for polystyrene-b-poly(methyl methacrylate) and is
usually made by first polymerizing styrene, and then subsequently polymerizing MMA from the reactive end of the
polystyrene chains. This polymer is a "diblock copolymer" because it contains two different chemical blocks.
Triblocks, tetrablocks, multiblocks, etc. can also be made. Diblock copolymers are made using living polymerization
techniques, such as atom transfer free radical polymerization (ATRP), reversible addition fragmentation chain
transfer (RAFT), ring-opening metathesis polymerization (ROMP), and living cationic or living anionic
polymerizations.[5] An emerging technique is chain shuttling polymerization. The most powerful strategy to prepare
block copolymers is the chemoselective stepwise coupling between polymeric precursors and heterofunctional
linking agents.[6] This method enables access to peculiarly exotic structures such as tetrablock quarterpolymers
ABCD.[7]
Recent research in block copolymers suggests that they may be useful in creating self-constructing fabrics with
potential utility in semiconductor arrays (for example, computer memory devices) by assembling fine details atop a
structured base created using conventional microlithography methods.[8]

Phase separation

Block copolymers are interesting because they can "microphase


separate" to form periodic nanostructures, as in the
styrene-butadiene-styrene block copolymer shown at right. The
polymer is known as Kraton and is used for shoe soles and adhesives.
Owing to the microfine structure, the transmission electron microscope
or TEM was needed to examine the structure. The butadiene matrix
was stained with osmium tetroxide to provide contrast in the image.
The material was made by living polymerization so that the blocks are
almost monodisperse, so helping to create a very regular SBS block copolymer in TEM
microstructure. The molecular weight of the polystyrene blocks in the
main picture is 102,000; the inset picture has a molecular weight of 91,000, producing slightly smaller domains.

Microphase separation is a situation similar to that of oil and water. Oil


and water are immiscible - they phase separate. Due to incompatibility
between the blocks, block copolymers undergo a similar phase
separation. Because the blocks are covalently bonded to each other,
they cannot demix macroscopically as water and oil. In "microphase
separation" the blocks form nanometer-sized structures. Depending on
the relative lengths of each block, several morphologies can be
obtained. In diblock copolymers, sufficiently different block lengths
lead to nanometer-sized spheres of one block in a matrix of the second
(for example PMMA in polystyrene). Using less different block
SBS block copolymer schematic microstructure
lengths, a "hexagonally packed cylinder" geometry can be obtained.
Copolymer 153

Blocks of similar length form layers (often called lamellae in the technical literature). Between the cylindrical and
lamellar phase is the gyroid phase. The nanoscale structures created from block copolymers could potentially be used
for creating devices for use in computer memory, nanoscale-templating and nanoscale separations.
Polymer scientists use thermodynamics to describe how the different blocks interact. The product of the degree of
polymerization, n, and the Flory-Huggins interaction parameter, , gives an indication of how incompatible the
two blocks are and whether or not they will microphase separate. For example, a diblock copolymer of symmetric
composition will microphase separate if the product is greater than 10.5. If is less than 10.5, the blocks
will mix and microphase separation is not observed.

Copolymer equation
An alternating copolymer has the formula: -A-B-A-B-A-B-A-B-A-B-, or -(-A-B-)n-. The molar ratios of the
monomer in the polymer is close to one, which happens when the reactivity ratios r1 & r2 are close to zero, as given
by the Mayo-Lewis equation also called the copolymerization equation:[9]

where r1 = k11/k12 & r2 = k22/k21

Copolymer engineering
Copolymerization is used to modify the properties of manufactured plastics to meet specific needs, for example to
reduce crystallinity, modify glass transition temperature or to improve solubility. It is a way of improving
mechanical properties, in a technique known as rubber toughening. Elastomeric phases within a rigid matrix act as
crack arrestors, and so increase the energy absorption when the material is impacted for example. Acrylonitrile
butadiene styrene is a common example.

References
[1] Odian, G. (2004). "6" (http:/ / books. google. com/ ?id=6cjgZbFHI4kC& pg=PA464). Principles of Polymerization. Wiley-Interscience.
p. 464. ISBN 0-471-27400-3. .
[2] Jenkins, A. D.; Kratochvíl, P.; Stepto, R. F. T.; Suter, U. W. (1996). "Glossary of Basic Terms in Polymer Science". Pure Appl. Chem. 68
(12): 2287–2311. doi:10.1351/pac199668122287.
[3] Painter P. C. and Coleman M. M., Fundamentals of Polymer Science, CRC Press, 1997, p 14.
[4] Polymer Research Laboratory (http:/ / www. princeton. edu/ ~polymer/ block. html) (Princeton.edu accessed Aug 15, 2008)
[5] Hadjichristidis N., Pispas S., Floudas G. Block copolymers: synthetic strategies, physical properties, and applications – Wiley, 2003.
[6] Bellas, Vasilios; Rehahn, Matthias (2007). "Universal Methodology for Block Copolymer Synthesis" (http:/ / www3. interscience. wiley.
com/ cgi-bin/ fulltext/ 114280481/ PDFSTART). Macromolecular Rapid Communications 28 (13): 1415. doi:10.1002/marc.200700127. .
[7] Bellas, Vasilios; Rehahn, Matthias (2009). "Block Copolymer Synthesis via Chemoselective Stepwise Coupling Reactions". Macromolecular
Chemistry and Physics 210 (5): 320. doi:10.1002/macp.200800463.
[8] Self-growing material promises chip, storage advances (http:/ / www. networkworld. com/ community/ node/ 31115) (NetworkWorld
accessed Aug 15, 2008)
[9] Copolymerization. I. A Basis for Comparing the Behavior of Monomers in Copolymerization; The Copolymerization of Styrene and Methyl
MethacrylateFrank R. Mayo and Frederick M. Lewis J. Am. Chem. Soc.; 1944; 66(9) pp 1594 - 1601; doi:10.1021/ja01237a052

External links
• Introduction to Polymer Chemistry (http://www.chem.rochester.edu/~chem421/copoly.htm)
Cytoplasm 154

Cytoplasm
The cytoplasm is the gel-like
substance residing between the cell
membrane holding all the cell's
internal sub-structures (called
organelles), except for the nucleus. All
the contents of the cells of prokaryote
organisms (which lack a cell nucleus)
are contained within the cytoplasm.
Within the cells of eukaryote
organisms the contents of the cell
nucleus are separated from the
cytoplasm, and are then called the
nucleoplasm. The cytoplasm is about Schematic of typical animal cell, showing subcellular components. Organelles: (1)
70% to 90% water and usually Nucleolus (2) Nucleus (3) Ribosomes (little dots) (4) Vesicle (5) Rough endoplasmic
transparent. reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) Smooth ER (9) Mitochondria
(10) Vacuole (11) Cytosol (12) Lysosome (13) Centrioles within Centrosome
It is within the cytoplasm that most
cellular activities occur, such as many metabolic pathways including glycolysis, and processes such as cell division.
The inner, granular mass is called the endoplasm and the outer, clear and glassy layer is called the cell cortex or the
ectoplasm.
The part of the cytoplasm that is not held within organelles is called the cytosol. The cytosol is a complex mixture of
cytoskeleton filaments, dissolved molecules, and water that fills much of the volume of a cell. The cytosol is a gel,
with a network of fibers dispersed in water. Due to this network of fibres and high concentrations of dissolved
macromolecules, such as proteins, an effect called macromolecular crowding occurs and the cytosol does not act as
an ideal solution. This crowding effect alters how the components of the cytosol interact with each other.
Movement of calcium ions in and out of the cytoplasm is thought to be a signaling activity for metabolic
processes.[1]
In plants, movements of the cytoplasm around vacuoles are known as cyclosis.

Constituents
The cytoplasm has three major elements; the cytosol, organelles and inclusions.

Cytosol
The cytosol is the portion of the cytoplasm not contained within membrane-bound organelles. Cytosol makes up
about 70% of the cell volume and is composed of water, salts and organic molecules.[2] The cytosol also contains the
protein filaments that make up the cytoskeleton, as well as soluble proteins and small structures such as ribosomes,
proteasomes, and the mysterious vault complexes.[3] The inner, granular and more fluid portion of the cytoplasm is
referred to as endoplasm.
Cytoplasm 155

Organelles
Organelles, literally little organs, are membrane-bound
structures inside the cell that have specific functions.
Some major organelles that are suspended in the
cytosol are the mitochondria, the endoplasmic
reticulum, the Golgi apparatus, vacuoles, lysosomes,
and in plant cells chloroplasts.

Cytoplasmic inclusions
The inclusions are small particles of insoluble
substances suspended in the cytosol. A huge range of
inclusions exist in different cell types, and range from
crystals of calcium oxalate or silicon dioxide in
plants,[4][5] to granules of energy-storage materials
such as starch,[6] glycogen,[7] or
polyhydroxybutyrate.[8] A particularly widespread
example are lipid droplets, which are spherical droplets
composed of lipids and proteins that are used in both
prokaryotes and eukaryotes as a way of storing lipids
such as fatty acids and sterols.[9] Lipid droplets make Proteins in different cellular compartments and structures tagged
up much of the volume of adipocytes, which are with green fluorescent protein

specialized lipid-storage cells, but they are also found


in a range of other cell types.

Notes
[1] C. Michael Hogan. 2010. Calcium. eds. A.Jorgensen, C. Cleveland. Encyclopedia of Earth (http:/ / www. eoearth. org/ article/
Calcium?topic=49557). National Council for Science and the Environment.
[2] Cytoplasm Composition (http:/ / sun. menloschool. org/ ~birchler/ cells/ animals/ cytoplasm/ )
[3] van Zon A, Mossink MH, Scheper RJ, Sonneveld P, Wiemer EA (September 2003). "The vault complex". Cell. Mol. Life Sci. 60 (9):
1828–37. doi:10.1007/s00018-003-3030-y. PMID 14523546.
[4] Prychid, Christina J.; Rudall, Paula J. (1999). "Calcium Oxalate Crystals in Monocotyledons: A Review of their Structure and Systematics"
(http:/ / aob. oxfordjournals. org/ cgi/ content/ abstract/ 84/ 6/ 725). Annals of Botany 84 (6): 725. doi:10.1006/anbo.1999.0975. .
[5] Prychid, C. J.; Rudall, P. J.; Gregory, M. (2003). "Systematics and Biology of Silica Bodies in Monocotyledons" (http:/ / www. bioone. org/
perlserv/ ?request=get-abstract). The Botanical Review 69 (4): 377–440. doi:10.1663/0006-8101(2004)069[0377:SABOSB]2.0.CO;2. .
[6] Ball SG, Morell MK (2003). "From bacterial glycogen to starch: understanding the biogenesis of the plant starch granule". Annu Rev Plant
Biol 54: 207–33. doi:10.1146/annurev.arplant.54.031902.134927. PMID 14502990.
[7] Shearer J, Graham TE (April 2002). "New perspectives on the storage and organization of muscle glycogen". Can J Appl Physiol 27 (2):
179–203. doi:10.1139/h02-012. PMID 12179957.
[8] Anderson AJ, Dawes EA (1 December 1990). "Occurrence, metabolism, metabolic role, and industrial uses of bacterial
polyhydroxyalkanoates" (http:/ / mmbr. asm. org/ cgi/ pmidlookup?view=long& pmid=2087222). Microbiol. Rev. 54 (4): 450–72.
PMC 372789. PMID 2087222. .
[9] Murphy DJ (September 2001). "The biogenesis and functions of lipid bodies in animals, growth and microorganisms". Prog. Lipid Res. 40
(5): 325–438. doi:10.1016/S0163-7827(01)00013-3. PMID 11470496.
Cytoplasm 156

External links
• Luby-Phelps K (2000). "Cytoarchitecture and physical properties of cytoplasm: volume, viscosity, diffusion,
intracellular surface area" (http://www.rpgroup.caltech.edu/courses/aph161/Handouts/Luby-Phelps2000.
pdf) (PDF). Int Rev Cytol 192: 189–221.

DNA
Deoxyribonucleic acid (
i
/diˌɒksiˌraɪbɵ.njuːˌkleɪ.ɪkˈæsɪd/; DNA)
is a nucleic acid containing the genetic
instructions used in the development
and functioning of all known living
organisms (with the exception of RNA
viruses). The DNA segments carrying
this genetic information are called
genes. Likewise, other DNA sequences
have structural purposes, or are
involved in regulating the use of this
genetic information. Along with RNA
and proteins, DNA is one of the three
major macromolecules that are
essential for all known forms of life.

DNA consists of two long polymers of


simple units called nucleotides, with
backbones made of sugars and
phosphate groups joined by ester
bonds. These two strands run in The structure of the DNA double helix. The atoms in the structure are colour coded by
element and the detailed structure of two base pairs is shown in the bottom right.
opposite directions to each other and
are therefore anti-parallel. Attached to
each sugar is one of four types of molecules called nucleobases (informally, bases). It is the sequence of these four
nucleobases along the backbone that encodes information. This information is read using the genetic code, which
specifies the sequence of the amino acids within proteins. The code is read by copying stretches of DNA into the
related nucleic acid RNA in a process called transcription.
DNA 157

Within cells DNA is organized into long structures called


chromosomes. During cell division these chromosomes are duplicated
in the process of DNA replication, providing each cell its own
complete set of chromosomes. Eukaryotic organisms (animals, plants,
fungi, and protists) store most of their DNA inside the cell nucleus and
some of their DNA in organelles, such as mitochondria or
chloroplasts.[1] In contrast, prokaryotes (bacteria and archaea) store
their DNA only in the cytoplasm. Within the chromosomes, chromatin
proteins such as histones compact and organize DNA. These compact
structures guide the interactions between DNA and other proteins,
helping control which parts of the DNA are transcribed.

The structure of part of a DNA double helix


DNA 158

Properties
DNA is a long polymer made from
repeating units called nucleotides.[2][3][4] As
first discovered by James D. Watson and
Francis Crick, the structure of DNA of all
species comprises two helical chains each
coiled round the same axis, and each with a
pitch of 34 Ångströms (3.4 nanometres) and
a radius of 10 Ångströms
(1.0 nanometres).[5] According to another
study, when measured in a particular
solution, the DNA chain measured 22 to
26 Ångströms wide (2.2 to 2.6 nanometres),
and one nucleotide unit measured 3.3 Å
(0.33 nm) long.[6] Although each individual
repeating unit is very small, DNA polymers
can be very large molecules containing
millions of nucleotides. For instance, the
largest human chromosome, chromosome
number 1, is approximately 220 million base
pairs long.[7]

In living organisms DNA does not usually


Chemical structure of DNA. Hydrogen bonds shown as dotted lines.
exist as a single molecule, but instead as a
pair of molecules that are held tightly
together.[5][8] These two long strands entwine like vines, in the shape of a double helix. The nucleotide repeats
contain both the segment of the backbone of the molecule, which holds the chain together, and a nucleobase, which
interacts with the other DNA strand in the helix. A nucleobase linked to a sugar is called a nucleoside and a base
linked to a sugar and one or more phosphate groups is called a nucleotide. Polymers comprising multiple linked
nucleotides (as in DNA) are called a polynucleotide.[9]

The backbone of the DNA strand is made from alternating phosphate and sugar residues.[10] The sugar in DNA is
2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined together by phosphate groups that form
phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These asymmetric bonds
mean a strand of DNA has a direction. In a double helix the direction of the nucleotides in one strand is opposite to
their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are called the 5′
(five prime) and 3′ (three prime) ends, with the 5' end having a terminal phosphate group and the 3' end a terminal
hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being
replaced by the alternative pentose sugar ribose in RNA.[8]
DNA 159

The DNA double helix is stabilized primarily by two forces: hydrogen bonds
between nucleotides and base-stacking interactions among the aromatic
nucleobases.[12] In the aqueous environment of the cell, the conjugated π bonds
of nucleotide bases align perpendicular to the axis of the DNA molecule,
minimizing their interaction with the solvation shell and therefore, the Gibbs free
energy. The four bases found in DNA are adenine (abbreviated A), cytosine (C),
guanine (G) and thymine (T). These four bases are attached to the
sugar/phosphate to form the complete nucleotide, as shown for adenosine
monophosphate.

The nucleobases are classified into two types: the purines, A and G, being fused
five- and six-membered heterocyclic compounds, and the pyrimidines, the
six-membered rings C and T.[8] A fifth pyrimidine nucleobase, uracil (U), usually
takes the place of thymine in RNA and differs from thymine by lacking a methyl
group on its ring. Uracil is not usually found in DNA, occurring only as a
breakdown product of cytosine. In addition to RNA and DNA a large number of
artificial nucleic acid analogues have also been created to study the proprieties of A section of DNA. The bases lie
nucleic acids, or for use in biotechnology.[13] horizontally between the two
[11]
spiraling strands. Animated
version at File:DNA orbit
animated.gif.

Grooves
Twin helical strands form the DNA backbone. Another double helix
may be found by tracing the spaces, or grooves, between the strands.
These voids are adjacent to the base pairs and may provide a binding
site. As the strands are not directly opposite each other, the grooves are
unequally sized. One groove, the major groove, is 22 Å wide and the
other, the minor groove, is 12 Å wide.[14] The narrowness of the minor
Major and minor grooves of DNA. Minor groove
groove means that the edges of the bases are more accessible in the
is a binding site for the dye Hoechst 33258. major groove. As a result, proteins like transcription factors that can
bind to specific sequences in double-stranded DNA usually make
contacts to the sides of the bases exposed in the major groove.[15] This situation varies in unusual conformations of
DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in size
that would be seen if the DNA is twisted back into the ordinary B form.

Base pairing
In a DNA double helix, each type of nucleobase on one strand normally interacts with just one type of nucleobase on
the other strand. This is called complementary base pairing. Here, purines form hydrogen bonds to pyrimidines, with
A bonding only to T, and C bonding only to G. This arrangement of two nucleotides binding together across the
double helix is called a base pair. As hydrogen bonds are not covalent, they can be broken and rejoined relatively
easily. The two strands of DNA in a double helix can therefore be pulled apart like a zipper, either by a mechanical
force or high temperature.[16] As a result of this complementarity, all the information in the double-stranded
sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. Indeed, this reversible and
specific interaction between complementary base pairs is critical for all the functions of DNA in living organisms.[3]
DNA 160

Top, a GC base pair with three hydrogen bonds. Bottom, an AT base pair with two hydrogen bonds. Non-covalent
hydrogen bonds between the pairs are shown as dashed lines.
The two types of base pairs form different numbers of hydrogen bonds, AT forming two hydrogen bonds, and GC
forming three hydrogen bonds (see figures, right). DNA with high GC-content is more stable than DNA with low
GC-content.
As noted above, most DNA molecules are actually two polymer strands, bound together in a helical fashion by
noncovalent bonds; this double stranded structure (dsDNA) is maintained largely by the intrastrand base stacking
interactions, which are strongest for G,C stacks. The two strands can come apart – a process known as melting – to
form two ss DNA molecules. Melting occurs when conditions favor ssDNA; such conditions are high temperature,
low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely
used).
The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since
stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in
various ways; a common way is the "melting temperature", which is the temperature at which 50% of the ds
molecules are converted to ss molecules; melting temperature is dependent on ionic strength and the concentration of
DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that
determine the strength of the association between the two strands of DNA. Long DNA helices with a high
GC-content have stronger-interacting strands, while short helices with high AT content have weaker-interacting
strands.[17] In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow
box in some promoters, tend to have a high AT content, making the strands easier to pull apart.[18]
In the laboratory, the strength of this interaction can be measured by finding the temperature required to break the
hydrogen bonds, their melting temperature (also called Tm value). When all the base pairs in a DNA double helix
melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA
molecules (ssDNA) have no single common shape, but some conformations are more stable than others.[19]

Sense and antisense


A DNA sequence is called "sense" if its sequence is the same as that of a messenger RNA copy that is translated into
protein.[20] The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense
sequences can exist on different parts of the same strand of DNA (i.e. both strands contain both sense and antisense
sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these
RNAs are not entirely clear.[21] One proposal is that antisense RNAs are involved in regulating gene expression
through RNA-RNA base pairing.[22]
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between
sense and antisense strands by having overlapping genes.[23] In these cases, some DNA sequences do double duty,
encoding one protein when read along one strand, and a second protein when read in the opposite direction along the
other strand. In bacteria, this overlap may be involved in the regulation of gene transcription,[24] while in viruses,
DNA 161

overlapping genes increase the amount of information that can be encoded within the small viral genome.[25]

Supercoiling
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand
usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become
more tightly or more loosely wound.[26] If the DNA is twisted in the direction of the helix, this is positive
supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is
negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling
that is introduced by enzymes called topoisomerases.[27] These enzymes are also needed to relieve the twisting
stresses introduced into DNA strands during processes such as transcription and DNA replication.[28]

Alternate DNA structures


DNA exists in many possible conformations that include A-DNA,
B-DNA, and Z-DNA forms, although, only B-DNA and Z-DNA have
been directly observed in functional organisms.[10] The conformation
that DNA adopts depends on the hydration level, DNA sequence, the
amount and direction of supercoiling, chemical modifications of the
bases, the type and concentration of metal ions, as well as the presence
of polyamines in solution.[29] From left to right, the structures of A, B and Z
DNA
The first published reports of A-DNA X-ray diffraction patterns— and
also B-DNA used analyses based on Patterson transforms that provided
only a limited amount of structural information for oriented fibers of DNA.[30][31] An alternate analysis was then
proposed by Wilkins et al., in 1953, for the in vivo B-DNA X-ray diffraction/scattering patterns of highly hydrated
DNA fibers in terms of squares of Bessel functions.[32] In the same journal, James D. Watson and Francis Crick
presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a
double-helix.[5]

Although the `B-DNA form' is most common under the conditions found in cells,[33] it is not a well-defined
conformation but a family of related DNA conformations[34] that occur at the high hydration levels present in living
cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a
significant degree of disorder.[35][36]
Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a
narrower, deeper major groove. The A form occurs under non-physiological conditions in partially dehydrated
samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, as well as in
enzyme-DNA complexes.[37][38] Segments of DNA where the bases have been chemically modified by methylation
may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a
left-handed spiral, the opposite of the more common B form.[39] These unusual structures can be recognized by
specific Z-DNA binding proteins and may be involved in the regulation of transcription.[40]
DNA 162

Alternate DNA chemistry


For a number of years exobiologists have proposed the existence of a shadow biosphere, a postulated microbial
biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One
of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA.
A December 2010 NASA press conference stated that the bacterium GFAJ-1, which has evolved in an arsenic-rich
environment, is the first terrestrial lifeform found which may have this ability. The bacterium was found in Mono
Lake, east of Yosemite National Park. GFAJ-1 is a rod-shaped extremophile bacterium in the family
Halomonadaceae that, when starved of phosphorus, may be capable of incorporating the usually poisonous element
arsenic in its DNA.[41] This discovery may lend weight to the long-standing idea that extraterrestrial life could have a
different chemical makeup from life on Earth.[41][42] The research was carried out by a team led by Felisa
Wolfe-Simon, a geomicrobiologist and geobiochemist, a Postdoctoral Fellow of the NASA Astrobiology Institute
with Arizona State University. This finding has, however, faced strong criticism from the scientific community;
scientists have argued that there is no evidence that arsenic is actually incorporated into biomolecules.[42][43]
Independent confirmation of this finding has also not yet been possible.

Quadruplex structures
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these
regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally
replicate DNA cannot copy the extreme 3′ ends of chromosomes.[44] These specialized chromosome caps also help
protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected.[45]
In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a
simple TTAGGG sequence.[46]
These guanine-rich sequences may stabilize chromosome ends by
forming structures of stacked sets of four-base units, rather than the
usual base pairs found in other DNA molecules. Here, four guanine
bases form a flat plate and these flat four-base units then stack on top
of each other, to form a stable G-quadruplex structure.[48] These
structures are stabilized by hydrogen bonding between the edges of the
bases and chelation of a metal ion in the centre of each four-base
unit.[49] Other structures can also be formed, with the central set of
four bases coming from either a single strand folded around the bases,
or several different parallel strands, each contributing one base to the
central structure.
DNA quadruplex formed by telomere repeats.
The looped conformation of the DNA backbone
In addition to these stacked structures, telomeres also form large loop [47]
is very different from the typical DNA helix.
structures called telomere loops, or T-loops. Here, the single-stranded
DNA curls around in a long circle stabilized by telomere-binding
proteins.[50] At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of
double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two
strands. This triple-stranded structure is called a displacement loop or D-loop.[48]

Single branch Multiple branches


DNA 163

Branched DNA can form networks containing multiple branches.

Branched DNA
In DNA fraying occurs when non-complementary regions exist at the end of an otherwise complementary
double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains
adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest
example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple
branches are also possible.[51] Branched DNA can be used in nanotechnology to construct geometric shapes, see the
section on uses in technology below.

Vibration
DNA may carry out low-frequency collective motion as observed by the Raman spectroscopy[52][53] and analyzed
with a quasi-continuum model.[54][55]

Chemical modifications

cytosine 5-methylcytosine thymine

Structure of cytosine with and without the 5-methyl group. Deamination converts 5-methylcytosine into thymine.

Base modifications
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin.
Base modifications can be involved in packaging, with regions that have low or no gene expression usually
containing high levels of methylation of cytosine bases. For example, cytosine methylation, produces
5-methylcytosine, which is important for X-chromosome inactivation.[56] The average level of methylation varies
between organisms – the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher
levels, with up to 1% of their DNA containing 5-methylcytosine.[57] Despite the importance of 5-methylcytosine, it
can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations.[58] Other base
modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain,[59] and
the glycosylation of uracil to produce the "J-base" in kinetoplastids.[60][61]
DNA 164

Damage
DNA can be damaged by many sorts of mutagens, which change the
DNA sequence. Mutagens include oxidizing agents, alkylating agents
and also high-energy electromagnetic radiation such as ultraviolet light
and X-rays. The type of DNA damage produced depends on the type of
mutagen. For example, UV light can damage DNA by producing
thymine dimers, which are cross-links between pyrimidine bases.[63]
On the other hand, oxidants such as free radicals or hydrogen peroxide
produce multiple forms of damage, including base modifications,
particularly of guanosine, and double-strand breaks.[64] A typical
human cell contains about 150,000 bases that have suffered oxidative
damage.[65] Of these oxidative lesions, the most dangerous are
double-strand breaks, as these are difficult to repair and can produce
point mutations, insertions and deletions from the DNA sequence, as
well as chromosomal translocations.[66] These mutations can cause
cancer. Because of inherent limitations in the DNA repair mechanisms,
if humans lived long enough, they would all eventually develop
A covalent adduct between a metabolically
cancer.[67][68] activated form of benzo[a]pyrene, the major
[62]
mutagen in tobacco smoke, and DNA
Many mutagens fit into the space between two adjacent base pairs, this
is called intercalation. Most intercalators are aromatic and planar
molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. In order for an intercalator
to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This
inhibits both transcription and DNA replication, causing toxicity and mutations.[69] As a result, DNA intercalators
may be carcinogens, and in the case of thalidomide, a teratogen.[70] Others such as benzo[a]pyrene diol epoxide and
aflatoxin form DNA adducts which induce errors in replication.[71] Nevertheless, due to their ability to inhibit DNA
transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer
cells.[72]

Biological functions
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of
chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA
arranged into 46 chromosomes.[73] The information carried by DNA is held in the sequence of pieces of DNA called
genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in
transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA
sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then
used to make a matching protein sequence in a process called translation, which depends on the same interaction
between RNA nucleotides. In alternative fashion, a cell may simply copy its genetic information in a process called
DNA replication. The details of these functions are covered in other articles; here we focus on the interactions
between DNA and other molecules that mediate the function of the genome.
DNA 165

Genes and genomes


Genomic DNA is tightly and orderly packed in the process called DNA condensation to fit the small available
volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, as well as small amounts in mitochondria and
chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the
nucleoid.[74] The genetic information in a genome is held within genes, and the complete set of this information in an
organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular
characteristic in an organism. Genes contain an open reading frame that can be transcribed, as well as regulatory
sequences such as promoters and enhancers, which control the transcription of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about
1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of
non-coding repetitive sequences.[75] The reasons for the presence of so much noncoding DNA in eukaryotic
genomes and the extraordinary differences in genome size, or C-value, among species represent a long-standing
puzzle known as the "C-value enigma".[76] However, DNA sequences that do not code protein may still encode
functional non-coding RNA molecules, which are involved in the regulation of gene expression.[77]
Some noncoding DNA sequences play structural roles in
chromosomes. Telomeres and centromeres typically contain few genes,
but are important for the function and stability of chromosomes.[45][79]
An abundant form of noncoding DNA in humans are pseudogenes,
which are copies of genes that have been disabled by mutation.[80]
These sequences are usually just molecular fossils, although they can
occasionally serve as raw genetic material for the creation of new
genes through the process of gene duplication and divergence.[81]

T7 RNA polymerase (blue) producing a mRNA


[78] Transcription and translation
(green) from a DNA template (orange).
A gene is a sequence of DNA that contains genetic information and
can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a
messenger RNA sequence, which then defines one or more protein sequences. The relationship between the
nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation,
known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a
sequence of three nucleotides (e.g. ACT, CAG, TTT).

In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then
decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which
carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (
combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible
codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAA,
TGA and TAG codons.
DNA 166

Replication
Cell division is essential for an
organism to grow, but, when a cell
divides, it must replicate the DNA in
its genome so that the two daughter
cells have the same genetic
information as their parent. The
double-stranded structure of DNA
provides a simple mechanism for DNA
replication. Here, the two strands are
DNA replication. The double helix is unwound by a helicase and topoisomerase. Next,
separated and then each strand's one DNA polymerase produces the leading strand copy. Another DNA polymerase binds
complementary DNA sequence is to the lagging strand. This enzyme makes discontinuous segments (called Okazaki
recreated by an enzyme called DNA fragments) before DNA ligase joins them together.

polymerase. This enzyme makes the


complementary strand by finding the correct base through complementary base pairing, and bonding it onto the
original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are
used to copy the antiparallel strands of the double helix.[82] In this way, the base on the old strand dictates which
base appears on the new strand, and the cell ends up with a perfect copy of its DNA.

Interactions with proteins


All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the
protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the
polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.

DNA-binding proteins

Interaction of DNA (shown in orange) with histones (shown in blue). These proteins' basic amino acids bind to the
acidic phosphate groups on DNA.
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within
chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact
structure called chromatin. In eukaryotes this structure involves DNA binding to a complex of small basic proteins
called histones, while in prokaryotes multiple types of proteins are involved.[83][84] The histones form a disk-shaped
complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its
surface. These non-specific interactions are formed through basic residues in the histones making ionic bonds to the
acidic sugar-phosphate backbone of the DNA, and are therefore largely independent of the base sequence.[85]
Chemical modifications of these basic amino acid residues include methylation, phosphorylation and acetylation.[86]
These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA
more or less accessible to transcription factors and changing the rate of transcription.[87] Other non-specific
DNA 167

DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted
DNA.[88] These proteins are important in bending arrays of nucleosomes and arranging them into the larger
structures that make up chromosomes.[89]
A distinct group of DNA-binding proteins are the DNA-binding proteins that specifically bind single-stranded DNA.
In humans, replication protein A is the best-understood member of this family and is used in processes where the
double helix is separated, including DNA replication, recombination and DNA repair.[90] These binding proteins
seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
In contrast, other proteins have evolved to bind to particular DNA sequences.
The most intensively studied of these are the various transcription factors, which
are proteins that regulate transcription. Each transcription factor binds to one
particular set of DNA sequences and activates or inhibits the transcription of
genes that have these sequences close to their promoters. The transcription
factors do this in two ways. Firstly, they can bind the RNA polymerase
responsible for transcription, either directly or through other mediator proteins;
this locates the polymerase at the promoter and allows it to begin
transcription.[92] Alternatively, transcription factors can bind enzymes that
modify the histones at the promoter; this will change the accessibility of the
DNA template to the polymerase.[93]

As these DNA targets can occur throughout an organism's genome, changes in


the activity of one type of transcription factor can affect thousands of genes.[94] The lambda repressor
helix-turn-helix transcription factor
Consequently, these proteins are often the targets of the signal transduction [91]
bound to its DNA target
processes that control responses to environmental changes or cellular
differentiation and development. The specificity of these transcription factors'
interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing
them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are
most accessible.[15]

DNA-modifying enzymes

Nucleases and ligases

Nucleases are enzymes that cut DNA strands by catalyzing the


hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse
nucleotides from the ends of DNA strands are called exonucleases,
while endonucleases cut within strands. The most frequently used
nucleases in molecular biology are the restriction endonucleases, which
The restriction enzyme EcoRV (green) in a
complex with its substrate DNA
[95] cut DNA at specific sequences. For instance, the EcoRV enzyme
shown to the left recognizes the 6-base sequence 5′-GATATC-3′ and
makes a cut at the vertical line. In nature, these enzymes protect bacteria against phage infection by digesting the
phage DNA when it enters the bacterial cell, acting as part of the restriction modification system.[96] In technology,
these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.

Enzymes called DNA ligases can rejoin cut or broken DNA strands.[97] Ligases are particularly important in lagging
strand DNA replication, as they join together the short segments of DNA produced at the replication fork into a
complete copy of the DNA template. They are also used in DNA repair and genetic recombination.[97]
DNA 168

Topoisomerases and helicases


Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of
supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate,
thereby reducing its level of supercoiling; the enzyme then seals the DNA break.[27] Other types of these enzymes
are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining
the helix.[98] Topoisomerases are required for many processes involving DNA, such as DNA replication and
transcription.[28]
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates,
predominantly ATP, to break hydrogen bonds between bases and unwind the DNA double helix into single
strands.[99] These enzymes are essential for most processes where enzymes need to access the DNA bases.

Polymerases
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their
products are copies of existing polynucleotide chains – which are called templates. These enzymes function by
adding nucleotides onto the 3′ hydroxyl group of the previous nucleotide in a DNA strand. As a consequence, all
polymerases work in a 5′ to 3′ direction.[100] In the active site of these enzymes, the incoming nucleoside
triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand
of their template. Polymerases are classified according to the type of template that they use.
In DNA replication, a DNA-dependent DNA polymerase makes a copy of a DNA sequence. Accuracy is vital in this
process, so many of these polymerases have a proofreading activity. Here, the polymerase recognizes the occasional
mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is
detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed.[101] In most organisms, DNA
polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the
DNA clamp or helicases.[102]
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand
into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by
retroviruses, and telomerase, which is required for the replication of telomeres.[44][103] Telomerase is an unusual
polymerase because it contains its own RNA template as part of its structure.[45]
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into
RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and
separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a
region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent
DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome,
operates as part of a large protein complex with multiple regulatory and accessory subunits.[104]
DNA 169

Genetic recombination

Structure of the Holliday junction intermediate in genetic recombination. The four separate DNA strands are
coloured red, blue, green and yellow.[105]
A DNA helix usually does not interact with other
segments of DNA, and in human cells the different
chromosomes even occupy separate areas in the
nucleus called "chromosome territories".[106] This
physical separation of different chromosomes is
important for the ability of DNA to function as a stable
repository for information, as one of the few times
chromosomes interact is during chromosomal crossover
when they recombine. Chromosomal crossover is when
two DNA helices break, swap a section and then rejoin.
Recombination involves the breakage and rejoining of two
Recombination allows chromosomes to exchange
chromosomes (M and F) to produce two re-arranged chromosomes
genetic information and produces new combinations of
(C1 and C2).
genes, which increases the efficiency of natural
selection and can be important in the rapid evolution of
[107]
new proteins. Genetic recombination can also be involved in DNA repair, particularly in the cell's response to
double-strand breaks.[108]

The most common form of chromosomal crossover is homologous recombination, where the two chromosomes
involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce
chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known
as recombinases, such as RAD51.[109] The first step in recombination is a double-stranded break either caused by an
endonuclease or damage to the DNA.[110] A series of steps catalyzed in part by the recombinase then leads to joining
of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to
the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be
moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted
by cleavage of the junction and re-ligation of the released DNA.[111]
DNA 170

Evolution
DNA contains the genetic information that allows all modern living things to function, grow and reproduce.
However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been
proposed that the earliest forms of life may have used RNA as their genetic material.[100][112] RNA may have acted
as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part
of ribozymes.[113] This ancient RNA world where nucleic acid would have been used for both catalysis and genetics
may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur,
since the number of different bases in such an organism is a trade-off between a small number of bases increasing
replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes.[114]
However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible.
This is because DNA will survive in the environment for less than one million years and slowly degrades into short
fragments in solution.[115] Claims for older DNA have been made, most notably a report of the isolation of a viable
bacterium from a salt crystal 250 million years old,[116] but these claims are controversial.[117][118]
On August 8, 2011, a report, based on NASA studies with meteorites found on Earth, was published suggesting
building blocks of DNA (adenine, guanine and related organic molecules) may have been formed extraterrestrially in
outer space.[119][120][121]

Uses in technology

Genetic engineering
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to
manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and
biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a
man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into
organisms in the form of plasmids or in the appropriate format, by using a viral vector.[122] The genetically modified
organisms produced can be used to produce products such as recombinant proteins, used in medical research,[123] or
be grown in agriculture.[124][125]

Forensics
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching
DNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, but may also be called
"genetic fingerprinting". In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem
repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for
identifying a matching DNA.[126] However, identification can be complicated if the scene is contaminated with DNA
from several people.[127] DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys,[128] and first
used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.[129]
The development of forensic science, and the ability to now obtain genetic matching on minute samples of blood,
skin, saliva or hair has led to a re-examination of a number of cases. Evidence can now be uncovered that was not
scientifically possible at the time of the original examination. Combined with the removal of the double jeopardy law
in some places, this can allow cases to be reopened where previous trials have failed to produce sufficient evidence
to convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matching
purposes. The most obvious defence to DNA matches obtained forensically is to claim that cross-contamination of
evidence has taken place. This has resulted in meticulous strict handling procedures with new cases of serious crime.
DNA profiling is also be used to identify victims of mass casualty incidents.[130] As well as positively identifying
bodies or body parts in serious accidents, DNA profiling is being successfully used to identify individual victims in
mass war graves – matching to family members.
DNA 171

Bioinformatics
Bioinformatics involves the manipulation, searching, and data mining of biological data, and this includes DNA
sequence data. The development of techniques to store and search DNA sequences have led to widely applied
advances in computer science, especially string searching algorithms, machine learning and database theory.[131]
String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence
of letters, were developed to search for specific sequences of nucleotides.[132] The DNA sequence may be aligned
with other DNA sequences to identify homologous sequences and locate the specific mutations that make them
distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships
and protein function.[133] Data sets representing entire genomes' worth of DNA sequences, such as those produced
by the Human Genome Project, are difficult to use without the annotations that identify the locations of genes and
regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated
with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict
the presence of particular gene products and their possible functions in an organism even before they have been
isolated experimentally.[134] Entire genomes may also be compared which can shed light on the evolutionary history
of particular organism and permit the examination of complex evolutionary events.

DNA nanotechnology
DNA nanotechnology uses the unique
molecular recognition properties of
DNA and other nucleic acids to create
self-assembling branched DNA
complexes with useful properties.[135]
DNA is thus used as a structural
material rather than as a carrier of
biological information. This has led to
the creation of two-dimensional
periodic lattices (both tile-based as
well as using the "DNA origami"
method) as well as three-dimensional The DNA structure at left (schematic shown) will self-assemble into the structure
structures in the shapes of visualized by atomic force microscopy at right. DNA nanotechnology is the field that
polyhedra.[136] Nanomechanical seeks to design nanoscale structures using the molecular recognition properties of DNA
molecules. Image from Strong, 2004 (doi:10.1371/journal.pbio.0020073).
devices and algorithmic self-assembly
have also been demonstrated,[137] and
these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and
streptavidin proteins.[138]

History and anthropology


Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by
comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny.[139] This
field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared,
population geneticists can learn the history of particular populations. This can be used in studies ranging from
ecological genetics to anthropology; For example, DNA evidence is being used to try to identify the Ten Lost Tribes
of Israel.[140][141]

DNA has also been used to look at modern family relationships, such as establishing family relationships between
the descendants of Sally Hemings and Thomas Jefferson. This usage is closely related to the use of DNA in criminal
DNA 172

investigations detailed above. Indeed, some criminal investigations have been solved when DNA from crime scenes
has matched relatives of the guilty individual.[142]

History of DNA research


DNA was first isolated by the Swiss physician Friedrich Miescher
who, in 1869, discovered a microscopic substance in the pus of
discarded surgical bandages. As it resided in the nuclei of cells, he
called it "nuclein".[143] In 1878, Albrecht Kossel isolated the
non-protein component of "nuclein", nucleic acid, and later isolated its
five primary nucleobases.[144] In 1919, Phoebus Levene identified the
base, sugar and phosphate nucleotide unit.[145] Levene suggested that
DNA consisted of a string of nucleotide units linked together through
the phosphate groups. However, Levene thought the chain was short
and the bases repeated in a fixed order. In 1937 William Astbury James D. Watson and Francis Crick (right),
produced the first X-ray diffraction patterns that showed that DNA had co-originators of the double-helix model, with
Maclyn McCarty (left).
a regular structure.[146]

In 1927 Nikolai Koltsov proposed that inherited traits would be inherited via a "giant hereditary molecule" which
would be made up of "two mirror strands that would replicate in a semi-conservative fashion using each strand as a
template".[147] In 1928, Frederick Griffith discovered that traits of the "smooth" form of the Pneumococcus could be
transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough"
form.[148] This system provided the first clear suggestion that DNA carries genetic information—the
Avery–MacLeod–McCarty experiment—when Oswald Avery, along with coworkers Colin MacLeod and Maclyn
McCarty, identified DNA as the transforming principle in 1943.[149] DNA's role in heredity was confirmed in 1952,
when Alfred Hershey and Martha Chase in the Hershey–Chase experiment showed that DNA is the genetic material
of the T2 phage.[150]

In 1953, James D. Watson and Francis Crick suggested what is now accepted as the first correct double-helix model
of DNA structure in the journal Nature.[5] Their double-helix, molecular model of DNA was then based on a single
X-ray diffraction image (labeled as "Photo 51")[151] taken by Rosalind Franklin and Raymond Gosling in May 1952,
as well as the information that the DNA bases are paired — also obtained through private communications from
Erwin Chargaff in the previous years. Chargaff's rules played a very important role in establishing double-helix
configurations for B-DNA as well as A-DNA.
Experimental evidence supporting the Watson and Crick model were published in a series of five articles in the same
issue of Nature.[152] Of these, Franklin and Gosling's paper was the first publication of their own X-ray diffraction
data and original analysis method that partially supported the Watson and Crick model;[31][153] this issue also
contained an article on DNA structure by Maurice Wilkins and two of his colleagues, whose analysis and in vivo
B-DNA X-ray patterns also supported the presence in vivo of the double-helical DNA configurations as proposed by
Crick and Watson for their double-helix molecular model of DNA in the previous two pages of Nature.[32] In 1962,
after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine.[154]
However, Nobel rules of the time allowed only living recipients, but a vigorous debate continues on who should
receive credit for the discovery.[155]
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the
relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis".[156] Final confirmation of
the replication mechanism that was implied by the double-helical structure followed in 1958 through the
Meselson–Stahl experiment.[157] Further work by Crick and coworkers showed that the genetic code was based on
non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley and Marshall
DNA 173

Warren Nirenberg to decipher the genetic code.[158] These findings represent the birth of molecular biology.
In 2010, NASA research confirms discovery of Bactrial DNA with arsenic instead of phosphorus at Mono Lake,
California.[159]

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[2] Saenger, Wolfram (1984). Principles of Nucleic Acid Structure. New York: Springer-Verlag. ISBN 0-387-90762-9.
[3] Alberts, Bruce; Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts and Peter Walters (2002). Molecular Biology of the Cell;
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Further reading
• Berry, Andrew; Watson, James D. (2003). DNA: the secret of life. New York: Alfred A. Knopf.
ISBN 0-375-41546-7.
• Calladine, Chris R.; Drew, Horace R.; Luisi, Ben F. and Travers, Andrew A. (2003). Understanding DNA: the
molecule & how it works. Amsterdam: Elsevier Academic Press. ISBN 0-12-155089-3.
• Dennis, Carina; Julie Clayton (2003). 50 years of DNA. Basingstoke: Palgrave Macmillan. ISBN 1-4039-1479-6.
• Judson, Horace F. 1979. The Eighth Day of Creation: Makers of the Revolution in Biology. Touchstone Books,
ISBN 0-671-22540-5. 2nd edition: Cold Spring Harbor Laboratory Press, 1996 paperback: ISBN 0-87969-478-5.
• Olby, Robert C. (1994). The path to the double helix: the discovery of DNA. New York: Dover Publications.
ISBN 0-486-68117-3., first published in October 1974 by MacMillan, with foreword by Francis Crick;the
definitive DNA textbook,revised in 1994 with a 9 page postscript
• Micklas, David. 2003. DNA Science: A First Course. Cold Spring Harbor Press: ISBN 978-0-87969-636-8
• Ridley, Matt (2006). Francis Crick: discoverer of the genetic code. Ashland, OH: Eminent Lives, Atlas Books.
ISBN 0-06-082333-X.
• Olby, Robert C. (2009). Francis Crick: A Biography. Plainview, N.Y: Cold Spring Harbor Laboratory Press.
ISBN 0-87969-798-9.
• Rosenfeld, Israel. 2010. DNA: A Graphic Guide to the Molecule that Shook the World. Columbia University
Press: ISBN 978-0-231-14271-7
DNA 179

• Schultz, Mark and Zander Cannon. 2009. The Stuff of Life: A Graphic Guide to Genetics and DNA. Hill and
Wang: ISBN 0-8090-8947-5
• Stent, Gunther Siegmund; Watson, James D. (1980). The double helix: a personal account of the discovery of the
structure of DNA. New York: Norton. ISBN 0-393-95075-1.
• Watson, James D. 2004. DNA: The Secret of Life. Random House: ISBN 978-0-09-945184-6
• Wilkins, Maurice (2003). The third man of the double helix the autobiography of Maurice Wilkins. Cambridge,
Eng: University Press. ISBN 0-19-860665-6.

External links
• DNA (http://www.dmoz.org/Science/Biology/Biochemistry_and_Molecular_Biology/Biomolecules/
Nucleic_Acids/DNA//) at the Open Directory Project
• DNA binding site prediction on protein (http://pipe.scs.fsu.edu/displar.html)
• DNA the Double Helix Game (http://nobelprize.org/educational_games/medicine/dna_double_helix/) From
the official Nobel Prize web site
• DNA under electron microscope (http://www.fidelitysystems.com/Unlinked_DNA.html)
• Dolan DNA Learning Center (http://www.dnalc.org/)
• Double Helix: 50 years of DNA (http://www.nature.com/nature/dna50/archive.html), Nature
• Proteopedia DNA (http://www.proteopedia.org/wiki/index.php/DNA)
• Double Helix 1953–2003 (http://www.ncbe.reading.ac.uk/DNA50/) National Centre for Biotechnology
Education
• Francis Crick and James Watson talking on the BBC in 1962, 1972, and 1974 (http://www.bbc.co.uk/bbcfour/
audiointerviews/profilepages/crickwatson1.shtml)
• Genetic Education Modules for Teachers (http://www.genome.gov/10506718)—DNA from the Beginning
Study Guide
• Olby R (2003). "Quiet debut for the double helix". Nature 421 (6921): 402–5. doi:10.1038/nature01397.
PMID 12540907.
• DNA from the Beginning (http://www.dnaftb.org/dnaftb/) Another DNA Learning Center site on DNA, genes,
and heredity from Mendel to the human genome project.
• PDB Molecule of the Month pdb23_1 (http://www.rcsb.org/pdb/static.do?p=education_discussion/
molecule_of_the_month/pdb23_1.html)
• Rosalind Franklin's contributions to the study of DNA (http://mason.gmu.edu/~emoody/rfranklin.html)
• The Register of Francis Crick Personal Papers 1938 – 2007 (http://orpheus.ucsd.edu/speccoll/testing/html/
mss0660a.html#abstract) at Mandeville Special Collections Library, University of California, San Diego
• U.S. National DNA Day (http://www.genome.gov/10506367)—watch videos and participate in real-time chat
with top scientists
• Clue to chemistry of heredity found (http://www.nytimes.com/packages/pdf/science/dna-article.pdf) The
New York Times June 1953. First American newspaper coverage of the discovery of the DNA structure
Fecal fat test 180

Fecal fat test


In medicine, the fecal fat test is a diagnostic test for fat malabsorption conditions, which lead to excess fat in the
feces (steatorrhea).

Background
In the small intestine, dietary fat (primarily triglycerides) is digested by enzymes such as pancreatic lipase into
smaller molecules which can be absorbed through the wall of the small intestine and enter the circulation for
metabolism and storage. As fat is a valuable nutrient, human feces normally contain very little undigested fat.
However, a number of diseases of the pancreas and gastrointestinal tract are characterized by fat malabsorption.
Examples of such diseases are:
• disorders of exocrine pancreatic function, such as chronic pancreatitis, cystic fibrosis and Shwachman–Diamond
syndrome (these are characterized by deficiency of pancreatic digestive enzymes)
• celiac disease (in which the fat malabsorption in severe cases is due to inflammatory damage to the integrity of
the intestinal lining)
• short bowel syndrome (in which much of the small intestine has had to be surgically removed and the remaining
portion cannot completely absorb all of the fat).
• small bowel bacterial overgrowth syndrome

Microscopy
In the simplest form of the fecal fat test, a random fecal specimen is submitted to the hospital laboratory and
examined under a microscope after staining with a Sudan III or Sudan IV dye ("Sudan staining"). Visible amounts of
fat indicate some degree of fat malabsorption.

Quantitative fecal fat test


Quantitative fecal fat tests measure and report an amount of fat. This usually done over a period of three days, the
patient collecting all of their feces into a container.
The container is thoroughly mixed to homogenize the feces, this can be done with a paint mixer. A small sample
from the feces is collected. The fat content is extracted with solvents and measured by saponification (turning the fat
into soap).
Normally up to 7 grams of fat can be malabsorbed in people consuming 100 grams of fat per day. In patients with
diarrhea, up to 12 grams of fat may be malabsorbed since the presence of diarrhea interferes with fat absorption,
even when the diarrhea is not due to fat malabsorption.
Flow cytometry 181

Flow cytometry
Flow cytometry is a laser based,
biophysical technology employed in Cell
counting, sorting, biomarker detection and
protein engineering, by suspending them in
a stream of fluid and passing them by an
electronic detection apparatus. It allows
simultaneous multiparametric analysis of the
physical and/or chemical characteristics of
up to thousands of particles per second.

Flow cytometry is routinely used in the


diagnosis of health disorders, especially
blood cancers, but has many other
applications in basic research, clinical
practice and clinical trials. A common Analysis of a marine sample of photosynthetic picoplankton by flow cytometry
showing three different populations (Prochlorococcus, Synechococcus, and
variation is to physically sort particles based
picoeukaryotes)
on their properties, so as to purify
populations of interest.

History
The first impedance-based flow cytometry device, using the Coulter principle, was disclosed in U.S. Patent
2,656,508, issued in 1953, to Wallace H. Coulter. Mack Fulwyler was the inventor of the forerunner to today's flow
cytometers - particularly the cell sorter.[1] Fulwyler developed this in 1965 with his publication in Science.[2] The
first fluorescence-based flow cytometry device (ICP 11) was developed in 1968 by Wolfgang Göhde from the
University of Münster, filed for patent on 18th December 1968[3] and first commercialized in 1968/69 by German
developer and manufacturer Partec through Phywe AG in Göttingen. At that time, absorption methods were still
widely favored by other scientists over fluorescence methods.[4] Soon after, flow cytometry instruments were
developed, including the Cytofluorograph (1971) from Bio/Physics Systems Inc. (later: Ortho Diagnostics), the PAS
8000 (1973) from Partec, the first FACS instrument from Becton Dickinson (1974), the ICP 22 (1975) from
Partec/Phywe and the Epics from Coulter (1977/78).

Name of the technology


The original name of the flow cytometry technology was "pulse cytophotometry" (German: Impulszytophotometrie),
based on the first patent application on fluorescence-based flow cytometry. At the 5th American Engineering
Foundation Conference on Automated Cytology in Pensacola (Florida) in 1976 - eight years after the introduction of
the first fluorescence-based flow cytometer (1968) - it was agreed to commonly use the name "flow cytometry", a
term that quickly became popular[5].
Flow cytometry 182

Principle
A beam of light (usually laser light) of a single wavelength is directed onto a hydrodynamically-focused stream of
liquid. A number of detectors are aimed at the point where the stream passes through the light beam: one in line with
the light beam (Forward Scatter or FSC) and several perpendicular to it (Side Scatter or SSC) and one or more
fluorescence detectors. Each suspended particle from 0.2 to 150 micrometers passing through the beam scatters the
ray, and fluorescent chemicals found in the particle or attached to the particle may be excited into emitting light at a
longer wavelength than the light source. This combination of scattered and fluorescent light is picked up by the
detectors, and, by analysing fluctuations in brightness at each detector (one for each fluorescent emission peak), it is
then possible to derive various types of information about the physical and chemical structure of each individual
particle. FSC correlates with the cell volume and SSC depends on the inner complexity of the particle (i.e., shape of
the nucleus, the amount and type of cytoplasmic granules or the membrane roughness). This is because the light is
scattered off of the internal components of the cell. Some flow cytometers on the market have eliminated the need
for fluorescence and use only light scatter for measurement. Other flow cytometers form images of each cell's
fluorescence, scattered light, and transmitted light.

Flow cytometers
Modern flow cytometers are able to analyze several thousand particles
every second, in "real time," and can actively separate and isolate
particles having specified properties. A flow cytometer is similar to a
microscope, except that, instead of producing an image of the cell,
flow cytometry offers "high-throughput" (for a large number of cells)
automated quantification of set parameters. To analyze solid tissues, a
single-cell suspension must first be prepared.
Front of desktop flow cytometer - the
A flow cytometer has five main components:
Becton-Dickinson Fluorescence activated cell
• a flow cell - liquid stream (sheath fluid), which carries and aligns sorter (FACSCalibur)
the cells so that they pass single file through the light beam for
sensing
• a measuring system - commonly used are measurement of impedance (or conductivity) and optical systems -
lamps (mercury, xenon); high-power water-cooled lasers (argon, krypton, dye laser); low-power air-cooled lasers
(argon (488 nm), red-HeNe (633 nm), green-HeNe, HeCd (UV)); diode lasers (blue, green, red, violet) resulting
in light signals
• a detector and Analogue-to-Digital Conversion (ADC) system - which generates FSC and SSC as well as
fluorescence signals from light into electrical signals that can be processed by a computer
• an amplification system - linear or logarithmic
• a computer for analysis of the signals.
The process of collecting data from samples using the flow cytometer is termed 'acquisition'. Acquisition is mediated
by a computer physically connected to the flow cytometer, and the software which handles the digital interface with
the cytometer. The software is capable of adjusting parameters (i.e. voltage, compensation, etc.) for the sample being
tested, and also assists in displaying initial sample information while acquiring sample data to insure that parameters
are set correctly. Early flow cytometers were, in general, experimental devices, but technological advances have
enabled widespread applications for use in a variety of both clinical and research purposes. Due to these
developments, a considerable market for instrumentation, analysis software, as well as the reagents used in
acquisition such as fluorescently-labeled antibodies has developed.
Modern instruments usually have multiple lasers and fluorescence detectors. The current record for a commercial
instrument is four lasers and 18 fluorescence detectors. Increasing the number of lasers and detectors allows for
Flow cytometry 183

multiple antibody labeling, and can more precisely identify a target population by their phenotypic markers. Certain
instruments can even take digital images of individual cells, allowing for the analysis of fluorescent signal location
within or on the surface of cells.

Data analysis

Gating
The data generated by flow-cytometers can be plotted in a single dimension, to produce a histogram, or in
two-dimensional dot plots or even in three dimensions. The regions on these plots can be sequentially separated,
based on fluorescence intensity, by creating a series of subset extractions, termed "gates." Specific gating protocols
exist for diagnostic and clinical purposes especially in relation to hematology.
The plots are often made on logarithmic scales. Because different fluorescent dyes' emission spectra overlap,[6]
signals at the detectors have to be compensated electronically as well as computationally. Data accumulated using
the flow cytometer can be analyzed using software, e.g., WinMDI[7] (only one which is freeware), Flowjo, FCS
Express, VenturiOne, CellQuest Pro, or Cytospec.[8] Once the data are collected, there is no need to stay connected
to the flow cytometer. For this reason, analysis is most often performed on a separate computer. This is especially
necessary in core facilities where usage of these machines is in high demand.

Computational analysis
Recent progress on automated population identification using computational methods has offered an alternative to
traditional gating strategies. Automated identification systems could potentially help findings of rare and hidden
populations. Representative automated methods include FLOCK [9] in Immunology Database and Analysis Portal
(ImmPort),[10] FLAME [11] in GenePattern and flowClust,[12][13][14] in Bioconductor. Collaborative efforts have
resulted in an open project called FlowCAP (Flow Cytometry: Critical Assessment of Population Identification
Methods,[15]) to provide an objective way to compare and evaluate the flow cytometry data clustering methods, and
also to establish guidance about appropriate use and application of these methods.

Fluorescence-activated cell sorting


Flow cytometry 184

Fluorescence-activated cell sorting (FACS) is a specialized type of flow cytometry. It provides a method for sorting
a heterogeneous mixture of biological cells into two or more containers, one cell at a time, based upon the specific
light scattering and fluorescent characteristics of each cell. It is a useful scientific instrument, as it provides fast,
objective and quantitative recording of fluorescent signals from individual cells as well as physical separation of
cells of particular interest. The acronym FACS is trademarked and owned by Becton, Dickinson and Company.[16]
Among the large majority of researchers who use this technology for sorting or analysis, this term has become
generic in common usage, much like xerox or kleenex. The first cell sorter was invented by Mack Fulwyler in 1965,
using the Coulter principle, a relatively difficult technique and one no longer used in modern instruments. The
technique was expanded by Len Herzenberg, who was responsible for coining the term FACS[17]. Herzenberg won
the Kyoto Prize in 2006 for his seminal work in flow cytometry.
The cell suspension is entrained in the center of a narrow, rapidly flowing stream of liquid. The flow is arranged so
that there is a large separation between cells relative to their diameter. A vibrating mechanism causes the stream of
cells to break into individual droplets. The system is adjusted so that there is a low probability of more than one cell
per droplet. Just before the stream breaks into droplets, the flow passes through a fluorescence measuring station
where the fluorescent character of interest of each cell is measured. An electrical charging ring is placed just at the
point where the stream breaks into droplets. A charge is placed on the ring based on the immediately prior
fluorescence intensity measurement, and the opposite charge is trapped on the droplet as it breaks from the stream.
The charged droplets then fall through an electrostatic deflection system that diverts droplets into containers based
upon their charge. In some systems, the charge is applied directly to the stream, and the droplet breaking off retains
charge of the same sign as the stream. The stream is then returned to neutral after the droplet breaks off.

Labels

Fluorescent labels
A wide range of fluorophores can be used as labels in flow cytometry. Fluorophores, or simply "fluors", are typically
attached to an antibody that recognises a target feature on or in the cell; they may also be attached to a chemical
entity with affinity for the cell membrane or another cellular structure. Each fluorophore has a characteristic peak
excitation and emission wavelength, and the emission spectra often overlap. Consequently, the combination of labels
Flow cytometry 185

which can be used depends on the wavelength of the lamp(s) or laser(s) used to excite the fluorochromes and on the
detectors available.[18] The maximum number of distinguishable fluorescent labels is thought to be 17 or 18, and this
level of complexity necessitates laborious optimization to limit artifacts, as well as complex deconvolution
algorithms to separate overlapping spectra.[19]

Quantum dots
Quantum dots are sometimes used in
place of traditional fluorophores
because of their narrower emission
peaks.

Isotope labeling
In one approach to overcoming the
fluorescent labeling limit, lanthanide
isotopes are attached to antibodies.
This method could theoretically allow
the use of 40 to 60 distinguishable
labels and has been demonstrated for
Use of flow cytometry to measure copy number variation of a specific DNA sequence
30 labels.[19] Cells are introduced into (Flow-FISH)
a plasma, ionizing them and allowing
time-of-flight mass spectrometry to identify the associated isotopes. Although this method permits the use of a large
number of labels, it currently has lower throughput capacity than traditional flow cytometry. It also destroys the
analysed cells, precluding their recovery by sorting.[19]

Measurable parameters
This list is very long and constantly expanding.
• volume and morphological complexity of cells
• cell pigments such as chlorophyll or phycoerythrin
• total DNA content (cell cycle analysis, cell kinetics, proliferation, ploidy, aneuploidy, endoreduplication, etc.)
• total RNA content
• DNA copy number variation (by Flow-FISH or BACs-on-Beads technology)
• chromosome analysis and sorting (library construction, chromosome paint)
• protein expression and localization
• Protein modifications, phospho-proteins
• transgenic products in vivo, particularly the Green fluorescent protein or related Fluorescent Proteins
• cell surface antigens (Cluster of differentiation (CD) markers)
• intracellular antigens (various cytokines, secondary mediators, etc.)
• nuclear antigens
• enzymatic activity
• pH, intracellular ionized calcium, magnesium, membrane potential
• membrane fluidity
• apoptosis (quantification, measurement of DNA degradation, mitochondrial membrane potential, permeability
changes, caspase activity)
• cell viability
• monitoring electropermeabilization of cells
Flow cytometry 186

• oxidative burst
• characterising multidrug resistance (MDR) in cancer cells
• glutathione
• various combinations (DNA/surface antigens, etc.)
• cell adherence (for instance pathogen-host cell adherence)

Applications
The technology has applications in a number of fields, including molecular biology, pathology, immunology, plant
biology and marine biology. It has broad application in medicine (especially in transplantation, hematology, tumor
immunology and chemotherapy, prenatal diagnosis, genetics and sperm sorting for sex preselection). In marine
biology, the autofluorescent properties of photosynthetic plankton can be exploited by flow cytometry in order to
characterise abundance and community structure. In protein engineering, flow cytometry is used in conjunction with
yeast display and bacterial display to identify cell surface-displayed protein variants with desired properties.

Bibliography
• Flow Cytometry First Principles by Alice Longobardi Givan. ISBN 0-471-38224-8
• Practical Flow Cytometry by Howard M. Shapiro. ISBN 0-471-41125-6
• Flow Cytometry for Biotechnology by Larry A. Sklar. ISBN 0-19-515234-4
• Handbook of Flow Cytometry Methods by J. Paul Robinson, et al. ISBN 0-471-59634-5
• Current Protocols in Cytometry, Wiley-Liss Pub. ISSN 1934-9297
• Flow Cytometry in Clinical Diagnosis, v4, (Carey, McCoy, and Keren, eds), ASCP Press, 2007. ISBN
0-89189-548-5
• Ormerod, M.G. (ed.) (2000) Flow Cytometry — A practical approach. 3rd edition. Oxford University Press,
Oxford, UK. ISBN 0-19-963824-1
• Ormerod, M.G. (1999) Flow Cytometry. 2nd edition. BIOS Scientific Publishers, Oxford. ISBN 1-85996-107-X
• Flow Cytometry — A basic introduction. Michael G. Ormerod, 2008. ISBN 978-0-9559812-0-3

References
[1] US 3380584 (http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=US3380584), Mack Fulwyler, "Particle Separator", issued
1965-06-01
[2] Fulwyler, M. J. (1965). "Electronic separation of biological cells by volume". Science 150 (698): 910–911.
doi:10.1126/science.150.3698.910. PMID 5891056.
[3] DE 1815352 (http:/ / worldwide. espacenet. com/ textdoc?DB=EPODOC& IDX=DE1815352), Wolfgang Dittrich & Wolfgang Göhde,
"Flow-through Chamber for Photometers to Measure and Count Particles in a Dispersion Medium"
[4] Kamentsky in Proceedings of the 1968 Conference „Cytology Automation" (1970), edited by D. M. D. Evans.
[5] Sack et al., Ulrich. Zelluläre Diagnostik. Karger Publishers (2006).
[6] http:/ / pingu. salk. edu/ flow/ fluo. html
[7] "TSRI Cytometry Software Page" (http:/ / facs. scripps. edu/ software. html). . Retrieved 2009-09-03.
[8] "PUCL Cytometry Software Page" (http:/ / www. cyto. purdue. edu/ Purdue_software). . Retrieved 2011-07-07.
[9] Qian, Yu; Wei, Chungwen; Eun-Hyung Lee, F.; Campbell, John; Halliley, Jessica; Lee, Jamie A.; Cai, Jennifer; Kong, Y. Megan et al.
(2010). "Elucidation of seventeen human peripheral blood B-cell subsets and quantification of the tetanus response using a density-based
method for the automated identification of cell populations in multidimensional flow cytometry data". Cytometry Part B: Clinical Cytometry
78B: S69. doi:10.1002/cyto.b.20554.
[10] "Immunology Database and Analysis Portal" (https:/ / www. immport. org/ immportWeb/ home/ home. do?loginType=full). . Retrieved
2009-09-03.
[11] "FLow analysis with Automated Multivariate Estimation (FLAME)" (http:/ / www. broadinstitute. org/ cancer/ software/ genepattern/
modules/ FLAME/ ). . Retrieved 2009-09-03.
[12] "flowClust" (http:/ / www. bioconductor. org/ packages/ 2. 5/ bioc/ html/ flowClust. html). . Retrieved 2009-09-03.
[13] http:/ / www3. interscience. wiley. com/ journal/ 117925662/ abstract?CRETRY=1& SRETRY=0
[14] http:/ / www. biomedcentral. com/ 1471-2105/ 10/ 145
Flow cytometry 187

[15] "FlowCAP - Flow Cytometry: Critical Assessment of Population Identification Methods" (http:/ / flowcap. flowsite. org/ ). . Retrieved
2009-09-03.
[16] "FACS MultiSET System" (http:/ / www. bdbiosciences. com/ pdfs/ brochures/ 23-3428-02. pdf) (PDF). Becton Dickinson. . Retrieved
2007-02-09.
[17] Herzenberg, LA; Julius MH, Masuda T (1972). "Demonstration that antigen-binding cells are precursors of antibody-producing cells after
purification with a fluorescence-activated cell sorter.". PNAS 69 (7): 1934–8. PMC 426835. PMID 4114858.
[18] Loken MR (1990). Immunofluorescence Techniques in Flow Cytometry and Sorting (2nd ed.). Wiley. pp. 341–53.
[19] Ornatsky, O.; Bandura, D.; Baranov, V.; Nitz, M.; Winnik, M. A.; Tanner, S. (2010). "Highly multiparametric analysis by mass cytometry".
Journal of Immunological Methods 361 (1–2): 1–20. doi:10.1016/j.jim.2010.07.002. PMID 20655312.

External links
• Flow cytometry - How does it work? (http://www.unsolvedmysteries.oregonstate.edu/flow_06) (Oregon State
University)
• How a flow cytometer operates (http://sciencepark.mdanderson.org/fcores/flow/files/Operation.html) (MD
Anderson Cancer Center)
• Learn About Flow Cytometry (http://www.millipore.com/flowcytometry/fc4/learn) (Millipore)
• Powerpoint lectures on flow cytometry (http://www.cyto.purdue.edu/flowcyt/educate/pptslide.htm) (Purdue
University)
• Tutorials on fluorescence and flow cytometry (http://probes.invitrogen.com/resources/education/)
(Invitrogen)
• Searchable database of fluorescent dyes (http://www.fluorophores.tugraz.at/) (Graz University of Technology)
• Table of fluorochromes (http://pingu.salk.edu/flow/fluo.html) (Salk Institute)
• Java Fluorescence Spectrum Viewer (http://www.bdbiosciences.com/spectra/) (Becton, Dickinson and
Company)
• Flow+cytometry (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Flow+cytometry) at the
US National Library of Medicine Medical Subject Headings (MeSH)
• FICCS (http://www.ficcs.org/) - the Flow Informatics and Computation Cytometry Society
• History of Flow Cytometry by Bob Auer (http://www.coulterflow.com/bciflow/history.php) (hosted by
Beckman Coulter)
• Flow Cytometry - A Basic Introduction (http://flowbook.denovosoftware.com/) (hosted by De Novo Software)
• Clinical Flow Wiki (http://wiki.clinicalflow.com/)
• The History of the Cell Sorter Interviews (http://siarchives.si.edu/collections/siris_arc_217722) from the
Smithsonian Institution Archives
Glucose 188

Glucose
D-glucose

Identifiers

Abbreviations Glc

CAS number [1]


50-99-7  

PubChem [2]
5793

ChemSpider [3]
5589  

UNII [4]
5SL0G7R0OK  

EC number [5]
200-075-1

KEGG [6]
C00031  

MeSH [7]
Glucose

ChEBI [8]
CHEBI:4167  

ChEMBL [9]
CHEMBL1222250  

RTECS number LZ6600000

ATC code [10] [11] [12]


B05 CX01 ,V04 CA02 , V06 DC01

Beilstein Reference 1281604

Gmelin Reference 83256

3DMet [13]
B04623

Jmol-3D images [14]


Image 1
[15]
Image 2

Properties

Molecular formula CH O
6 12 6
Molar mass 180.16 g/mol

Density 1.54 g/cm3

Melting point α-D-glucose: 146 °C


β-D-glucose: 150 °C

Solubility in water 91 g/100 mL


Glucose 189

Thermochemistry

Std enthalpy of −1271 kJ/mol


formation ΔfHo298

Std enthalpy of −2805 kJ/mol


combustion ΔcHo298

Standard molar 209.2 J K−1 mol−1


entropy So298

Hazards

MSDS [16]
ICSC 0865

EU Index not listed

[17]
  (verify)  (what is:  / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Glucose (/ˈɡluːkoʊs/ or /ʔkoʊz/; C6H12O6, also known as D-glucose, dextrose, or grape sugar) is a simple sugar
(monosaccharide) and an important carbohydrate in biology. Cells use it as the primary source of energy[18] and a
metabolic intermediate. Glucose is one of the main products of photosynthesis and fuels for cellular respiration.
Glucose exists in several different molecular structures, but all of these structures can be divided into two families of
mirror-images (stereoisomers). Only one set of these isomers exists in nature, those derived from the "right-handed
form" of glucose, denoted D-glucose. D-glucose is sometimes referred to as dextrose, although the use of this name is
strongly discouraged. The term dextrose is derived from dextrorotatory glucose.[19] This name is therefore confusing
when applied to the enantiomer, which rotates light the opposite direction. Starch and cellulose are polymers derived
from the dehydration of D-glucose. The other stereoisomer, called L-glucose, is hardly ever found in nature.
The name "glucose" comes from the Greek word glukus (γλυκύς), meaning "sweet", and is the preferred name. The
suffix "-ose" denotes a sugar.
Glucose 190

Function
Scientists can speculate on the reasons that glucose, and not another
monosaccharide such as fructose, is so widely used in organisms. One
reason might be that glucose has a lower tendency, relative to other
hexose sugars, to react non-specifically with the amino groups of
proteins. This reaction (glycation) reduces or destroys the function of
many enzymes. The low rate of glycation is due to glucose's preference
for the less reactive cyclic isomer. Nevertheless, many of the long-term
complications of diabetes (e.g., blindness, renal failure, and peripheral
neuropathy) are probably due to the glycation of proteins or lipids.[20]
In contrast, enzyme-regulated addition of glucose to proteins by Glucose metabolism and various forms of it in the
process.
glycosylation is often essential to their function.
-Glucose-containing compounds and isomeric
forms are digested and taken up by the body in
Analyte in medical blood test the intestines, including starch, glycogen,
disaccharides and monosaccharides.
Glucose is a common medical analyte measured in blood samples. -Glucose is stored in mainly the liver and muscles
Eating or fasting prior to taking a blood sample has an effect on the as glycogen.
-It is distributed and utilized in tissues as free
result. Higher than usual glucose levels may be a sign of prediabetes or
glucose.
diabetes mellitus.

As an energy source
Glucose is a ubiquitous fuel in biology. It is used as an energy source in most organisms, from bacteria to humans.
Use of glucose may be by either aerobic respiration, anaerobic respiration, or fermentation. Glucose is the human
body's key source of energy, through aerobic respiration, providing approximately 3.75 kilocalories (16 kilojoules)
of food energy per gram.[21] Breakdown of carbohydrates (e.g. starch) yields mono- and disaccharides, most of
which is glucose. Through glycolysis and later in the reactions of the citric acid cycle (TCAC), glucose is oxidized to
eventually form CO2 and water, yielding energy sources, mostly in the form of ATP. The insulin reaction, and other
mechanisms, regulate the concentration of glucose in the blood. A high fasting blood sugar level is an indication of
prediabetic and diabetic conditions.

Glucose is a primary source of energy for the brain, and hence its availability influences psychological processes.
When glucose is low, psychological processes requiring mental effort (e.g., self-control, effortful decision-making)
are impaired.[22][23][24][25]

Glucose in glycolysis

α-D-Glucose Hexokinase α-D-Glucose-6-phosphate

ATP ADP

[26] [27] [28]


Compound C00031 at KEGG Pathway Database. Enzyme 2.7.1.1 at KEGG Pathway Database. Compound C00668 at KEGG
[29]
Pathway Database. Reaction R01786 at KEGG Pathway Database.
Glucose 191

Use of glucose as an energy source in cells is via aerobic or anaerobic respiration. Both of these start with the early
steps of the glycolysis metabolic pathway. The first step of this is the phosphorylation of glucose by hexokinase to
prepare it for later breakdown to provide energy. The major reason for the immediate phosphorylation of glucose by
a hexokinase is to prevent diffusion out of the cell. The phosphorylation adds a charged phosphate group so the
glucose 6-phosphate cannot easily cross the cell membrane. Irreversible first steps of a metabolic pathway are
common for regulatory purposes.
In anaerobic respiration one glucose molecule produces a net gain of two ATP molecules (four ATP molecules are
produced during glycolysis but two are required by enzymes used during the process).[30] In aerobic respiration a
molecule of glucose is much more profitable in that a net worth of 34 ATP molecules are generated (32 gross with
two being required in the process).[31]

As a precursor
Organisms use glucose as a precursor for the synthesis of several important substances. Starch, cellulose, and
glycogen ("animal starch") are common glucose polymers (polysaccharides). Some of these polymers like starch or
glycogen serve as energy stores while others like cellulose and chitin (which is made from a derivative of glucose)
have structural roles. Oligosaccharides of glucose combined with other sugars serve as important energy stores.
These include lactose, the predominant sugar in milk which a glucose-galactose disaccharide and sucrose, another
disaccharide of glucose and fructose. Glucose is also added onto certain proteins and lipids in a process called
glycosylation. This is often critical for their functioning. The enzymes that join glucose to other molecules usually
use phosphorylated glucose to power the formation of the new bond by breaking the glucose-phosphate bond.
Other than its direct use as a monomer, glucose can be broken down to synthesize a wide variety of other
biomolecules. This is important as glucose serves both as a primary store of energy but also as a source of organic
carbon. Glucose can be broken down and converted into lipids and amino acids. It is also a precursor for the
synthesis of other important molecules like vitamin C (ascorbic acid). Though plants and some microbes can create
all the compounds they need from glucose given the necessary minerals, all animals and many microbes cannot
synthesize some or the other essential nutrient. For example, humans cannot synthesize Vitamin C and certain
essential amino acids and need them in their diet.
Glucose 192

Industrial use
In industry, glucose is used as a precursor to make vitamin C (L-ascorbic acid) in the Reichstein process, to make
citric acid, gluconic acid, bio-ethanol, polylactic acid, sorbitol.

Structure and nomenclature


Glucose is a monosaccharide with formula C6H12O6 or H-(C=O)-(CHOH)5-H, whose five hydroxyl (OH) groups are
arranged in a specific way along its six-carbon backbone.

Open-chain form
In its fleeting open-chain form, the glucose molecule has an open (as opposed to cyclic)
and unbranched backbone of six carbon atoms, C-1 through C-6; where C-1 is part of an
aldehyde group H(C=O)-, and each of the other five carbons bears one hydroxyl group
-OH. The remaining bonds of the backbone carbons are satisfied by hydrogen atoms -H.
Therefore glucose is an hexose and an aldose, or an aldohexose.
Each of the four carbons C-2 through C-5 is a stereocenter, meaning that its four bonds
connect to four different substituents. (Carbon C-2, for example, connects to -(C=O)H,
-OH, -H, and -(CHOH)4H.) In D-glucose, these four parts must be in a specific
three-dimensional arrangement. Namely, when the molecule is drawn in the Fischer
projection, the hydroxyls on C-2, C-4, and C-5 must be on the right side, while that on
D-glucose in Fischer
C-3 must be on the left side.
projection The positions of those four hydroxyls are exactly reversed in the Fischer diagram of
L-glucose. D- and L-glucose are two of the 16 possible aldohexoses; the other 14 are
allose, altrose, mannose, gulose, idose, galactose, and talose, each with two isomers, "D-" and "L-".

Cyclic forms
In solutions, the open-chain form of glucose (either "D-" or "L-") exists in equilibrium with several cyclic isomers,
each containing a ring of carbons closed by one oxygen atom. In aqueous solution, however, glucose exists as
pyranose for more than 99%. The open-chain form is limited to about 0.25% and furanose exists in negligible
amounts. The terms "glucose" and "D-glucose" are generally used for these cyclic forms as well. The ring arises from
the open-chain form by a nucleophilic addition reaction between the aldehyde group -(C=O)H at C-1 and the
hydroxyl group -OH at C-4 or C-5, yielding a hemiacetal group -C(OH)H-O-.
The reaction between C-1 and C-5 creates a molecule with a six-membered ring, called pyranose, after the cyclic
ether pyran, the simplest molecule with the same carbon-oxygen ring. The (much rarer) reaction between C-1 and
C-4 creates a molecule with a five-membered ring, called furanose, after the cyclic ether furan. In either case, each
carbon in the ring has one hydrogen and one hydroxyl attached, except for the last carbon (C-4 or C-5) where the
hydroxyl is replaced by the remainder of the open molecule (which is -(CHOH)2-H or -(CHOH)-H, respectively).
The ring-closing reaction makes carbon C-1 chiral, too, since its four bonds lead to -H, to -OH, to carbon C-2, and to
the ring oxygen. These four parts of the molecule may be arranged around C-1 (the anomeric carbon) in two distinct
ways, designated by the prefixes "α-" and "β-". When a glucopyranose molecule is drawn in the Haworth projection,
the designation "α-" means that the hydroxyl group attached to C-1 and the -CH2OH group at C-5 lies on opposite
sides of the ring's plane (a trans arrangement), while "β-" means that they are on the same side of the plane (a cis
arrangement).
Therefore, the open isomer D-glucose gives rise to four distinct cyclic isomers: α-D-glucopyranose,
β-D-glucopyranose, α-D-glucofuranose, and β-D-glucofuranose; which are all chiral.
Glucose 193

α-D- β-D- α-D- β-D-


Glucopyranose Glucopyranose Glucofuranose Glucofuranose

α-D-Glucopyranose β-D-Glucopyranose

The other open-chain isomer L-glucose similarly gives rise to four distinct cyclic forms of L-glucose, each the mirror
image of the corresponding D-glucose.
The rings are not planar but twisted in three dimensions. The glucopyranose ring (α or β) can assume several
non-planar shapes, analogous to the "chair" and "boat" conformations of cyclohexane. Similarly, the glucofuranose
ring may assume several shapes, analogous to the "envelope" conformations of cyclopentane.
The glucopyranose forms of glucose predominate in solution, and are the only forms observed in the solid state.
They are crystalline colorless solids, highly soluble in water and acetic acid, poorly soluble in methanol and ethanol.
They melt at 146 °C (unknown operator: u'strong' °F) (α) and 150 °C (unknown operator: u'strong' °F) (β), and
decompose at higher temperatures into carbon and water.

Rotational isomers
Each glucose isomer is subject to rotational isomerism. Within the cyclic form of glucose, rotation may occur around
the O6-C6-C5-O5 torsion angle, termed the ω-angle, to form three staggered rotamer conformations called
gauche-gauche (gg), gauche-trans (gt) and trans-gauche (tg). For methyl α-D-glucopyranose at equilibrium the ratio
of molecules in each rotamer conformation is reported as 57:38:5 gg:gt:tg.[32] This tendency for the ω-angle to prefer
to adopt a gauche conformation is attributed to the gauche effect.
Glucose 194

Physical properties

Solutions
All forms of glucose are colorless and easily soluble in water, acetic acid, and several other solvents. They are only
sparingly soluble in methanol and ethanol.
The open-chain form is thermodynamically unstable, and it spontaneously tautomerizes to the cyclic forms.
(Although the ring closure reaction could in theory create four- or three-atom rings, these would be highly strained
and are not observed.) In solutions at room temperature, the four cyclic isomers interconvert over a timescale of
hours, in a process called mutarotation.[33] Starting from any proportions, the mixture converges stable ratio of α:β
36:64. The ratio would be α:β 11:89 if it were not for the influence of the anomeric effect.[34] Mutarotation is
considerably slower at temperatures close to 0 °C.
Mutarotation consists of a temporary reversal of the ring-forming reaction, resulting in the open-chain form,
followed by a re-forming of the ring. The ring closure step may use a different -OH group than the one recreated by
the opening step (thus switching between pyranose and furanose forms), and/or the new hemiacetal group created on
C-1 may have the same or opposite handedness as the original one (thus switching between the α and β forms).
Thus, even though the open-chain form is barely detectable in solution, it is an essential component of the
equilibrium.

Solid state
Depending on conditions, three major solid forms of glucose can be crystallised from water solutions:
α-glucopyranose, β-glucopyranose, and β-glucopyranose hydrate.[35]

Optical activity
Whether in water or in the solid form, D-glucose is dextrorotatory, meaning that it will rotate the direction of
polarized light clockwise. The effect is due to the chirality of the molecules, and indeed the mirror-image isomer,
L-glucose, is levorotatory (rotates polarized light counterclockwise) by the same amount. The strength of the effect is
different for each of the five tautomers.
Note that the D- prefix does not refer directly to the optical properties of the compound. It indicates that the C-2
chiral center has the same handedness as that of D-glyceraldehyde (which was so labeled because it is
dextrorotatory). The fact that D-glucose is dextrorotatory is a combined effect of its four chiral centers, not just of
C-2; and indeed some of the other D-aldohexoses are levorotatory.

Production

Biosynthesis
In plants and some prokaryotes, glucose is a product of photosynthesis.
In animals and fungi, glucose results from the breakdown of glycogen,
a process known as glycogenolysis. In plants the breakdown substrate
is starch.
In animals, glucose is synthesized in the liver and kidneys from
non-carbohydrate intermediates, such as pyruvate and glycerol, by a
process known as gluconeogenesis.
Glucose tablets
In some deep-sea bacteria glucose is produced by chemosynthesis.
Glucose 195

Commercial
Glucose is produced commercially via the enzymatic hydrolysis of starch. Many crops can be used as the source of
starch. Maize, rice, wheat, cassava, corn husk and sago are all used in various parts of the world. In the United
States, cornstarch (from maize) is used almost exclusively. Most commercial glucose occurs as a component of
invert sugar, an approximately 1:1 mixture of glucose and fructose. In principle, cellulose could be hydrolysed to
glucose, but this process is not yet commercially practical.[35]

Sources and absorption


Most dietary carbohydrates contain glucose, either as their only building block, as in starch and glycogen, or together
with another monosaccharide, as in sucrose and lactose.
In the lumen of the duodenum and small intestine, the glucose oligo- and polysaccharides are broken down to
monosaccharides by the pancreatic and intestinal glycosidases. Other polysaccharides cannot be processed by the
human intestine and require assistance by intestinal flora if they are to be broken down; the most notable exceptions
are sucrose (fructose-glucose) and lactose (galactose-glucose). Glucose is then transported across the apical
membrane of the enterocytes by SLC5A1, and later across their basal membrane by SLC2A2.[36] Some of the
glucose is converted to lactic acid by astrocytes, which is then utilized as an energy source by brain cells, some of
the glucose is used by intestinal cells and red blood cells, while the rest reaches the liver, adipose tissue and muscle
cells, where it is absorbed and stored as glycogen (under the influence of insulin). Liver cell glycogen can be
converted to glucose and returned to the blood when insulin is low or absent; muscle cell glycogen is not returned to
the blood because of a lack of enzymes. In fat cells, glucose is used to power reactions that synthesize some fat types
and have other purposes. Glycogen is the body's "glucose energy storage" mechanism, because it is much more
"space efficient" and less reactive than glucose itself.

History
Because glucose is a basic necessity of many organisms, a correct understanding of its chemical makeup and
structure contributed greatly to a general advancement in organic chemistry. This understanding occurred largely as
a result of the investigations of Emil Fischer, a German chemist who received the 1902 Nobel Prize in Chemistry as
a result of his findings.[37] The synthesis of glucose established the structure of organic material and consequently
formed the first definitive validation of Jacobus Henricus van't Hoff's theories of chemical kinetics and the
arrangements of chemical bonds in carbon-bearing molecules.[38] Between 1891 and 1894, Fischer established the
stereochemical configuration of all the known sugars and correctly predicted the possible isomers, applying van't
Hoff's theory of asymmetrical carbon atoms.

References
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[2] http:/ / pubchem. ncbi. nlm. nih. gov/ summary/ summary. cgi?cid=5793
[3] http:/ / www. chemspider. com/ 5589
[4] http:/ / fdasis. nlm. nih. gov/ srs/ srsdirect. jsp?regno=5SL0G7R0OK
[5] http:/ / esis. jrc. ec. europa. eu/ lib/ einecs_IS_reponse. php?genre=ECNO& entree=200-075-1
[6] http:/ / www. kegg. jp/ entry/ C00031
[7] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2007/ MB_cgi?mode=& term=Glucose
[8] https:/ / www. ebi. ac. uk/ chebi/ searchId. do?chebiId=4167
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[13] http:/ / www. 3dmet. dna. affrc. go. jp/ html/ B04623. html
Glucose 196

[14] http:/ / chemapps. stolaf. edu/ jmol/ jmol.


php?model=OC%5BC%40H%5D1OC%28O%29%5BC%40H%5D%28O%29%5BC%40%40H%5D%28O%29%5BC%40%40H%5D1O
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[17] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=480476804& page2=%3AGlucose
[18] Clark, D.; Sokoloff, L. (1999), Basic Neurochemistry: Molecular, Cellular and Medical Aspects, Lippincott, pp. 637–670
[19] "dextrose" (http:/ / www. m-w. com/ dictionary/ dextrose), Merriam-Webster Online Dictionary, , retrieved 2009-09-02.
[20] High Blood Glucose and Diabetes Complications: The buildup of molecules known as AGEs may be the key link (http:/ / forecast. diabetes.
org/ magazine/ features/ high-blood-glucose-and-diabetes-complications), American Diabetes Association, 2010, ISSN 0095-8301,
[21] "Chapter 3: Calculation of the Energy Content of Foods – Energy Conversion Factors" (http:/ / www. fao. org/ docrep/ 006/ Y5022E/
y5022e04. htm), Food energy — methods of analysis and conversion factors, FAO Food and Nutrition Paper 77, Rome: Food and Agriculture
Organization, 2003, ISBN 92-5-105014-7, .
[22] Fairclough, Stephen H.; Houston, Kim (2004), "A metabolic measure of mental effort", Biol. Psychol. 66 (2): 177–90,
doi:10.1016/j.biopsycho.2003.10.001, PMID 15041139.
[23] Gailliot, Matthew T.; Baumeister, Roy F.; DeWall, C. Nathan; Plant, E. Ashby; Brewer, Lauren E.; Schmeichel, Brandon J.; Tice, Dianne
M.; Maner, Jon K. (2007), "Self-Control Relies on Glucose as a Limited Energy Source: Willpower is More than a Metaphor", J. Personal.
Soc. Psychol. 92 (2): 325–36, doi:10.1037/0022-3514.92.2.325, PMID 17279852.
[24] Gailliot, Matthew T.; Baumeister, Roy F. (2007), "The Physiology of Willpower: Linking Blood Glucose to Self-Control", Personal. Soc.
Psychol. Rev. 11 (4): 303–27, doi:10.1177/1088868307303030, PMID 18453466.
[25] Masicampo, E. J.; Baumeister, Roy F. (2008), "Toward a Physiology of Dual-Process Reasoning and Judgment: Lemonade, Willpower, and
Expensive Rule-Based Analysis", Psychol. Sci. 19 (3): 255–60, doi:10.1111/j.1467-9280.2008.02077.x, PMID 18315798.
[26] http:/ / www. genome. jp/ dbget-bin/ www_bget?compound+ C00031
[27] http:/ / www. genome. jp/ dbget-bin/ www_bget?enzyme+ 2. 7. 1. 1
[28] http:/ / www. genome. jp/ dbget-bin/ www_bget?compound+ C00668
[29] http:/ / www. genome. jp/ dbget-bin/ www_bget?rn+ R01786
[30] Medical Biochemistry at a Glance @Google books (http:/ / books. google. co. uk/ books?id=9BtxCWxrWRoC& pg=PA52), Blackwell
Publishing, 2006, ISBN 978-1-4051-1322-9,
[31] Medical Biochemistry at a Glance @Google books (http:/ / books. google. co. uk/ books?id=9BtxCWxrWRoC& pg=PA50), Blackwell
Publishing, 2006, ISBN 978-1-4051-1322-9,
[32] Kirschner, Karl N.; Woods, Robert J. (2001), "Solvent interactions determine carbohydrate conformation", Proc. Natl. Acad. Sci. USA 98
(19): 10541–45, doi:10.1073/pnas.191362798, PMC 58501, PMID 11526221
[33] McMurry, John E. (1988), Organic Chemistry (2nd ed.), Brooks/Cole, p. 866, ISBN 0534079687.
[34] Juaristi, Eusebio; Cuevas, Gabriel (1995), The Anomeric Effect, CRC Press, pp. 9–10, ISBN 0-8493-8941-0.
[35] Fred W. Schenck “Glucose and Glucose-Containing Syrups” in Ullmann's Encyclopedia of Industrial Chemistry 2006, Wiley-VCH,
Weinheim. doi: 10.1002/14356007.a12_457.pub2
[36] Ferraris, Ronaldo P. (2001), "Dietary and developmental regulation of intestinal sugar transport" (http:/ / www. biochemj. org/ bj/ 360/
0265/ bj3600265. htm), Biochem. J. 360 (Pt 2): 265–76, doi:10.1042/0264-6021:3600265, PMC 1222226, PMID 11716754, .
[37] Emil Fischer (http:/ / nobelprize. org/ nobel_prizes/ chemistry/ laureates/ 1902/ fischer-bio. html), Nobel Foundation, , retrieved 2009-09-02.
[38] Fraser-Reid, Bert, "van't Hoff's Glucose", Chem. Eng. News 77 (39): 8.

External links
• International Chemical Safety Card 0865 (http://www.inchem.org/documents/icsc/icsc/eics0865.htm)
Glycogen 197

Glycogen
Glycogen is a multibranched polysaccharide
that serves as a form of energy storage in
animals[2] and fungi. In humans, glycogen is
made and stored primarily in the cells of the
liver and the muscles, and functions as the
secondary long-term energy storage (with
the primary energy stores being fats held in
adipose tissue). Glycogen can also be made
via glycogenesis within the brain and
stomach.[3]

Glycogen is the analogue of starch, a


glucose polymer in plants, and is sometimes
referred to as animal starch, having a
similar structure to amylopectin but more
extensively branched and compact than
starch. Glycogen is found in the form of
granules in the cytosol/cytoplasm in many
cell types, and plays an important role in the
glucose cycle. Glycogen forms an energy Schematic 2-D cross-sectional view of glycogen. A core protein of glycogenin is
surrounded by branches of glucose units. The entire globular granule may contain
reserve that can be quickly mobilized to [1]
approximately 30,000 glucose units.
meet a sudden need for glucose, but one that
is less compact than the energy reserves of
triglycerides (lipids).

In the liver hepatocytes, glycogen can


compose up to eight percent of the fresh
weight (100–120 g in an adult) soon after a
meal.[4] Only the glycogen stored in the
liver can be made accessible to other organs.
In the muscles, glycogen is found in a low
concentration (one to two percent of the
muscle mass). The amount of glycogen
stored in the body—especially within the
muscles, liver, and red blood
[5][6][7]
cells —mostly depends on physical
training, basal metabolic rate, and eating
habits such as intermittent fasting. Small
amounts of glycogen are found in the
kidneys, and even smaller amounts in
certain glial cells in the brain and white
blood cells. The uterus also stores glycogen
during pregnancy to nourish the embryo.[8] A view of the atomic structure of a single branched strand of glucose units in a
glycogen molecule.
Glycogen 198

Structure
Glycogen is a branched biopolymer
consisting of linear chains of glucose
residues with further chains branching
off every ten glucoses or so. Glucoses
are linked together linearly by α(1→4)
glycosidic bonds from one glucose to
the next. Branches are linked to the
chains they are branching off from by
α(1→6) glycosidic bonds between the
first glucose of the new branch and a Schematic of glycogen structure
glucose on the stem chain. [9]

Due to the way that glycogen is synthesised, every glycogen granule has at its core a glycogenin protein.[10]

Function

Liver
As a meal containing carbohydrates is eaten and digested, blood glucose levels rise, and the pancreas secretes
insulin. Glucose from the portal vein enters liver cells (hepatocytes). Insulin acts on the hepatocytes to stimulate the
action of several enzymes, including glycogen synthase. Glucose molecules are added to the chains of glycogen as
long as both insulin and glucose remain plentiful. In this postprandial or "fed" state, the liver takes in more glucose
from the blood than it releases.
After a meal has been digested and glucose levels begin to fall, insulin secretion is reduced, and glycogen synthesis
stops. When it is needed for energy, glycogen is broken down and converted again to glucose. Glycogen
phosphorylase is the primary enzyme of glycogen breakdown. For the next 8–12 hours, glucose derived from liver
glycogen will be the primary source of blood glucose to be used by the rest of the body for fuel.
Glucagon is another hormone produced by the pancreas, which in many respects serves as a counter-signal to insulin.
In response to insulin level below normal (when blood levels of glucose begin to fall below the normal range),
glucagon is secreted in increasing amounts to stimulate glycogenolysis and gluconeogenesis pathways.

Muscle
Muscle cell glycogen appears to function as an immediate reserve source of available glucose for muscle cells. Other
cells that contain small amounts use it locally as well. Muscle cells lack the enzyme glucose-6-phosphatase, which is
required to pass glucose into the blood, so the glycogen they store is destined for internal use and is not shared with
other cells. (This is in contrast to liver cells, which, on demand, readily do break down their stored glycogen into
glucose and send it through the blood stream as fuel for the brain or muscles). Glycogen is also a suitable storage
substance due to its insolubility in water, which means it does not affect the osmotistic levels and pressure of a cell.
Glycogen 199

Metabolism

Synthesis
Glycogen synthesis is, unlike its breakdown, endergonic. This means that glycogen synthesis requires the input of
energy. Energy for glycogen synthesis comes from UTP, which reacts with glucose-1-phosphate, forming
UDP-glucose, in a reaction catalysed by UDP-glucose pyrophosphorylase. Glycogen is synthesized from monomers
of UDP-glucose by the enzyme glycogen synthase, which progressively lengthens the glycogen chain with (α1→4)
bonded glucose. As glycogen synthase can lengthen only an existing chain, the protein glycogenin is needed to
initiate the synthesis of glycogen. The glycogen-branching enzyme, amylo (α1→4) to (α1→6) transglycosylase,
catalyzes the transfer of a terminal fragment of 6-7 glucose residues from a nonreducing end to the C-6 hydroxyl
group of a glucose residue deeper into the interior of the glycogen molecule. The branching enzyme can act upon
only a branch having at least 11 residues, and the enzyme may transfer to the same glucose chain or adjacent glucose
chains.

Breakdown
Glycogen is cleaved from the nonreducing ends of the chain by the
enzyme glycogen phosphorylase to produce monomers of
glucose-1-phosphate, which is then converted to glucose 6-phosphate
by phosphoglucomutase. A special debranching enzyme is needed to Action of Glycogen Phosphorylase on Glycogen

remove the alpha(1-6) branches in branched glycogen and reshape the


chain into linear polymer. The G6P monomers produced have three possible fates:

• G6P can continue on the glycolysis pathway and be used as fuel.


• G6P can enter the pentose phosphate pathway via the enzyme Glucose-6-phosphate dehydrogenase to produce
NADPH and 5-carbon sugars.
• In the liver and kidney, G6P can be dephosphorylated back to Glucose by the enzyme Glucose 6-phosphatase.
This is the final step in the gluconeogenesis pathway.

Clinical relevance

Disorders of glycogen metabolism


The most common disease in which glycogen metabolism becomes abnormal is diabetes, in which, because of
abnormal amounts of insulin, liver glycogen can be abnormally accumulated or depleted. Restoration of normal
glucose metabolism usually normalizes glycogen metabolism as well.
In hypoglycemia caused by excessive insulin, liver glycogen levels are high, but the high insulin level prevents the
glycogenolysis necessary to maintain normal blood sugar levels. Glucagon is a common treatment for this type of
hypoglycemia.
Various inborn errors of metabolism are caused by deficiencies of enzymes necessary for glycogen synthesis or
breakdown. These are collectively referred to as glycogen storage diseases.
Glycogen 200

Glycogen depletion and endurance exercise


Long-distance athletes such as marathon runners, cross-country skiers, and cyclists often experience glycogen
depletion, where almost all of the athlete's glycogen stores are depleted after long periods of exertion without enough
energy consumption. This phenomenon is referred to as "hitting the wall". In marathon runners, it normally happens
around the 20-mile (32 km) point of a marathon, depending on the size of the runner and the race course.
Glycogen depletion can be forestalled in four possible ways. First, during exercise carbohydrates with the highest
possible rate of conversion to blood glucose per time (high glycemic Index) are ingested continuously. The best
possible outcome of this strategy replaces about 35% of glucose consumed at heart rates above about 80% of
maximum. Second, through training, the body can be conditioned to burn fat earlier, faster, and more efficiently,
sparing carbohydrate use from all sources. Third, by consuming foods low on the glycemic Index for 12–18 hours
before the event, the liver and muscles will store the resulting slow but steady stream of glucose as glycogen, instead
of fat. This process is known as carbohydrate loading.
When experiencing glycogen debt, athletes often experience extreme fatigue to the point that it is difficult to move.
As a reference, the very best professional cyclists in the world will usually finish a 4-5hr stage race right at the limit
of glycogen depletion using the first 3 strategies.
A study published in the Journal of Applied Physiology (online May 8, 2008) suggests that, when athletes ingest
both carbohydrate and caffeine following exhaustive exercise, their glycogen is replenished more rapidly.[11][12]

References
[1] Page 12 in: (http:/ / books. google. dk/ books?id=SRptlOx7yj4C& printsec=frontcover& hl=en) Exercise physiology: energy, nutrition, and
human performance By William D. McArdle, Frank I. Katch, Victor L. Katch Edition: 6, illustrated Published by Lippincott Williams &
Wilkins, 2006 ISBN 0-7817-4990-5, ISBN 978-0-7817-4990-9, 1068 pages
[2] Sadava et al (2011). Life (9th, International ed.). W. H. Freeman. ISBN 9781429254311.
[3] Anatomy and Physiology. Saladin, Kenneth S. McGraw-Hill, 2007.
[4] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[5] Moses SW, Bashan N, Gutman A (December 1972). "Glycogen metabolism in the normal red blood cell" (http:/ / www. bloodjournal. org/
cgi/ pmidlookup?view=long& pmid=5083874). Blood 40 (6): 836–43. PMID 5083874. .
[6] http:/ / jeb. biologists. org/ cgi/ reprint/ 129/ 1/ 141. pdf
[7] Miwa I, Suzuki S (November 2002). "An improved quantitative assay of glycogen in erythrocytes". Annals of Clinical Biochemistry 39 (Pt 6):
612–3. doi:10.1258/000456302760413432. PMID 12564847.
[8] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[9] Berg, Tymoczko & Stryer (2012). Biochemistry (7th, International ed.). W. H. Freeman. p. 338. ISBN 1429203145.
[10] Berg et al (2012). Biochemistry (7th, International ed.). W. H. Freeman. p. 650.
[11] Pedersen DJ, Lessard SJ, Coffey VG, et al. (July 2008). "High rates of muscle glycogen resynthesis after exhaustive exercise when
carbohydrate is coingested with caffeine". Journal of Applied Physiology 105 (1): 7–13. doi:10.1152/japplphysiol.01121.2007.
PMID 18467543.
[12] Post-exercise Caffeine Helps Muscles Refuel (http:/ / newswise. com/ articles/ view/ 542216/ ) Newswise, Retrieved on July 6, 2008.

External links
• Glycogen detection using Periodic Acid Schiff Staining (http://www.histochem.net/protocol periodic acid
schiff.htm)
• Glycogen storage disease - McArdle's Disease Website (http://mcardlesdisease.org)
• Glycogen (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Glycogen) at the US National
Library of Medicine Medical Subject Headings (MeSH)
Glycoprotein 201

Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains
(glycans) covalently attached to polypeptide side-chains. The
carbohydrate is attached to the protein in a cotranslational or
posttranslational modification. This process is known as glycosylation.
In proteins that have segments extending extracellularly, the
extracellular segments are often glycosylated. Glycoproteins are often
important integral membrane proteins, where they play a role in
cell–cell interactions. Glycoproteins are also formed in the cytosol, but
their functions and the pathways producing these modifications in this
compartment are less well understood.[2]
N-linked protein glycosylation (N-glycosylation
of N-glycans) at Asn residues (Asn-x-Ser/Thr
N-glycosylation and O-glycosylation motifs) in glycoproteins.
[1]

There are two types of glycoproteins:

• In N-glycosylation (see on the right), the addition of sugar chains can happen at the amide nitrogen on the
side-chain of the asparagine.
• In O-glycosylation, the addition of sugar chains can happen on the hydroxyl oxygen on the side-chain of
hydroxylysine, hydroxyproline, serine, or threonine.

Monosaccharides
Monosaccharides commonly found in eukaryotic glycoproteins
include:[3]:526

Eight sugars commonly found in glycoproteins.


Glycoprotein 202

The principal sugars found in human glycoproteins[4]


Sugar Type Abbreviation

β-D-Glucose Hexose Glc

β-D-Galactose Hexose Gal

β-D-Mannose Hexose Man

α-L-Fucose Deoxyhexose Fuc

N-Acetylgalactosamine Aminohexose GalNAc

N-Acetylglucosamine Aminohexose GlcNAc

N-Acetylneuraminic acid Aminononulosonic NeuNAc


acid
(Sialic acid)

Xylose Pentose Xyl

The sugar group(s) can assist in protein folding or improve proteins' stability.

Examples
One example of glycoproteins found in the body is mucins, which are secreted in the mucus of the respiratory and
digestive tracts. The sugars attached to mucins give them considerable water-holding capacity and also make them
resistant to proteolysis by digestive enzymes.
Glycoproteins are important for white blood cell recognition, especially in mammals. Examples of glycoproteins in
the immune system are:
• molecules such as antibodies (immunoglobulins), which interact directly with antigens.
• molecules of the major histocompatibility complex (or MHC), which are expressed on the surface of cells and
interact with T cells as part of the adaptive immune response.
Other examples of glycoproteins include:
• glycoprotein IIb/IIIa, an integrin found on platelets that is required for normal platelet aggregation and adherence
to the endothelium.
• components of the zona pellucida, which surrounds the oocyte, and is important for sperm-egg interaction.
• structural glycoproteins, which occur in connective tissue. These help bind together the fibers, cells, and ground
substance of connective tissue. They may also help components of the tissue bind to inorganic substances, such as
calcium in bone.
• Glycoprotein-41 (gp41) and glycoprotein-120 (gp120) are HIV viral coat proteins.
Soluble glycoproteins often show a high viscosity, for example, in egg white and blood plasma.
• Miraculin, which alters human tongue receptors to recognize sour foods as sweet.
Glycoprotein 203

Hormones
Hormones that are glycoproteins include:
• Follicle-stimulating hormone
• Luteinizing hormone
• Thyroid-stimulating hormone
• Human chorionic gonadotropin
• Alpha-fetoprotein
• Erythropoietin (EPO)

Functions

Some functions served by glycoproteins[3]:524


Function Glycoproteins

Structural molecule Collagens

Lubricant and protective agent Mucins

Transport molecule Transferrin, ceruloplasmin

Immunologic molecule Immunoglobins, histocompatibility antigens

Hormone Human chorionic gonadotropin (HCG), thyroid-stimulating hormone (TSH)

Enzyme Various, e.g., alkaline phosphatase

Cell attachment-recognition site Various proteins involved in cell–cell (e.g., sperm–oocyte), virus–cell, bacterium–cell, and hormone–cell
interactions

Antifreeze protein Certain plasma proteins of coldwater fish

Interact with specific Lectins, selectins (cell adhesion lectins), antibodies


carbohydrates

Receptor Various proteins involved in hormone and drug action

Affect folding of certain proteins Calnexin, calreticulin

Regulation of development Notch and its analogs, key proteins in development

Hemostasis (and thrombosis) Specific glycoproteins on the surface membranes of platelets

Analysis
A variety of methods used in detection, purification, and structural analysis of glycoproteins are[3]:525[5]
Glycoprotein 204

Some important methods used to study glycoproteins


Method Use

Periodic acid-Schiff stain Detects glycoproteins as pink bands after electrophoretic separation.

Incubation of cultured cells with glycoproteins Leads to detection of a radioactive sugar after electrophoretic separation.
as radioactive decay bands

Treatment with appropriate endo- or Resultant shifts in electrophoretic migration help distinguish among proteins with N-glycan,
exoglycosidase or phospholipases O-glycan, or GPI linkages and also between high mannose and complex N-glycans.

Agarose-lectin column chromatography, lectin To purify glycoproteins or glycopeptides that bind the particular lectin used.
affinity chromatography

Lectin affinity electrophoresis Resultant shifts in electrophoretic migration help distinguish and characterize glycoforms, i.e.
variants of a glycoprotein differing in carbohydrate.

Compositional analysis following acid Identifies sugars that the glycoprotein contains and their stoichiometry.
hydrolysis

Mass spectrometry Provides information on molecular mass, composition, sequence, and sometimes branching of a
glycan chain.

NMR spectroscopy To identify specific sugars, their sequence, linkages, and the anomeric nature of glycosidic chain.

Dual Polarisation Interferometry Measures the mechanisms underlying the biomolecular interactions, including reaction rates,
affinities and associated conformational changes.

Methylation (linkage) analysis To determine linkage between sugars.

Amino acid or cDNA sequencing Determination of amino acid sequence.

References
[1] Ruddock & Molinari (2006) Journal of Cell Science 119, 4373–4380
[2] Funakoshi Y, Suzuki T (January 2009). "Glycobiology in the cytosol: The bitter side of a sweet world". Biochim. Biophys. Acta 1790 (2):
81–94. doi:10.1016/j.bbagen.2008.09.009. PMID 18952151.
[3] Robert K. Murray, Daryl K. Granner & Victor W. Rodwell: "Harper's Illustrated Biochemistry 27th Ed.", McGraw-Hill, 2006
[4] https:/ / www. sigmaaldrich. com/ img/ assets/ 15880/ glycan_classification. pdf
[5] Anne Dell, Howard R Morris: "Glycoprotein structure determination by mass spectrometry", Science 291(5512), 2351–2356 (2001), Review

External links
• Structure of Glycoprotein and Carbohydrate Chain (http://www.ecosci.jp/chem10/weekmol101j_e.html) –
Home Page for Learning Environmental Chemistry
• Biochemistry 5thE 11.3. Carbohydrates Can Be Attached to Proteins to Form Glycoproteins (http://www.ncbi.
nlm.nih.gov/books/bv.fcgi?indexed=google&rid=stryer.section.1531)
• Carbohydrate Chemistry and Glycobiology: A Web Tour (http://www.sciencemag.org/feature/data/
carbohydrates.dtl#glycoproteins) SPECIAL WeB SUPPLEMENT Science 23 March 2001 Vol 291, Issue 5512,
Pages 2263–2502
• Glycoproteins (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Glycoproteins) at the US
National Library of Medicine Medical Subject Headings (MeSH)
Histology 205

Histology
Histology (compound of the Greek words:
ἱστός "tissue", and -λογία -logia) is the
study of the microscopic anatomy of cells
and tissues of plants and animals. It is
commonly performed by examining cells
and tissues by sectioning and staining,
followed by examination under a light
microscope or electron microscope.
Histological studies may be conducted via
tissue culture, where live cells can be
isolated and maintained in a proper
environment outside the body for various
research projects. The ability to visualize or
differentially identify microscopic structures
is frequently enhanced through the use of A stained histologic specimen, sandwiched between a glass microscope slide and
histological stains. Histology is an essential coverslip, mounted on the stage of a light microscope.

tool of biology and medicine.

Histopathology, the microscopic study of


diseased tissue, is an important tool in
anatomical pathology, since accurate
diagnosis of cancer and other diseases
usually requires histopathological
examination of samples. Trained medical
doctors, frequently board-certified as
pathologists, are the personnel who perform
histopathological examination and provide
diagnostic information based on their
observations.

The trained scientists who perform the


preparation of histological sections are
histotechnicians, histology technicians Microscopic view of a histologic specimen of human lung tissue stained with
(HT), histology technologists (HTL), hematoxylin and eosin.

medical scientists, medical laboratory


technicians, or biomedical scientists. Their field of study is called histotechnology.

Histology

Fixing

Chemical fixation with formaldehyde or other chemicals


Chemical fixatives are used to preserve tissue from degradation, and to maintain the structure of the cell and of
sub-cellular components such as cell organelles (e.g., nucleus, endoplasmic reticulum, mitochondria). The most
common fixative for light microscopy is 10% neutral buffered formalin (4% formaldehyde in phosphate buffered
Histology 206

saline). For electron microscopy, the most commonly used fixative is glutaraldehyde, usually as a 2.5% solution in
phosphate buffered saline. These fixatives preserve tissues or cells mainly by irreversibly cross-linking proteins. The
main action of these aldehyde fixatives is to cross-link amino groups in proteins through the formation of CH2
(methylene) linkage, in the case of formaldehyde, or by a C5H10 cross-links in the case of glutaraldehyde. This
process, while preserving the structural integrity of the cells and tissue can damage the biological functionality of
proteins, particularly enzymes, and can also denature them to a certain extent. This can be detrimental to certain
histological techniques. Further fixatives are often used for electron microscopy such as osmium tetroxide or uranyl
acetate
Formalin fixation leads to degradation of mRNA, miRNA and DNA in tissues. However, extraction, amplification
and analysis of these nucleic acids from formalin-fixed, paraffin-embedded tissues is possible using appropriate
protocols.[1]

Frozen section fixation


Frozen section is a rapid way to fix and mount histology sections. It is used in surgical removal of tumors, and allow
rapid determination of margin (that the tumor has been completely removed). It is done using a refrigeration device
called a cryostat. The frozen tissue is sliced using a microtome, and the frozen slices are mounted on a glass slide
and stained the same way as other methods. It is a necessary way to fix tissue for certain stain such as antibody
linked immunofluorescence staining. It can also be used to determine if a tumour is malignant when it is found
incidentally during surgery on a patient.

Processing - dehydration, clearing, and infiltration


The aim of Tissue Processing is to remove water from tissues and replace with a medium that solidifies to allow thin
sections to be cut. Biological tissue must be supported in a hard matrix to allow sufficiently thin sections to be cut,
typically 5 μm (micrometres; 1000 micrometres = 1 mm) thick for light microscopy and 80-100 nm (nanometre;
1,000,000 nanometres = 1 mm) thick for electron microscopy. For light microscopy, paraffin wax is most frequently
used. Since it is immiscible with water, the main constituent of biological tissue, water must first be removed in the
process of dehydration. Samples are transferred through baths of progressively more concentrated ethanol to remove
the water. This is followed by a hydrophobic clearing agent (such as xylene) to remove the alcohol, and finally
molten paraffin wax, the infiltration agent, which replaces the xylene. Paraffin wax does not provide a sufficiently
hard matrix for cutting very thin sections for electron microscopy. Instead, resins are used. Epoxy resins are the most
commonly employed embedding media, but acrylic resins are also used, particularly where immunohistochemistry is
required. Thicker sections (0.35μm to 5μm) of resin-embedded tissue can also be cut for light microscopy. Again, the
immiscibility of most epoxy and acrylic resins with water necessitates the use of dehydration, usually with ethanol.

Embedding
After the tissues have been dehydrated, cleared, and infiltrated with the embedding material, they are ready for
external embedding. During this process the tissue samples are placed into molds along with liquid embedding
material (such as agar, gelatine, or wax) which is then hardened. This is achieved by cooling in the case of paraffin
wax and heating (curing) in the case of the epoxy resins. The acrylic resins are polymerised by heat, ultraviolet light,
or chemical catalysts. The hardened blocks containing the tissue samples are then ready to be sectioned.
Because Formalin-fixed, paraffin-embedded (FFPE) tissues may be stored indefinitely at room temperature, and
nucleic acids (both DNA and RNA) may be recovered from them decades after fixation, FFPE tissues are an
important resource for historical studies in medicine.
Embedding can also be accomplished using frozen, non-fixed tissue in a water-based medium. Pre-frozen tissues are
placed into molds with the liquid embedding material, usually a water-based glycol, OCT, TBS, Cryogel, or resin,
which is then frozen to form hardened blocks.
Histology 207

Sectioning
Sectioning can be done in limited ways. Vertical sectioning perpendicular to the surface of the tissue is the usual
method. Horizontal sectioning is often done in the evaluation of the hair follicles and pilosebaceous units. Tangential
to horizontal sectioning is done in Mohs surgery and in methods of CCPDMA.
For light microscopy, a steel knife mounted in a microtome is used to cut 10-micrometer-thick tissue sections which
are mounted on a glass microscope slide. For transmission electron microscopy, a diamond knife mounted in an
ultramicrotome is used to cut 50-nanometer-thick tissue sections which are mounted on a 3-millimeter-diameter
copper grid. Then the mounted sections are treated with the appropriate stain.
Frozen tissue embedded in a freezing medium is cut on a microtome in a cooled machine called a cryostat.

Staining
Biological tissue has little inherent contrast in either the light or electron microscope. Staining is employed to give
both contrast to the tissue as well as highlighting particular features of interest. Where the underlying mechanistic
chemistry of staining is understood, the term histochemistry is used. Hematoxylin and eosin (H&E stain) is the most
commonly used light microscopical stain in histology and histopathology. Hematoxylin, a basic dye, stains nuclei
blue due to an affinity to nucleic acids in the cell nucleus; eosin, an acidic dye, stains the cytoplasm pink. Uranyl
acetate and lead citrate are commonly used to impart contrast to tissue in the electron microscope.
Special staining: There are hundreds of various other techniques that have been used to selectively stain cells and
cellular components. Other compounds used to color tissue sections include safranin, oil red o, Congo red, fast green
FCF, silver salts, and numerous natural and artificial dyes that were usually originated from the development dyes
for the textile industry.
Histochemistry refers to the science of using chemical reactions between laboratory chemicals and components
within tissue. A commonly performed histochemical technique is the Perls Prussian blue reaction, used to
demonstrate iron deposits in diseases like hemochromatosis.
Histology samples have often been examined by radioactive techniques. In historadiography, a slide (sometimes
stained histochemically) is X-rayed. More commonly, autoradiography is used to visualize the locations to which a
radioactive substance has been transported within the body, such as cells in S phase (undergoing DNA replication)
which incorporate tritiated thymidine, or sites to which radiolabeled nucleic acid probes bind in in situ hybridization.
For autoradiography on a microscopic level, the slide is typically dipped into liquid nuclear tract emulsion, which
dries to form the exposure film. Individual silver grains in the film are visualized with dark field microscopy.
Recently, antibodies have been used to specifically visualize proteins, carbohydrates, and lipids. This process is
called immunohistochemistry, or when the stain is a fluorescent molecule, immunofluorescence. This technique has
greatly increased the ability to identify categories of cells under a microscope. Other advanced techniques, such as
nonradioactive in situ hybridization, can be combined with immunochemistry to identify specific DNA or RNA
molecules with fluorescent probes or tags that can be used for immunofluorescence and enzyme-linked fluorescence
amplification (especially alkaline phosphatase and tyramide signal amplification). Fluorescence microscopy and
confocal microscopy are used to detect fluorescent signals with good intracellular detail. Digital cameras are
increasingly used to capture histological and histopathological image
Histology 208

Common laboratory stains


Stain Common use Nucleus Cytoplasm Red blood cell Collagen Specifically stains
(RBC) fibers

Haematoxylin General staining when paired Blue N/A N/A N/A Nucleic acids—blue
with eosin (i.e. H&E) ER (endoplasmic
reticulum)—blue

Eosin General staining when paired N/A Pink Orange/red Pink Elastic fibers—pink
with haematoxylin (i.e. H&E) Collagen fibers—pink
Reticular fibers—pink

Toluidine blue General staining Blue Blue Blue Blue Mast cells granules—purple

Masson's trichrome Connective tissue Black Red/pink Red Blue/green Cartilage—blue/green


stain Muscle fibers—red

Mallory's trichrome Connective tissue Red Pale red Orange Deep blue Keratin—orange
stain Cartilage—blue
Bone matrix—deep blue
Muscle fibers—red

Weigert's elastic Elastic fibers Blue/black N/A N/A N/A Elastic fibers—blue/black
stain

Heidenhain's AZAN Distinguishing cells from Red/purple Pink Red Blue Muscle fibers—red
trichrome stain extracellular components Cartilage—blue
Bone matrix—blue

Silver stain Reticular fibers, nerve fibers, N/A N/A N/A N/A Reticular fibers—brown/black
fungi Nerve fibers—brown/black
Fungi—black

Wright's stain Blood cells Bluish/purple Bluish/gray Red/pink N/A Neutrophil


granules—purple/pink
Eosinophil granules—bright
red/orange
Basophil granules—deep
purple/violet
Platelet granules—red/purple

Orcein stain Elastic fibres Deep blue N/A Bright red Pink Elastic fibres—dark brown
Mast cells granules—purple
Smooth muscle—light blue

Periodic acid-Schiff Basement membrane, Blue N/A N/A Pink Glycogen and other
stain (PAS) localizing carbohydrates carbohydrates—magenta

Table sourced from Michael H. Ross, Wojciech Pawlina, (2006). Histology: A Text and Atlas. Hagerstown, MD:
Lippincott Williams & Wilkins. ISBN 0-7817-5056-3.
The Nissl method and Golgi's method are useful in identifying neurons.

Alternative techniques
Alternative techniques include cryosection. The tissue is frozen using a cryostat, and cut. Tissue staining methods are
similar to those of wax sections. Plastic embedding is commonly used in the preparation of material for electron
microscopy. Tissues are embedded in epoxy resin. Very thin sections (less than 0.1 micrometer) are cut using
diamond or glass knives. The sections are stained with electron dense stains (uranium and lead) so that they can
possibly be seen with the electron microscope.
Histology 209

History
In the 19th century, histology was an academic discipline in its own right.
The 1906 Nobel Prize in Physiology or Medicine was awarded to histologists
Camillo Golgi and Santiago Ramon y Cajal. They had dueling interpretations
of the neural structure of the brain based in differing interpretations of the
same images. Cajal won the prize for his correct theory and Golgi for the
staining technique he invented to make it possible.

Histological classification of animal tissues


There are four basic types of tissues: muscle tissue, nervous tissue, connective
Santiago Ramón y Cajal in his laboratory
tissue, and epithelial tissue. All tissue types are subtypes of these four basic
tissue types (for example, blood cells are classified as connective tissue, since
they generally originate inside bone marrow).
• Epithelium: the lining of glands, bowel, skin, and some organs like the liver, lung, and kidney
• Endothelium: the lining of blood and lymphatic vessels
• Mesothelium: the lining of pleural and pericardial spaces
• Mesenchyme: the cells filling the spaces between the organs, including fat, muscle, bone, cartilage, and tendon
cells
• Blood cells: the red and white blood cells, including those found in lymph nodes and spleen
• Neurons: any of the conducting cells of the nervous system
• Germ cells: reproductive cells (spermatozoa in men, oocytes in women)
• Placenta: an organ characteristic of true mammals during pregnancy, joining mother and offspring, providing
endocrine secretion and selective exchange of soluble, but not particulate, blood-borne substances through an
apposition of uterine and trophoblastic vascularised parts
• Stem cells: cells with the ability to develop into different cell types
Note that tissues from plants, fungi, and microorganisms can also be examined histologically. Their structure is very
different from animal tissues.

Related sciences
• Cell biology is the study of living cells, their DNA and RNA and the proteins they express.
• Anatomy is the study of organs visible by the naked eye.
• Morphology studies entire organisms.

Artifacts
Artifacts are structures or features in tissue that interfere with normal histological examination. These are not always
present in normal tissue and can come from outside sources. Artifacts interfere with histology by changing the
tissues appearance and hiding structures. These can be divided into two categories:
Histology 210

Pre-histology
These are features and structures that have been introduced prior to the collection of the tissues. A common example
of these include: ink from tattoos and freckles (melanin) in skin samples.

Post-histology
Artifacts can result from tissue processing. Processing commonly leads to changes like shrinkage, washing out of
particular cellular components, color changes in different tissues types and alterations of the structures in the tissue.
Because these are caused in a laboratory the majority of post histology artifacts can be avoided or removed after
being discovered. A common example is mercury pigment left behind after using Zenker's fixative to fix a section.

Notes
[1] Weiss AT, Delcour NM, Meyer A, Klopfleisch R. (2010). "Efficient and Cost-Effective Extraction of Genomic DNA From Formalin-Fixed
and Paraffin-Embedded Tissues". Veterinary Pathology 227 (4): 834–8. doi:10.1177/0300985810380399. PMID 20817894.

References
1. Merck Source (2002). Dorland's Medical Dictionary. Retrieved 2005-01-26.
2. Stedman's Medical Dictionaries (2005). Stedman's Online Medical Dictionary (http://stedmans.com/).
Retrieved 2005-01-26.
3. 4,000‫ﻱ‬online histology images (2007). (http://histology-online.com)

External links
• Meyer's Histology - a complete online histology course (http://meyershistology.moodle.com.au/)
• Histology-online (http://histology-online.com/)
• Histology Protocols (http://www.ihcworld.com/protocol_database.htm)
• Histology atlas and more (http://sites.google.com/site/estudehistologia/)
• Histoweb (http://www.kumc.edu/instruction/medicine/anatomy/histoweb)
• SIU SOM Histology (http://www.siumed.edu/~dking2/index.htm)
• Visual Histology Atlas (http://www.visualhistology.com/Visual_Histology_Atlas/)
• Histology Glossary (http://www.histology-world.com/glossary/glossary1.htm)
• Histology Group of Victoria Incorporated (http://www.hgv.org.au)
• Histology Photomicrographs (http://www.histology-world.com/photoalbum/)
• Virtual Slidebox (http://www.path.uiowa.edu/virtualslidebox)
• Blue Histology (http://www.lab.anhb.uwa.edu.au/mb140/)
• BiMed - 20.000 histology images of fundamental tissues (http://www.informed.unal.edu.co/)
• The Histology Image Dataset (histologyDS) (http://www.informed.unal.edu.co/histologyDS/)
Immunohistochemistry 211

Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting
antigens (e.g., proteins) in cells of a tissue section by exploiting the
principle of antibodies binding specifically to antigens in biological
tissues.[1] IHC takes its name from the roots "immuno," in reference to
antibodies used in the procedure, and "histo," meaning tissue (compare
to immunocytochemistry).

Immunohistochemical staining is widely used in the diagnosis of


abnormal cells such as those found in cancerous tumors. Specific
molecular markers are characteristic of particular cellular events such
as proliferation or cell death (apoptosis). IHC is also widely used in
basic research to understand the distribution and localization of
biomarkers and differentially expressed proteins in different parts of a Immunohistochemistry labels individual proteins,
biological tissue. such as TH (green) in the axons of sympathetic
autonomic neurons.
Visualising an antibody-antigen interaction can be accomplished in a
number of ways. In the most common instance, an antibody is conjugated to an enzyme, such as peroxidase, that can
catalyse a colour-producing reaction (see immunoperoxidase staining). Alternatively, the antibody can also be tagged
to a fluorophore, such as fluorescein or rhodamine (see immunofluorescence).

Sample preparation
While using the right antibodies to target the correct antigens and amplify the signal is important for visualization,
complete preparation of the sample is critical to maintain cell morphology, tissue architecture and the antigenicity of
target epitopes. This requires proper tissue collection, fixation and sectioning. Paraformaldehyde is usually used with
fixation. Depending on the purpose and the thickness of the experimental sample, either thin (about 4-40 μm)
sections are sliced from the tissue of interest, or if the tissue is not very thick and is penetrable it is used whole. The
slicing is usually accomplished through the use of a microtome, and slices are mounted on slides. "Free-floating
IHC" uses slices that are not mounted; these slices are normally produced using a vibrating microtome.
Because of the method of fixation and tissue preservation, the sample may require additional steps to make the
epitopes available for antibody binding, including deparaffinization and antigen retrieval (microwave method,
enzyme method, hot incubation method); these steps often make the difference between staining and no staining.
Additionally, depending on the tissue type and the method of antigen detection, endogenous biotin or enzymes may
need to be blocked or quenched, respectively, prior to antibody staining.
Unlike immunocytochemistry, the tissue does not need to be permeabilized because this has already been
accomplished by the microtome blade during sample preparation. Detergents like Triton X-100 are generally used in
immunohistochemistry to reduce surface tension, allowing less reagent to be used to achieve better and more even
coverage of the sample. Although antibodies show preferential avidity for specific epitopes, they may partially or
weakly bind to sites on nonspecific proteins (also called reactive sites) that are similar to the cognate binding sites on
the target antigen.
In the context of antibody-mediated antigen detection, nonspecific binding causes high background staining that can
mask the detection of the target antigen. To reduce background staining in IHC, ICC and any other immunostaining
application, the samples are incubated with a buffer that blocks the reactive sites to which the primary or secondary
antibodies may otherwise bind. Common blocking buffers include normal serum, non-fat dry milk, BSA, or gelatin.
Commercial blocking buffers with proprietary formulations are available for greater efficiency.
Immunohistochemistry 212

Sample Labeling

Antibody types
The antibodies used for specific detection can be polyclonal or monoclonal. Polyclonal antibodies are made by
injecting animals with peptide Ag and, after a secondary immune response is stimulated, isolating antibodies from
whole serum. Thus, polyclonal antibodies are a heterogeneous mix of antibodies that recognize several epitopes.
Monoclonal antibodies show specificity for a single epitope and are therefore considered more specific to the target
antigen than polyclonal antibodies.
For IHC detection strategies, antibodies are classified as primary or secondary reagents. Primary antibodies are
raised against an antigen of interest and are typically unconjugated (unlabelled), while secondary antibodies are
raised against immunoglobulins of the primary antibody species. The secondary antibody is usually conjugated to a
linker molecule, such as biotin, that then recruits reporter molecules, or the secondary antibody is directly bound to
the reporter molecule itself.

IHC reporters
Reporter molecules vary based on the nature of the detection method, and the most popular methods of detection are
with enzyme- and fluorophore-mediated chromogenic and fluorescence detection, respectively. With chromogenic
reporters, an enzyme label is reacted with a substrate to yield an intensely colored product that can be analyzed with
an ordinary light microscope. While the list of enzyme substrates is extensive, Alkaline phosphatase (AP) and
horseradish peroxidase (HRP) are the two enzymes used most extensively as labels for protein detection. An array of
chromogenic, fluorogenic and chemiluminescent substrates is available for use with either enzyme, including DAB
or BCIP/NBT, which produce a brown or purple staining, respectively, wherever the enzymes are bound.
Reaction with DAB can be enhanced using nickel, producing a deep purple/black staining. Fluorescent reporters are
small, organic molecules used for IHC detection and traditionally include FITC, TRITC and AMCA, while
commercial derivatives, including the Alexa Fluors and Dylight Fluors, show similar enhanced performance but vary
in price. For chromogenic and fluorescent detection methods, densitometric analysis of the signal can provide semi-
and fully quantitative data, respectively, to correlate the level of reporter signal to the level of protein expression or
localization.

Target antigen detection methods


The direct method is a one-step staining
method and involves a labeled antibody (e.g.
FITC-conjugated antiserum) reacting
directly with the antigen in tissue sections.
While this technique utilizes only one
antibody and therefore is simple and rapid,
the sensitivity is lower due to little signal
amplification, such as with indirect
The direct method of immunohistochemical staining uses one labelled antibody,
methods, and is less commonly used than
which binds directly to the antigen being stained for.
indirect methods.

The indirect method involves an unlabeled primary antibody (first layer) that binds to the target antigen in the tissue
and a labeled
Immunohistochemistry 213

secondary antibody (second layer) that


reacts with the primary antibody. As
mentioned above, the secondary antibody
must be raised against the IgG of the animal
species in which the primary antibody has
been raised. This method is more sensitive
than direct detection strategies because of
signal amplification due to the binding of
several secondary antibodies to each
primary antibody if the secondary antibody
is conjugated to the fluorescent or enzyme
reporter. The indirect method of immunohistochemical staining uses one antibody against
the antigen being probed for, and a second, labelled, antibody against the first.
Further amplification can be achieved if the
secondary antibody is conjugated to several biotin molecules, which can recruit complexes of avidin-, streptavidin or
NeutrAvidin proteinbound-enzyme. The difference between these three biotin-binding proteins is their individual
binding affinity to endogenous tissue targets leading to nonspecific binding and high background; the ranking of
these proteins based on their nonspecific binding affinities, from highest to lowest, is: 1) avidin, 2) streptavidin and
3) Neutravidin protein.

The indirect method, aside from its greater sensitivity, also has the advantage that only a relatively small number of
standard conjugated (labeled) secondary antibodies needs to be generated. For example, a labeled secondary
antibody raised against rabbit IgG, which can be purchased "off the shelf," is useful with any primary antibody raised
in rabbit. With the direct method, it would be necessary to label each primary antibody for every antigen of interest.

Counterstains
After immunohistochemical staining of the target antigen, a second stain is often applied to provide contrast that
helps the primary stain stand out. Many of these stains show specificity for discrete cellular compartments or
antigens, while others will stain the whole cell. Both chromogenic and fluorescent dyes are available for IHC to
provide a vast array of reagents to fit every experimental design, and include: hematoxylin, Hoechst stain and DAPI
are commonly used.

IHC Troubleshooting
In immunohistochemical techniques, there are several steps prior to the final staining of the tissue antigen, and many
potential problems affect the outcome of the procedure. The major problem areas in IHC staining include strong
background staining, weak target antigen staining and autofluorescence. Endogenous biotin or reporter enzymes or
primary/secondary antibody cross-reactivity are common causes of strong background staining, while weak staining
may be caused by poor enzyme activity or primary antibody potency. Furthermore, autofluorescence may be due to
the nature of the tissue or the fixation method. These aspects of IHC tissue prep and antibody staining must be
systematically addressed to identify and overcome staining issues.
Immunohistochemistry 214

Diagnostic IHC markers


IHC is an excellent detection technique and has the tremendous
advantage of being able to show exactly where a given protein is
located within the tissue examined. It is also an effective way to
examine the tissues .This has made it a widely used technique in the
neurosciences, enabling researchers to examine protein expression
within specific brain structures. Its major disadvantage is that, unlike
immunoblotting techniques where staining is checked against a
molecular weight ladder, it is impossible to show in IHC that the
staining corresponds with the protein of interest. For this reason,
primary antibodies must be well-validated in a Western Blot or similar Immunohistochemical staining of normal kidney
procedure. The technique is even more widely used in diagnostic with CD10.
surgical pathology for typing tumors (e.g. immunostaining for
e-cadherin to differentiate between DCIS (ductal carcinoma in situ: stains positive) and LCIS (lobular carcinoma in
situ: does not stain positive)[2]).

• Carcinoembryonic antigen (CEA): used for identification of adenocarcinomas. Not specific for site.
• Cytokeratins: used for identification of carcinomas but may also be expressed in some sarcomas.[3]
• CD15 and CD30 : used for Hodgkin's disease
• Alpha fetoprotein: for yolk sac tumors and hepatocellular carcinoma
• CD117 (KIT): for gastrointestinal stromal tumors (GIST)
• CD10 (CALLA): for renal cell carcinoma and acute lymphoblastic leukemia
• Prostate specific antigen (PSA): for prostate cancer
• estrogens and progesterone staining for tumour identification
• Identification of B-cell lymphomas using CD20
• Identification of T-cell lymphomas using CD3

Directing therapy
A variety of molecular pathways are altered in cancer and some of the alterations can be targeted in cancer therapy.
Immunohistochemistry can be used to assess which tumors are likely to respond to therapy, by detecting the
presence or elevated levels of the molecular target.

Chemical inhibitors
Tumor biology allows for a number of potential intracellular targets. Many tumors are hormone dependent. The
presence of hormone receptors can be used to determine if a tumor is potentially responsive to antihormonal therapy.
One of the first therapies was the antiestrogen, tamoxifen, used to treat breast cancer. Such hormone receptors can be
detected by immunohistochemistry.[4] Imatinib, an intracellualar tyrosine kinase inhibitor, was developed to treat
chronic myelogenous leukemia, a disease characterized by the formation of a specific abnormal tyrosine kinase.
Imitanib has proven effective in tumors, that express other tyrosine kinases, most notably KIT. Most gastrointestinal
stromal tumors express KIT, which can be detected by immunohistochemistry.[5]
Immunohistochemistry 215

Monoclonal antibodies
Many proteins shown to be highly upregulated in pathological states by immunohistochemistry are potential targets
for therapies utilising monoclonal antibodies. Monoclonal antibodies, due to their size, are utilized against cell
surface targets. Among the overexpressed targets, the members of the epidermal growth factor receptor (EGFR)
family, transmembrane proteins with an extracellular receptor domain regulating an intracellular tyrosine kinase,[6]
Of these, HER2/neu (also known as Erb-B2) was the first to be developed. The molecule is highly expressed in a
variety of cancer cell types, most notably breast cancer. As such, antibodies against HER2/neu have been FDA
approved for clinical treatment of cancer under the drug name Herceptin. There are commercially available
immunohistochemical tests, Dako HercepTest [7] and Ventana Pathway.[8]
Similarly, EGFR (HER-1) is overexpressed in a variety of cancers including head and neck and colon.
Immunohistochemistry is used to determine patients who may benefit from therapeutic antibodies such as Erbitux
(cetuximab).[9] Commercial systems to detect EGFR by immunohistochemistry include the Dako pharmDx [10].

References
[1] Ramos-Vara, JA (2005). "Technical Aspects of Immunohistochemistry" (http:/ / www. vetpathology. org/ cgi/ content/ short/ 42/ 4/ 405). Vet
Pathol 42 (4): 405–426. doi:10.1354/vp.42-4-405. PMID 16006601. .
[2] O'Malley F and Pinder S, Breast Pathology, 1st. Ed. Elsevier 2006. ISBN 978-0-443-06680-1
[3] Leader M, Patel J, Makin C, Henry K (December 1986). "An analysis of the sensitivity and specificity of the cytokeratin marker CAM 5.2 for
epithelial tumours. Results of a study of 203 sarcomas, 50 carcinomas and 28 malignant melanomas". Histopathology 10 (12): 1315–24.
doi:10.1111/j.1365-2559.1986.tb02574.x. PMID 2434403.
[4] Jørgensen, Jan Trøst; Kirsten Vang Nielsen, Bent Ejlertsen (April 2007). "Pharmacodiagnostics and targeted therapies - a rational approach
for individualizing medical anticancer therapy in breast cancer" (http:/ / theoncologist. alphamedpress. org/ cgi/ content/ full/ 12/ 4/ 397). The
Oncologist (United States: AlphaMed Press) 12 (4): 397–405. doi:10.1634/theoncologist.12-4-397. ISSN 1083-7159. PMID 17470682. .
Retrieved 2008-03-14.
[5] Gold JS, Dematteo RP (August 2006). "Combined Surgical and Molecular Therapy: The Gastrointestinal Stromal Tumor Model". Ann. Surg.
244 (2): 176–84. doi:10.1097/01.sla.0000218080.94145.cf. PMC 1602162. PMID 16858179.
[6] Harari, P M (December 2004). "Epidermal growth factor receptor inhibition strategies in oncology" (http:/ / erc. endocrinology-journals. org/
cgi/ content/ full/ 11/ 4/ 689?ijkey=9caa7985e4396550fdc851b303ea7958513e070e). Endocrine-Related Cancer (England: Society for
Endocrinology) 11 (4): 689–708. doi:10.1677/erc.1.00600. ISSN 1351-0088. PMID 15613446. . Retrieved 2008-03-14.
[7] http:/ / www. dakousa. com/ index/ prod_search/ prod_baseproducts. htm?productareaid=1& productgroupid=3&
productsubgroupid=1003000
[8] Press, Michael F.; Guido Sauter, Leslie Bernstein, Ivonne E.Villalobos, MartinaMirlacher, Jian-Yuan Zhou, RoobaWardeh, Yong-Tian Li,
Roberta Guzman, Yanling Ma, Jane Sullivan-Halley, Angela Santiago, Jinha M. Park, Alessandro Riva, Dennis J.Slamon (September 15,
2005). "Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large,
prospective, randomized clinical trials" (http:/ / clincancerres. aacrjournals. org/ cgi/ content/ full/ 11/ 18/ 6598). Clinical Cancer Research
(United States: American Association for Cancer Research.) 2005 15;11(18): (18): 6598–6607. doi:10.1158/1078-0432.CCR-05-0636.
ISSN 1078-0432. PMID 16166438. . Retrieved 2008-03-14.
[9] Bibeau F, Boissière-Michot F, Sabourin JC, et al. (September 2006). "Assessment of epidermal growth factor receptor (EGFR) expression in
primary colorectal carcinomas and their related metastases on tissue sections and tissue microarray". Virchows Arch. 449 (3): 281–7.
doi:10.1007/s00428-006-0247-9. PMC 1888717. PMID 16865406.
[10] http:/ / www. dakousa. com/ index/ prod_search/ prod_groups. htm?productareaid=1
Immunohistochemistry 216

External links
• Overview of Immunohistochemistry--describes all aspects of IHC including sample prep, staining and
troubleshooting (http://www.piercenet.com/browse.
cfm?fldID=F95B91A9-3DC1-4B56-8E8D-59CA044A8BA7)
• Yale Core Tissue Microarray Facility (http://tissuearray.org/yale/)
• Histochemical Staining Methods (http://www.urmc.rochester.edu/path/zqu/Histostain/index.html) -
University of Rochester Department of Pathology
• Immunohistochemistry Staining Protocol (http://www.prosci-inc.com/Immunohistochemistry-Protocol.html)
• HistoWiki entry for Immunohistochemistry (http://www.ihcworld.com/histowiki/doku.
php?id=immunohistochemistry#immunohistochemistry)
• Burnett R, Guichard Y, Barale E (1997). "Immunohistochemistry for light microscopy in safety evaluation of
therapeutic agents: an overview". Toxicology 119 (1): 83–93. doi:10.1016/S0300-483X(96)03600-1.
PMID 9129199.
• Immunohistochemistry (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&
term=Immunohistochemistry) at the US National Library of Medicine Medical Subject Headings (MeSH)
• Joyner, A.; Wall, N. (2008). "Immunohistochemistry of Whole-Mount Mouse Embryos". Cold Spring Harbor
Protocols 2008 (2): pdb.prot4820. doi:10.1101/pdb.prot4820.

Immunology
Immunology is a branch of biomedical science that covers the study of all aspects of the immune system in all
organisms.[1] It deals with the physiological functioning of the immune system in states of both health and diseases;
malfunctions of the immune system in immunological disorders (autoimmune diseases, hypersensitivities, immune
deficiency, transplant rejection); the physical, chemical and physiological characteristics of the components of the
immune system in vitro, in situ, and in vivo. Immunology has applications in several disciplines of science, and as
such is further divided.
Even before the concept of immunity (from immunis, Latin for "exempt") was developed, numerous early physicians
characterized organs that would later prove to be part of the immune system. The key primary lymphoid organs of
the immune system are the thymus and bone marrow, and secondary lymphatic tissues such as spleen, tonsils, lymph
vessels, lymph nodes, adenoids, and skin and liver. When health conditions warrant, immune system organs
including the thymus, spleen, portions of bone marrow, lymph nodes and secondary lymphatic tissues can be
surgically excised for examination while patients are still alive.
Many components of the immune system are actually cellular in nature and not associated with any specific organ
but rather are embedded or circulating in various tissues located throughout the body.

Classical immunology
Classical immunology ties in with the fields of epidemiology and medicine. It studies the relationship between the
body systems, pathogens, and immunity. The earliest written mention of immunity can be traced back to the plague
of Athens in 430 BCE. Thucydides noted that people who had recovered from a previous bout of the disease could
nurse the sick without contracting the illness a second time. Many other ancient societies have references to this
phenomenon, but it was not until the 19th and 20th centuries before the concept developed into scientific theory.
The study of the molecular and cellular components that comprise the immune system, including their function and
interaction, is the central science of immunology. The immune system has been divided into a more primitive innate
immune system, and acquired or adaptive immune system of vertebrates, the latter of which is further divided into
humoral and cellular components.
Immunology 217

The humoral (antibody) response is defined as the interaction between antibodies and antigens. Antibodies are
specific proteins released from a certain class of immune cells (B lymphocytes). Antigens are defined as anything
that elicits generation of antibodies, hence they are Antibody Generators. Immunology itself rests on an
understanding of the properties of these two biological entities. However, equally important is the cellular response,
which can not only kill infected cells in its own right, but is also crucial in controlling the antibody response. Put
simply, both systems are highly interdependent.
In the 21st century, immunology has broadened its horizons with much research being performed in the more
specialized niches of immunology. This includes the immunological function of cells, organs and systems not
normally associated with the immune system, as well as the function of the immune system outside classical models
of immunity (Yemeserach 2010).

Clinical immunology
Clinical immunology is the study of diseases caused by disorders of the immune system (failure, aberrant action, and
malignant growth of the cellular elements of the system). It also involves diseases of other systems, where immune
reactions play a part in the pathology and clinical features.
The diseases caused by disorders of the immune system fall into two broad categories: immunodeficiency, in which
parts of the immune system fail to provide an adequate response (examples include chronic granulomatous disease),
and autoimmunity, in which the immune system attacks its own host's body (examples include systemic lupus
erythematosus, rheumatoid arthritis, Hashimoto's disease and myasthenia gravis). Other immune system disorders
include different hypersensitivities, in which the system responds inappropriately to harmless compounds (asthma
and other allergies) or responds too intensely.
The most well-known disease that affects the immune system itself is AIDS, caused by HIV. AIDS is an
immunodeficiency characterized by the lack of CD4+ ("helper") T cells, dendritic cells and macrophages, which are
destroyed by HIV.
Clinical immunologists also study ways to prevent transplant rejection, in which the immune system attempts to
destroy allografts.

Developmental immunology
The body’s capability to react to antigen depends on a person's age, antigen type, maternal factors and the area where
the antigen is presented.[2] Neonates are said to be in a state of physiological immunodeficiency, because both their
innate and adaptive immunological responses are greatly suppressed. Once born, a child’s immune system responds
favorably to protein antigens while not as well to glycoproteins and polysaccharides. In fact, many of the infections
acquired by neonates are caused by low virulence organisms like Staphylococcus and Pseudomonas. In neonates,
opsonic activity and the ability to activate the complement cascade is very limited. For example, the mean level of
C3 in a newborn is approximately 65% of that found in the adult. Phagocytic activity is also greatly impaired in
newborns. This is due to lower opsonic activity, as well as diminished up-regulation of integrin and selectin
receptors, which limit the ability of neutrophils to interact with adhesion molecules in the endothelium. Their
monocytes are slow and have a reduced ATP production, which also limits the newborns phagocytic activity.
Although, the number of total lymphocytes is significantly higher than in adults, the cellular and humoral immunity
is also impaired. Antigen presenting cells in newborns have a reduced capability to activate T cells. Also, T cells of a
newborn proliferate poorly and produce very small amounts of cytokines like IL-2, IL-4, IL-5, IL-12, and IFN-g
which limits their capacity to activate the humoral response as well as the phagocitic activity of macrophage. B cells
develop early in gestation but are not fully active.[3]
Immunology 218

Maternal factors also play a role in the body’s immune response. At


birth most of the immunoglobulin is present is maternal IgG. Because
IgM, IgD, IgE and IgA don’t cross the placenta, they are almost
undetectable at birth. Although some IgA is provided in breast milk.
These passively acquired antibodies can protect the newborn up to 18
months, but their response is usually short-lived and of low affinity.[3]
Monocytes: An Artist's Impression
These antibodies can also produce a negative response. If a child is
exposed to the antibody for a particular antigen before being exposed
to the antigen itself then the child will produce a dampened response. Passively acquired maternal antibodies can
suppress the antibody response to active immunization. Similarly the response of T-cells to vaccination differs in
children compared to adults, and vaccines that induce Th1 responses in adults do not readily elicit these same
responses in neonates.[3] By 6-9 months after birth, a child’s immune system begins to respond more strongly to
glycoproteins. Not until 12-24 months of age is there a marked improvement in the body’s response to
polysaccharides. This can be the reason for the specific time frames found in vaccination schedules.[4][5]

During adolescence the human body undergoes several physical, physiological and immunological changes. These
changes are started and mediated by different hormones. Depending on the sex either testosterone or 17-β-oestradiol,
act on male and female bodies accordingly, start acting at ages of 12 and 10 years.[6]
There is evidence that these steroids act directly not only on the primary and secondary sexual characteristics, but
also have an effect on the development and regulation of the immune system.[7]
There is an increased risk in developing autoimmunity for pubescent and post pubescent females and males.[8] There
is also some evidence that cell surface receptors on B cells and macrophages may detect sex hormones in the
system.[9]
The female sex hormone 17-β-oestradiol has been shown to regulate the level of immunological response.[10]
Similarly, some male androgens, like testosterone, seem to suppress the stress response to infection; but other
androgens like DHEA have the opposite effect, as it increases the immune response instead of down playing it.[11]
As in females, the male sex hormones seem to have more control of the immune system during puberty and the time
right after than in fully developed adults. Other than hormonal changes physical changes like the involution of the
Thymus during puberty will also affect the immunological response of the subject or patient.[12]

Immunotherapy
The use of immune system components to treat a disease or disorder is known as immunotherapy. Immunotherapy is
most commonly used in the context of the treatment of cancers together with chemotherapy (drugs) and radiotherapy
(radiation). However, immunotherapy is also often used in the immunosuppressed (such as HIV patients) and people
suffering from other immune deficiencies or autoimmune diseases.

Diagnostic immunology
The specificity of the bond between antibody and antigen has made it an excellent tool in the detection of substances
in a variety of diagnostic techniques. Antibodies specific for a desired antigen can be conjugated with a radiolabel,
fluorescent label, or color-forming enzyme and are used as a "probe" to detect it. However, the similarity between
some antigens can lead to false positives and other errors in such tests by antibodies cross-reacting with antigens that
aren't exact matches.[13]
Immunology 219

Evolutionary immunology
Study of the immune system in extant species is capable of giving us a key understanding of the evolution of species
and the immune system.
A development of complexity of the immune system can be seen from simple phagocytotic protection of single
celled organisms, to circulating antimicrobial peptides in insects to lymphoid organs in vertebrates. However, it is
important to recognize that every organism living today has an immune system that has evolved to be absolutely
capable of protecting it from most forms of harm; those organisms that did not adapt their immune systems to
external threats are no longer around to be observed.
Insects and other arthropods, while not possessing true adaptive immunity, show highly evolved systems of innate
immunity, and are additionally protected from external injury (and exposure to pathogens) by their chitinous shells.

Reproductive immunology
This area of the immunology is devoted to the study of immunological aspects of the reproductive process including
fetus acceptance. The term has also been used by fertility clinics to address fertility problems, recurrent miscarriages,
premature deliveries, and dangerous complications such as pre-eclampsia.

Immunologist

Immunologist
Occupation

Activity sectors Science, Laboratory, Medicine

Description

Education required Doctor of Philosophy, Doctor of Medicine, Doctor of Osteopathic Medicine

According to the American Academy of Allergy, Asthma, and Immunology (AAAAI), "an immunologist is a
research scientist who investigates the immune system of vertebrates (including the human immune system).
Immunologists include research scientists (Ph.D.) who work in laboratories. Immunologists also include physicians
who, for example, treat patients with immune system disorders. Some immunologists are physician-scientists who
combine laboratory research with patient care."[14]

References
[1] Janeway's Immunobiology textbook (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=imm. TOC& depth=2) Searchable free online
version at the National Center for Biotechnology Information
[2] Goldsby RA, Kindt TK, Osborne BA and Kuby J (2003). Immunology (5th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-4947-5.
[3] Jaspan HB, Lawn SD, Safrit JT, Bekker LG (February 2006). "The maturing immune system: implications for development and testing
HIV-1 vaccines for children and adolescents". AIDS 20 (4): 483–94. doi:10.1097/01.aids.0000210602.40267.60. PMID 16470112.
[4] Glezen WP (December 2001). "Maternal vaccines". Prim. Care 28 (4): 791–806, vi–vii. doi:10.1016/S0095-4543(05)70041-5.
PMID 11739030.
[5] Holt PG, Macaubas C, Cooper D, Nelson DJ, McWilliam AS (1997). "Th-1/Th-2 switch regulation in immune responses to inhaled antigens.
Role of dendritic cells in the aetiology of allergic respiratory disease". Adv. Exp. Med. Biol. 417: 301–6. PMID 9286377.
[6] Sizonenko PC, Paunier L (November 1975). "Hormonal changes in puberty III: Correlation of plasma dehydroepiandrosterone, testosterone,
FSH, and LH with stages of puberty and bone age in normal boys and girls and in patients with Addison's disease or hypogonadism or with
premature or late adrenarche". J. Clin. Endocrinol. Metab. 41 (5): 894–904. doi:10.1210/jcem-41-5-894. PMID 127002.
[7] Verthelyi D (June 2001). "Sex hormones as immunomodulators in health and disease". Int. Immunopharmacol. 1 (6): 983–93.
doi:10.1016/S1567-5769(01)00044-3. PMID 11407317.
[8] Stimson WH (September 1988). "Oestrogen and human T lymphocytes: presence of specific receptors in the T-suppressor/cytotoxic subset".
Scand. J. Immunol. 28 (3): 345–50. doi:10.1111/j.1365-3083.1988.tb01459.x. PMID 2973658.
Immunology 220

[9] Benten WP, Stephan C, Wunderlich F (June 2002). "B cells express intracellular but not surface receptors for testosterone and estradiol".
Steroids 67 (7): 647–54. doi:10.1016/S0039-128X(02)00013-2. PMID 11996938.
[10] Beagley KW, Gockel CM (August 2003). "Regulation of innate and adaptive immunity by the female sex hormones oestradiol and
progesterone". FEMS Immunol. Med. Microbiol. 38 (1): 13–22. doi:10.1016/S0928-8244(03)00202-5. PMID 12900050.
[11] Kanda N, Tamaki K (February 1999). "Estrogen enhances immunoglobulin production by human PBMCs". J. Allergy Clin. Immunol. 103 (2
Pt 1): 282–8. doi:10.1016/S0091-6749(99)70503-8. PMID 9949320.
[12] McFarland RD, Douek DC, Koup RA, Picker LJ (April 2000). "Identification of a human recent thymic emigrant phenotype". Proc. Natl.
Acad. Sci. U.S.A. 97 (8): 4215–20. doi:10.1073/pnas.070061597. PMC 18202. PMID 10737767.
[13] Miller JJ, Valdes R (February 1991). "Approaches to minimizing interference by cross-reacting molecules in immunoassays". Clin. Chem.
37 (2): 144–53. PMID 1993317.
[14] "Office of Science Education - LifeWorks - Immunologist" (http:/ / science. education. nih. gov/ LifeWorks. nsf/ Alphabetical+ List/
Immunologist). . Retrieved 2009-09-10.

External links
• The Immunology Link, a rich resource for Immunology information (http://www.immunologylink.com/)
• American Academy of Allergy, Asthma & Immunology (http://www.aaaai.org/)
• British Society for Immunology (http://bsi.immunology.org/)
• Annual Review of Immunology (journal) (http://arjournals.annualreviews.org/loi/immunol)
• BMC: Immunology (http://www.biomedcentral.com/bmcimmunol/)- BioMed Central:Immunology is an open
access journal publishing original peer-reviewed research articles.
• journal home Nature Reviews Immunology (http://www.nature.com/nri/index.html)
• The Immunology Database and Analysis Portal (http://www.immport.org) - an NIAID-funded database
resource of reference and experiment data covering the entire immunology domain
• Current discussions on Immunology in a scientific community (https://www.researchgate.net/group/
Immunology)
Lipid 221

Lipid
Lipids constitute a broad group of
naturally occurring molecules that
include fats, waxes, sterols, fat-soluble
vitamins (such as vitamins A, D, E,
and K), monoglycerides, diglycerides,
triglycerides, phospholipids, and
others. The main biological functions
of lipids include energy storage, as
structural components of cell
membranes, and as important signaling
molecules.[4][5]

Lipids may be broadly defined as


hydrophobic or amphiphilic small
molecules; the amphiphilic nature of
some lipids allows them to form
structures such as vesicles, liposomes,
or membranes in an aqueous
environment. Biological lipids
originate entirely or in part from two
distinct types of biochemical subunits [1] [2]
Structures of some common lipids. At the top are cholesterol and oleic acid. The
or "building-blocks": ketoacyl and middle structure is a triglyceride composed of oleoyl, stearoyl, and palmitoyl chains
isoprene groups.[4] Using this attached to a glycerol backbone. At the bottom is the common phospholipid,
[3]
approach, lipids may be divided into phosphatidylcholine.

eight categories: fatty acids,


glycerolipids, glycerophospholipids, sphingolipids, saccharolipids, and polyketides (derived from condensation of
ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits).[4]

Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides.
Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, monoglycerides, and
phospholipids), as well as other sterol-containing metabolites such as cholesterol.[6] Although humans and other
mammals use various biosynthetic pathways to both break down and synthesize lipids, some essential lipids cannot
be made this way and must be obtained from the diet.

Categories of lipids

Fatty acids
Fatty acids, or fatty acid residues when they form part of a lipid, are a diverse group of molecules synthesized by
chain-elongation of an acetyl-CoA primer with malonyl-CoA or methylmalonyl-CoA groups in a process called fatty
acid synthesis.[7][8] They are made of a hydrocarbon chain that terminates with a carboxylic acid group; this
arrangement confers the molecule with a polar, hydrophilic end, and a nonpolar, hydrophobic end that is insoluble in
water. The fatty acid structure is one of the most fundamental categories of biological lipids, and is commonly used
as a building-block of more structurally complex lipids.[9] The carbon chain, typically between four and 24 carbons
long,[10] may be saturated or unsaturated, and may be attached to functional groups containing oxygen, halogens,
Lipid 222

nitrogen, and sulfur. Where a double bond exists, there is the possibility of either a cis or a trans geometric
isomerism, which significantly affects the molecule's molecular configuration. Cis-double bonds cause the fatty acid
chain to bend, an effect that is more pronounced the more double bonds there are in a chain. This in turn plays an
important role in the structure and function of cell membranes.[11] Most naturally occurring fatty acids are of the cis
configuration, although the trans form does exist in some natural and partially hydrogenated fats and oils.[12]
Examples of biologically important fatty acids are the eicosanoids, derived primarily from arachidonic acid and
eicosapentaenoic acid, that include prostaglandins, leukotrienes, and thromboxanes. Docosahexaenoic acid is also
important in biological systems, particularly with respect to sight.[13][14] Other major lipid classes in the fatty acid
category are the fatty esters and fatty amides. Fatty esters include important biochemical intermediates such as wax
esters, fatty acid thioester coenzyme A derivatives, fatty acid thioester ACP derivatives and fatty acid carnitines. The
fatty amides include N-acyl ethanolamines, such as the cannabinoid neurotransmitter anandamide.[15]

Glycerolipids
Glycerolipids are composed mainly of mono-, di-, and tri-substituted glycerols,[16] the most well-known being the
fatty acid triesters of glycerol, called triglycerides. The word triacylglycerol is sometimes used synonymously with
triglyceride, however this is misleading with respect to these compounds as they contain no hydroxyl group. In these
compounds, the three hydroxyl groups of glycerol are each esterified, typically by different fatty acids. Because they
function as an energy store, these lipids comprise the bulk of storage fat in animal tissues. The hydrolysis of the ester
bonds of triglycerides and the release of glycerol and fatty acids from adipose tissue are the initial steps in
metabolising fat.[17]
Additional subclasses of glycerolipids are represented by glycosylglycerols, which are characterized by the presence
of one or more sugar residues attached to glycerol via a glycosidic linkage. Examples of structures in this category
are the digalactosyldiacylglycerols found in plant membranes[18] and seminolipid from mammalian sperm cells.[19]

Glycerophospholipids
Glycerophospholipids, usually referred to as phospholipids, are ubiquitous in nature and are key components of the
lipid bilayer of cells,[20] as well as being involved in metabolism and cell signaling .[21] Neural tissue (including the
brain) contains relatively high amounts of glycerophospholipids, and alterations in their composition has been
implicated in various neurological disorders.[22] Glycerophospholipids may be subdivided into distinct classes, based
on the nature of the polar headgroup at the sn-3 position of the glycerol backbone in eukaryotes and eubacteria, or
the sn-1 position in the case of archaebacteria.[23]
Examples of glycerophospholipids found in biological membranes are
phosphatidylcholine (also known as PC, GPCho or lecithin),
phosphatidylethanolamine (PE or GPEtn) and phosphatidylserine (PS
or GPSer). In addition to serving as a primary component of cellular
membranes and binding sites for intra- and intercellular proteins, some
Phosphatidylethanolamine glycerophospholipids in eukaryotic cells, such as phosphatidylinositols
and phosphatidic acids are either precursors of or, themselves,
[24]
membrane-derived second messengers. Typically, one or both of these hydroxyl groups are acylated with
long-chain fatty acids, but there are also alkyl-linked and 1Z-alkenyl-linked (plasmalogen) glycerophospholipids, as
well as dialkylether variants in archaebacteria.[25]
Lipid 223

Sphingolipids
Sphingolipids are a complicated family of compounds[26] that share a common structural feature, a sphingoid base
backbone that is synthesized de novo from the amino acid serine and a long-chain fatty acyl CoA, then converted
into ceramides, phosphosphingolipids, glycosphingolipids and other compounds. The major sphingoid base of
mammals is commonly referred to as sphingosine. Ceramides (N-acyl-sphingoid bases) are a major subclass of
sphingoid base derivatives with an amide-linked fatty acid. The fatty acids are typically saturated or
mono-unsaturated with chain lengths from 16 to 26 carbon atoms.[27]
The major phosphosphingolipids of mammals are sphingomyelins
(ceramide phosphocholines),[28] whereas insects contain mainly
ceramide phosphoethanolamines[29] and fungi have phytoceramide
phosphoinositols and mannose-containing headgroups.[30] The
Sphingomyelin
glycosphingolipids are a diverse family of molecules composed of one
or more sugar residues linked via a glycosidic bond to the sphingoid
base. Examples of these are the simple and complex glycosphingolipids such as cerebrosides and gangliosides.

Sterol lipids
Sterol lipids, such as cholesterol and its derivatives, are an important component of membrane lipids,[31] along with
the glycerophospholipids and sphingomyelins. The steroids, all derived from the same fused four-ring core structure,
have different biological roles as hormones and signaling molecules. The eighteen-carbon (C18) steroids include the
estrogen family whereas the C19 steroids comprise the androgens such as testosterone and androsterone. The C21
subclass includes the progestogens as well as the glucocorticoids and mineralocorticoids.[32] The secosteroids,
comprising various forms of vitamin D, are characterized by cleavage of the B ring of the core structure.[33] Other
examples of sterols are the bile acids and their conjugates,[34] which in mammals are oxidized derivatives of
cholesterol and are synthesized in the liver. The plant equivalents are the phytosterols, such as β-sitosterol,
stigmasterol, and brassicasterol; the latter compound is also used as a biomarker for algal growth.[35] The
predominant sterol in fungal cell membranes is ergosterol.[36]

Prenol lipids
Prenol lipids are synthesized from the five-carbon-unit precursors isopentenyl diphosphate and dimethylallyl
diphosphate that are produced mainly via the mevalonic acid (MVA) pathway.[37] The simple isoprenoids (linear
alcohols, diphosphates, etc.) are formed by the successive addition of C5 units, and are classified according to
number of these terpene units. Structures containing greater than 40 carbons are known as polyterpenes. Carotenoids
are important simple isoprenoids that function as antioxidants and as precursors of vitamin A.[38] Another
biologically important class of molecules is exemplified by the quinones and hydroquinones, which contain an
isoprenoid tail attached to a quinonoid core of non-isoprenoid origin.[39] Vitamin E and vitamin K, as well as the
ubiquinones, are examples of this class. Prokaryotes synthesize polyprenols (called bactoprenols) in which the
terminal isoprenoid unit attached to oxygen remains unsaturated, whereas in animal polyprenols (dolichols) the
terminal isoprenoid is reduced.[40]
Lipid 224

Saccharolipids
Saccharolipids describe compounds in
which fatty acids are linked directly to a
sugar backbone, forming structures that are
compatible with membrane bilayers. In the
saccharolipids, a monosaccharide substitutes
for the glycerol backbone present in
glycerolipids and glycerophospholipids. The
most familiar saccharolipids are the acylated
glucosamine precursors of the Lipid A
component of the lipopolysaccharides in
Gram-negative bacteria. Typical lipid A
molecules are disaccharides of glucosamine,
which are derivatized with as many as seven
fatty-acyl chains. The minimal
lipopolysaccharide required for growth in E.
coli is Kdo2-Lipid A, a hexa-acylated
[41]
disaccharide of glucosamine that is Structure of the saccharolipid Kdo2-Lipid A. Glucosamine residues in blue,
glycosylated with two Kdo residues in red, acyl chains in black and phosphate groups in green.

3-deoxy-D-manno-octulosonic acid (Kdo)


residues.[41]

Polyketides
Polyketides are synthesized by polymerization of acetyl and propionyl subunits by classic enzymes as well as
iterative and multimodular enzymes that share mechanistic features with the fatty acid synthases. They comprise a
large number of secondary metabolites and natural products from animal, plant, bacterial, fungal and marine sources,
and have great structural diversity.[42][43] Many polyketides are cyclic molecules whose backbones are often further
modified by glycosylation, methylation, hydroxylation, oxidation, and/or other processes. Many commonly used
anti-microbial, anti-parasitic, and anti-cancer agents are polyketides or polyketide derivatives, such as
erythromycins, tetracyclines, avermectins, and antitumor epothilones.[44]

Biological functions

Membranes
Eukaryotic cells are compartmentalized into membrane-bound organelles that carry out different biological
functions. The glycerophospholipids are the main structural component of biological membranes, such as the cellular
plasma membrane and the intracellular membranes of organelles; in animal cells the plasma membrane physically
separates the intracellular components from the extracellular environment. The glycerophospholipids are
amphipathic molecules (containing both hydrophobic and hydrophilic regions) that contain a glycerol core linked to
two fatty acid-derived "tails" by ester linkages and to one "head" group by a phosphate ester linkage. While
glycerophospholipids are the major component of biological membranes, other non-glyceride lipid components such
as sphingomyelin and sterols (mainly cholesterol in animal cell membranes) are also found in biological
membranes.[45] In plants and algae, the galactosyldiacylglycerols,[46] and sulfoquinovosyldiacylglycerol,[18] which
lack a phosphate group, are important components of membranes of chloroplasts and related organelles and are the
most abundant lipids in photosynthetic tissues, including those of higher plants, algae and certain bacteria.
Lipid 225

Bilayers have been found to exhibit high levels of birefringence, which can be used to probe the degree of order (or
disruption) within the bilayer using techniques such as dual polarization interferometry and Circular dichroism.
A biological membrane is a form of lipid bilayer. The
formation of lipid bilayers is an energetically preferred
process when the glycerophospholipids described
above are in an aqueous environment.[47] This is known
as the hydrophobic effect. In an aqueous system, the
polar heads of lipids align towards the polar, aqueous
environment, while the hydrophobic tails minimize
their contact with water and tend to cluster together,
forming a vesicle; depending on the concentration of
the lipid, this biophysical interaction may result in the
formation of micelles, liposomes, or lipid bilayers.
Other aggregations are also observed and form part of
the polymorphism of amphiphile (lipid) behavior.
Phase behavior is an area of study within biophysics
and is the subject of current academic research.[48][49]
Micelles and bilayers form in the polar medium by a
process known as the hydrophobic effect.[50] When
dissolving a lipophilic or amphiphilic substance in a
polar environment, the polar molecules (i.e., water in
an aqueous solution) become more ordered around the Self-organization of phospholipids: a spherical liposome, a micelle,
and a lipid bilayer.
dissolved lipophilic substance, since the polar
molecules cannot form hydrogen bonds to the
lipophilic areas of the amphiphile. So in an aqueous environment, the water molecules form an ordered "clathrate"
cage around the dissolved lipophilic molecule.[51]

Energy storage
Triglycerides, stored in adipose tissue, are a major form of energy storage both in animals and plants. The adipocyte,
or fat cell, is designed for continuous synthesis and breakdown of triglycerides in animals, with breakdown
controlled mainly by the activation of hormone-sensitive enzyme lipase.[52] The complete oxidation of fatty acids
provides high caloric content, about 9 kcal/g, compared with 4 kcal/g for the breakdown of carbohydrates and
proteins. Migratory birds that must fly long distances without eating use stored energy of triglycerides to fuel their
flights.[53]

Signaling
In recent years, evidence has emerged showing that lipid signaling is a vital part of the cell signaling.[54][55] Lipid
signaling may occur via activation of G protein-coupled or nuclear receptors, and members of several different lipid
categories have been identified as signaling molecules and cellular messengers.[56] These include
sphingosine-1-phosphate, a sphingolipid derived from ceramide that is a potent messenger molecule involved in
regulating calcium mobilization,[57] cell growth, and apoptosis;[58] diacylglycerol (DAG) and the
phosphatidylinositol phosphates (PIPs), involved in calcium-mediated activation of protein kinase C;[59] the
prostaglandins, which are one type of fatty-acid derived eicosanoid involved in inflammation and immunity;[60] the
steroid hormones such as estrogen, testosterone and cortisol, which modulate a host of functions such as
reproduction, metabolism and blood pressure; and the oxysterols such as 25-hydroxy-cholesterol that are liver X
receptor agonists.[61]
Lipid 226

Other functions
The "fat-soluble" vitamins (A, D, E and K) – which are isoprene-based lipids – are essential nutrients stored in the
liver and fatty tissues, with a diverse range of functions. Acyl-carnitines are involved in the transport and metabolism
of fatty acids in and out of mitochondria, where they undergo beta oxidation.[62] Polyprenols and their
phosphorylated derivatives also play important transport roles, in this case the transport of oligosaccharides across
membranes. Polyprenol phosphate sugars and polyprenol diphosphate sugars function in extra-cytoplasmic
glycosylation reactions, in extracellular polysaccharide biosynthesis (for instance, peptidoglycan polymerization in
bacteria), and in eukaryotic protein N-glycosylation.[63][64] Cardiolipins are a subclass of glycerophospholipids
containing four acyl chains and three glycerol groups that are particularly abundant in the inner mitochondrial
membrane.[65][66][67] They are believed to activate enzymes involved with oxidative phosphorylation.[68] Lipids also
form the basis of steroid hormones.[69]

Metabolism
The major dietary lipids for humans and other animals are animal and plant triglycerides, sterols, and membrane
phospholipids. The process of lipid metabolism synthesizes and degrades the lipid stores and produces the structural
and functional lipids characteristic of individual tissues.

Biosynthesis
In animals, when there is an oversupply of dietary carbohydrate, the excess carbohydrate is converted to
triglycerides. This involves the synthesis of fatty acids from acetyl-CoA and the esterification of fatty acids in the
production of triglycerides, a process called lipogenesis.[70] Fatty acids are made by fatty acid synthases that
polymerize and then reduce acetyl-CoA units. The acyl chains in the fatty acids are extended by a cycle of reactions
that add the acetyl group, reduce it to an alcohol, dehydrate it to an alkene group and then reduce it again to an
alkane group. The enzymes of fatty acid biosynthesis are divided into two groups, in animals and fungi all these fatty
acid synthase reactions are carried out by a single multifunctional protein,[71] while in plant plastids and bacteria
separate enzymes perform each step in the pathway.[72][73] The fatty acids may be subsequently converted to
triglycerides that are packaged in lipoproteins and secreted from the liver.
The synthesis of unsaturated fatty acids involves a desaturation reaction, whereby a double bond is introduced into
the fatty acyl chain. For example, in humans, the desaturation of stearic acid by stearoyl-CoA desaturase-1 produces
oleic acid. The doubly unsaturated fatty acid linoleic acid as well as the triply unsaturated α-linolenic acid cannot be
synthesized in mammalian tissues, and are therefore essential fatty acids and must be obtained from the diet.[74]
Triglyceride synthesis takes place in the endoplasmic reticulum by metabolic pathways in which acyl groups in fatty
acyl-CoAs are transferred to the hydroxyl groups of glycerol-3-phosphate and diacylglycerol.[75]
Terpenes and isoprenoids, including the carotenoids, are made by the assembly and modification of isoprene units
donated from the reactive precursors isopentenyl pyrophosphate and dimethylallyl pyrophosphate.[76] These
precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these
compounds from acetyl-CoA,[77] while in plants and bacteria the non-mevalonate pathway uses pyruvate and
glyceraldehyde 3-phosphate as substrates.[76][78] One important reaction that uses these activated isoprene donors is
steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed
into a set of rings to make lanosterol.[79] Lanosterol can then be converted into other steroids such as cholesterol and
ergosterol.[79][80]
Lipid 227

Degradation
Beta oxidation is the metabolic process by which fatty acids are broken down in the mitochondria and/or in
peroxisomes to generate acetyl-CoA. For the most part, fatty acids are oxidized by a mechanism that is similar to,
but not identical with, a reversal of the process of fatty acid synthesis. That is, two-carbon fragments are removed
sequentially from the carboxyl end of the acid after steps of dehydrogenation, hydration, and oxidation to form a
beta-keto acid, which is split by thiolysis. The acetyl-CoA is then ultimately converted into ATP, CO2, and H2O
using the citric acid cycle and the electron transport chain.
Hence the Krebs Cycle can start at acetyl-CoA when fat is being broken down for energy if there is little or no
glucose available.
The energy yield of the complete oxidation of the fatty acid palmitate is 106 ATP.[81] Unsaturated and odd-chain
fatty acids require additional enzymatic steps for degradation.

Nutrition and health


Most of the fat found in food is in the form of triglycerides, cholesterol, and phospholipids. Some dietary fat is
necessary to facilitate absorption of fat-soluble vitamins (A, D, E, and K) and carotenoids.[82] Humans and other
mammals have a dietary requirement for certain essential fatty acids, such as linoleic acid (an omega-6 fatty acid)
and alpha-linolenic acid (an omega-3 fatty acid) because they cannot be synthesized from simple precursors in the
diet.[74] Both of these fatty acids are 18-carbon polyunsaturated fatty acids differing in the number and position of
the double bonds. Most vegetable oils are rich in linoleic acid (safflower, sunflower, and corn oils). Alpha-linolenic
acid is found in the green leaves of plants, and in selected seeds, nuts, and legumes (in particular flax, rapeseed,
walnut, and soy).[83] Fish oils are particularly rich in the longer-chain omega-3 fatty acids eicosapentaenoic acid
(EPA) and docosahexaenoic acid (DHA).[84] A large number of studies have shown positive health benefits
associated with consumption of omega-3 fatty acids on infant development, cancer, cardiovascular diseases, and
various mental illnesses, such as depression, attention-deficit hyperactivity disorder, and dementia.[85][86] In contrast,
it is now well-established that consumption of trans fats, such as those present in partially hydrogenated vegetable
oils, are a risk factor for cardiovascular disease.[87][88][89]
A few studies have suggested that total dietary fat intake is linked to an increased risk of obesity[90][91] and
diabetes.[92][93] However, a number of very large studies, including the Women's Health Initiative Dietary
Modification Trial, an eight year study of 49,000 women, the Nurses' Health Study and the Health Professionals
Follow-up Study, revealed no such links.[94][95][96] None of these studies suggested any connection between
percentage of calories from fat and risk of cancer, heart disease, or weight gain. The Nutrition Source, a website
maintained by the Department of Nutrition at the Harvard School of Public Health, summarizes the current evidence
on the impact of dietary fat: "Detailed research—much of it done at Harvard—shows that the total amount of fat in
the diet isn't really linked with weight or disease."[97]
Lipid 228

References
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[2] Stryer et al., p. 328.
[3] Stryer et al., p. 330.
[4] Fahy E, Subramaniam S, Murphy R, Nishijima M, Raetz C, Shimizu T, Spener F, Van Meer G, Wakelam M and Dennis E.A (2009). "Update
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External links
Introductory
• List of lipid-related web sites (http://www.cyberlipid.org/cyberlip/link0041.htm)
• Nature Lipidomics Gateway (http://www.lipidmaps.org/) - Round-up and summaries of recent lipid research
• Lipid Library (http://www.lipidlibrary.co.uk/) - General reference on lipid chemistry and biochemistry
• Cyberlipid.org (http://www.cyberlipid.org/) - Resources and history for lipids.
• Molecular Computer Simulations (http://www.fos.su.se/~sasha/Lipid_membranes.html) - Modeling of Lipid
Membranes
• Lipids, Membranes and Vesicle Trafficking (http://www.biochemweb.org/lipids_membranes.shtml) - The
Virtual Library of Biochemistry and Cell Biology
Nomenclature
• IUPAC nomenclature of lipids (http://www.chem.qmul.ac.uk/iupac/lipid/)
• IUPAC glossary entry for the lipid class of molecules (http://www.chem.qmul.ac.uk/iupac/class/lipid.html)
Databases
• LIPID MAPS (http://www.lipidmaps.org/data/databases.html) - Comprehensive lipid and lipid-associated
gene/protein databases.
• LipidBank (http://lipidbank.jp/) - Japanese database of lipids and related properties, spectral data and
references.
Lipid 232

• LIPIDAT (http://www.lipidat.tcd.ie/) - Database composed mainly of phospholipids and associated


thermodynamic data.
General
• ApolloLipids (http://www.apollolipids.org/) - Provides dyslipidemia and cardiovascular disease prevention and
treatment information as well as continuing medical education programs
• National Lipid Association (http://www.lipid.org/) - Professional medical education organization for health
care professionals who seek to prevent morbidity and mortality stemming from dyslipidemias and other
cholesterol-related disorders.

Lipopolysaccharide
Lipopolysaccharides (LPS), also known as lipoglycans, are large
molecules consisting of a lipid and a polysaccharide joined by a covalent
bond; they are found in the outer membrane of Gram-negative bacteria, act
as endotoxins and elicit strong immune responses in animals.

Functions
LPS is the major component of the outer membrane of Gram-negative
bacteria, contributing greatly to the structural integrity of the bacteria, and
protecting the membrane from certain kinds of chemical attack. LPS also
increases the negative charge of the cell membrane and helps stabilize the
overall membrane structure. It is of crucial importance to gram-negative
bacteria, whose death results if it is mutated or removed. LPS is an
endotoxin, and induces a strong response from normal animal immune
systems. It has also been implicated in non-pathogenic aspects of bacterial
ecology, including surface adhesion, bacteriophage sensitivity, and
interactions with predators such as amoebae.

LPS is required for the proper conformation of Omptin activity; however,


smooth LPS will sterically hinder omptins.
LPS acts as the prototypical endotoxin because it binds the
CD14/TLR4/MD2 receptor complex, which promotes the secretion of
pro-inflammatory cytokines in many cell types, but especially in
macrophages and B cells. In Immunology, the term "LPS challenge" refers Structure of a lipopolysaccharide

to the process of exposing a subject to an LPS that may act as a toxin.


LPS is also an exogenous pyrogen (external fever-inducing substance).
Being of crucial importance to gram-negative bacteria, these molecules make candidate targets for new antimicrobial
agents.
Some researchers doubt reports of generalized toxic effects attributed to all lipopolysaccharides, in particular, for
cyanobacteria.[1]
Lipopolysaccharide 233

Composition
It comprises three parts:
1. O antigen (or O polysaccharide)
2. Core oligosaccharide
3. Lipid A

O-antigen
A repetitive glycan polymer contained
within an LPS is referred to as the O
antigen, O polysaccharide, or O side-chain
of the bacteria. The O antigen is attached to
the core oligosaccharide, and comprises the
outermost domain of the LPS molecule. The
composition of the O chain varies from
strain to strain. For example, there are over
160 different O antigen structures produced
by different E. coli strains.[2] The presence The saccharolipid Kdo2-Lipid A. Glucosamine residues in blue, Kdo residues in
or absence of O chains determines whether red, acyl chains in black and phosphate groups in green.
the LPS is considered rough or smooth.
Full-length O-chains would render the LPS smooth, whereas the absence or reduction of O-chains would make the
LPS rough.[3] Bacteria with rough LPS usually have more penetrable cell membranes to hydrophobic antibiotics,
since a rough LPS is more hydrophobic.[4] O antigen is exposed on the very outer surface of the bacterial cell, and, as
a consequence, is a target for recognition by host antibodies.

Core
The Core domain always contains an oligosaccharide component that attaches directly to lipid A and commonly
contains sugars such as heptose and 3-deoxy-D-mannooctulosonic Acid (also known as KDO,
keto-deoxyoctulosonate).[5] The LPS Cores of many bacteria also contain non-carbohydrate components, such as
phosphate, amino acids, and ethanolamine substitutents.

Lipid A
Lipid A is, in normal circumstances, a phosphorylated glucosamine disaccharide decorated with multiple fatty acids.
These hydrophobic fatty acid chains anchor the LPS into the bacterial membrane, and the rest of the LPS projects
from the cell surface. The lipid A domain is responsible for much of the toxicity of Gram-negative bacteria. When
bacterial cells are lysed by the immune system, fragments of membrane containing lipid A are released into the
circulation, causing fever, diarrhea, and possible fatal endotoxic shock (also called septic shock).
Lipopolysaccharide 234

Biosynthesis and Transport

LPS modifications
The making of LPS can be modified in
order to present a specific sugar
structure. Those can be recognised by
either other LPS (which enables to
inhibit LPS toxins) or
glycosyltransferases that use those
sugar structure to add more specific
sugars. It has recently been shown that
a specific enzyme in the intestine
(alkaline phosphatase) can detoxify
LPS by removing the two phosphate
LPS Final Assembly: O-antigen subunits are translocated across the inner membrane (by
groups found on LPS carbohydrates.[8]
Wzx) where they are polymerized (by Wzy, chain length determined by Wzz) and ligated
(by WaaL) on to complete Core-Lipid A molecules (which were translocated by This may function as an adaptive
[6]
MsbA). mechanism to help the host manage
potentially toxic effects of
gram-negative bacteria normally found
in the small intestine.

LPS Transport: Completed LPS molecules are transported across the periplasm and
[7]
outer membrane by the proteins LptA, B, C, D, E, F, and G
Lipopolysaccharide 235

Variability and effect upon specificity


O-antigens (the outer carbohydrates) are the
most variable portion of the LPS molecule,
imparting the antigenic specificity. In
contrast, lipid A is the most conserved part.
However, lipid A composition also may
vary (e.g., in number and nature of acyl
chains even within or between genera).
Some of these variations may impart
antagonistic properties to these LPS. For
example Rhodobacter sphaeroides
diphosphoryl lipid A (RsDPLA) is a potent
antagonist of LPS in human cells, but is an
agonist in hamster and equine cells.

It has been speculated that conical Lipid A


Toll-like receptors of the innate immune system recognize LPS and trigger an
(e.g., from E. coli) are more agonistic, less immune response.
conical lipid A like those of Porphyromonas
gingivalis may activate a different signal (TLR2 instead of TLR4), and completely cylindrical lipid A like that of
Rhodobacter sphaeroides is antagonistic to TLRs.[9][10]
Lipopolysaccharide gene clusters are highly variable between different strains, subspecies, species of bacterial
pathogens of plants and animals.[11][12]

Immune response
LPS function has been under experimental research for several years due to its role in activating many transcription
factors. LPS challenge also produces many types of mediators involved in septic shock. Humans are much more
sensitive to LPS than other animals (e.g., mice). A dose of 1 µg/kg induces shock in humans, but mice will tolerate a
dose up to a thousand times higher.[13] This may relate to differences in the level of circulating natural antibodies
between the two species.[14][15] Said et al. showed that LPS causes an IL-10-dependent inhibition of CD4 T-cell
expansion and function by up-regulating PD-1 levels on monocytes which leads to IL-10 production by monocytes
after binding of PD-1 by PD-L.[16]
Bruce Beutler was awarded a portion of the 2011 Nobel Prize in Physiology or Medicine for his work demonstrating
that TLR4 is the LPS receptor.[17][18]

References
[1] Stewart I, Schluter PJ, Shaw GR (2006). "Cyanobacterial lipopolysaccharides and human health – a review". Environ Health 5: 7.
doi:10.1186/1476-069X-5-7. PMC 1489932. PMID 16563160.
[2] Christian Raetz and Chris Whitfield (2002) Lipopolysaccharide Endotoxins Annu. Rev. Biochem. 71:635-700
[3] Rittig MG et al. (2004). "Smooth and rough lipopolysaccharide phenotypes of Brucella induce different intracellular trafficking and
cytokine/chemokine release in human monocytes". Journal of Leukocyte Biology 5 (4): 196–200. doi:10.1189/jlb.0103015. PMID 12960272.
[4] Tsujimoto H et al. (2003). "Diffusion of macrolide antibiotics through the outer membrane of Moraxella catarrhalis". Journal of Infection and
Chemotherapy 74 (4): 1045–1055. doi:10.1007/s101569900025. PMID 11810516.
[5] Hershberger C and Binkley SB (1968). "Chemistry and Metabolism of 3-Deoxy-d-mannooctulosonic Acid. I. STEREOCHEMICAL
DETERMINATION" (http:/ / www. jbc. org/ cgi/ reprint/ 243/ 7/ 1578?maxtoshow=& HITS=10& hits=10& RESULTFORMAT=&
fulltext=3-Deoxy-D-mannooctulosonic+ Acid+ & searchid=1& FIRSTINDEX=0& volume=243& issue=7& resourcetype=HWCIT). Journal
of Biological Chemistry 243 (7): 1578–1584. PMID 4296687. .
[6] Wang, Xiaoyuan and Quinn, Peter J. (2010). "Lipopolysaccharide:Biosynthetic pathway and structure modification". Progress in Lipid
Research 49 (2): 97–107. doi:10.1016/j.plipres.2009.06.002. PMID 19815028.
Lipopolysaccharide 236

[7] Ruiz, Natividad; Kahne, Daniel; Silhavy, Thomas J (2009). "Transport of lipopolysaccharide across the cell envelope: the long road of
discovery". Nature Reviews Microbiology 7 (9): 677–683. doi:10.1038/nrmicro2184. PMC 2790178. PMID 19633680.
[8] Bates J.M. et al. (2007). "Intestinal Alkaline Phosphatase Detoxifies Lipopolysaccharide and Prevents Inflammation in Response to the Gut
Microbiota". Cell Host and Microbe 2 (6): 371–382. doi:10.1016/j.chom.2007.10.010. PMC 2730374. PMID 18078689.
[9] Netea M et al. (2002). "Does the shape of lipid A determine the interaction of LPS with Toll-like receptors?". Trends Immunol 23 (3): 135–9.
doi:10.1016/S1471-4906(01)02169-X. PMID 11864841.
[10] Seydel U, Oikawa M, Fukase K, Kusumoto S, Brandenburg K (2000). "Intrinsic conformation of lipid A is responsible for agonistic and
antagonistic activity". Eur J Biochem 267 (10): 3032–9. doi:10.1046/j.1432-1033.2000.01326.x. PMID 10806403.
[11] Reeves P, Wang L (2002). "Genomic organization of LPS-specific loci". Curr Top Microbiol Immunol. Current Topics in Microbiology and
Immunology 264 (1): 109–35. doi:10.1007/978-3-642-56031-6_7. ISBN 978-3-540-42682-0. PMID 12014174.
[12] Patil P, Sonti R (2004). "Variation suggestive of horizontal gene transfer at a lipopolysaccharide (lps) biosynthetic locus in Xanthomonas
oryzae pv. oryzae, the bacterial leaf blight pathogen of rice". BMC Microbiol 4: 40. doi:10.1186/1471-2180-4-40. PMC 524487.
PMID 15473911.
[13] Warren, HS; Fitting, C; Hoff, E; Adib-Conquy, M; Beasley-Topliffe, L; Tesini, B; Liang, X; Valentine, C et al. (2010). "Resilience to
bacterial infection: difference between species could be due to proteins in serum". J Infect Dis 201 (2): 223–232. doi:10.1086/649557.
PMC 2798011. PMID 20001600.
[14] Reid RR, Prodeus AP, Khan W, Hsu T, Rosen FS, Carroll MC (1997). "Endotoxin shock in antibody-deficient mice: unraveling the role of
natural antibody and complement in the clearance of lipopolysaccharide". J. Immunol. 159 (2): 970–5. PMID 9218618.
[15] Boes M, Prodeus AP, Schmidt T, Carroll MC, Chen J (1998). "A Critical Role of Natural Immunoglobulin M in Immediate Defense Against
Systemic Bacterial Infection". J. Exp. Med. 188 (12): 2381–6. doi:10.1084/jem.188.12.2381. PMC 2212438. PMID 9858525.
[16] Said EA et al. (2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV
infection". Nature Medicine 16 (4): 452–9. doi:10.1038/nm.2106. PMID 20208540.
[17] Poltorak A et al. (1998). "Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene". Science 282 (5396):
2085–2088. doi:10.1126/science.282.5396.2085. PMID 9851930.
[18] http:/ / www. nobelprize. org/ nobel_prizes/ medicine/ laureates/ 2011/ press. html

External links
• Lipopolysaccharides (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Lipopolysaccharides)
at the US National Library of Medicine Medical Subject Headings (MeSH)
Metabolism 237

Metabolism
Metabolism (from Greek: μεταβολή "metabolē", "change" or Greek:
μεταβολισμός metabolismos, "outthrow") is the set of chemical
reactions that happen in the cells of living organisms to sustain life.
These processes allow organisms to grow and reproduce, maintain
their structures, and respond to their environments. The word
metabolism can also refer to all chemical reactions that occur in living
organisms, including digestion and the transport of substances into and
between different cells, in which case the set of reactions within the
cells is called intermediary metabolism or intermediate Structure of adenosine triphosphate (ATP), a
metabolism. central intermediate in energy metabolism

Metabolism is usually divided into two categories. Catabolism breaks


down organic matter, for example to harvest energy in cellular respiration. Anabolism uses energy to construct
components of cells such as proteins and nucleic acids.
The chemical reactions of metabolism are organized into metabolic pathways, in which one chemical is transformed
through a series of steps into another chemical, by a sequence of enzymes. Enzymes are crucial to metabolism
because they allow organisms to drive desirable reactions that require energy and will not occur by themselves, by
coupling them to spontaneous reactions that release energy. As enzymes act as catalysts they allow these reactions to
proceed quickly and efficiently. Enzymes also allow the regulation of metabolic pathways in response to changes in
the cell's environment or signals from other cells.

The metabolism of an organism determines which substances it will find nutritious and which it will find poisonous.
For example, some prokaryotes use hydrogen sulfide as a nutrient, yet this gas is poisonous to animals.[1] The speed
of metabolism, the metabolic rate, influences how much food an organism will require, and also affects how it is able
to obtain that food.
A striking feature of metabolism is the similarity of the basic metabolic pathways and components between even
vastly different species.[2] For example, the set of carboxylic acids that are best known as the intermediates in the
citric acid cycle are present in all known organisms, being found in species as diverse as the unicellular bacteria
Escherichia coli and huge multicellular organisms like elephants.[3] These striking similarities in metabolic pathways
are likely due to their early appearance in evolutionary history, and being retained because of their efficacy.[4][5]
Metabolism 238

Key biochemicals
Most of the structures that make up animals, plants and
microbes are made from three basic classes of
molecule: amino acids, carbohydrates and lipids (often
called fats). As these molecules are vital for life,
metabolic reactions either focus on making these
molecules during the construction of cells and tissues,
or breaking them down and using them as a source of
energy, in the digestion and use of food. Many
important biochemicals can be joined together to make
polymers such as DNA and proteins. These
macromolecules are essential.

Structure of a triacylglycerol lipid

Type of molecule Name of monomer forms Name of polymer forms Examples of polymer forms

Amino acids Amino acids Proteins (also called polypeptides) Fibrous proteins and globular proteins

Carbohydrates Monosaccharides Polysaccharides Starch, glycogen and cellulose

Nucleic acids Nucleotides Polynucleotides DNA and RNA

Amino acids and proteins


Proteins are made of amino acids arranged in a linear chain and joined together by peptide bonds. Many proteins are
the enzymes that catalyze the chemical reactions in metabolism. Other proteins have structural or mechanical
functions, such as the proteins that form the cytoskeleton, a system of scaffolding that maintains the cell shape.[6]
Proteins are also important in cell signaling, immune responses, cell adhesion, active transport across membranes,
and the cell cycle.[7]

Lipids
Lipids are the most diverse group of biochemicals. Their main structural uses are as part of biological membranes
such as the cell membrane, or as a source of energy.[7] Lipids are usually defined as hydrophobic or amphipathic
biological molecules that will dissolve in organic solvents such as benzene or chloroform.[8] The fats are a large
group of compounds that contain fatty acids and glycerol; a glycerol molecule attached to three fatty acid esters is a
triacylglyceride.[9] Several variations on this basic structure exist, including alternate backbones such as sphingosine
in the sphingolipids, and hydrophilic groups such as phosphate in phospholipids. Steroids such as cholesterol are
another major class of lipids that are made in cells.[10]
Metabolism 239

Carbohydrates
Carbohydrates are aldehydes or ketones with many
hydroxyl groups that can exist as straight chains or
rings. Carbohydrates are the most abundant biological
molecules, and fill numerous roles, such as the storage
and transport of energy (starch, glycogen) and structural
components (cellulose in plants, chitin in animals).[7]
The basic carbohydrate units are called
monosaccharides and include galactose, fructose, and
most importantly glucose. Monosaccharides can be
linked together to form polysaccharides in almost
limitless ways.[11]

Nucleotides Glucose can exist in both a straight-chain and ring form.

The two nucleic acids, DNA and RNA are polymers of


nucleotides, each nucleotide comprising a phosphate group, a ribose sugar group, and a nitrogenous base. Nucleic
acids are critical for the storage and use of genetic information, through the processes of transcription and protein
biosynthesis.[7] This information is protected by DNA repair mechanisms and propagated through DNA replication.
Many viruses have an RNA genome, for example HIV, which uses reverse transcription to create a DNA template
from its viral RNA genome.[12] RNA in ribozymes such as spliceosomes and ribosomes is similar to enzymes as it
can catalyze chemical reactions. Individual nucleosides are made by attaching a nucleobase to a ribose sugar. These
bases are heterocyclic rings containing nitrogen, classified as purines or pyrimidines. Nucleotides also act as
coenzymes in metabolic group transfer reactions.[13]

Coenzymes
Metabolism involves a vast array of
chemical reactions, but most fall under a
few basic types of reactions that involve the
transfer of functional groups.[14] This
common chemistry allows cells to use a
small set of metabolic intermediates to carry
chemical groups between different
[13]
reactions. These group-transfer Structure of the coenzyme acetyl-CoA.The transferable acetyl group is bonded to
intermediates are called coenzymes. Each the sulfur atom at the extreme left.

class of group-transfer reaction is carried out


by a particular coenzyme, which is the substrate for a set of enzymes that produce it, and a set of enzymes that
consume it. These coenzymes are therefore continuously being made, consumed and then recycled.[15]

One central coenzyme is adenosine triphosphate (ATP), the universal energy currency of cells. This nucleotide is
used to transfer chemical energy between different chemical reactions. There is only a small amount of ATP in cells,
but as it is continuously regenerated, the human body can use about its own weight in ATP per day.[15] ATP acts as a
bridge between catabolism and anabolism, with catabolic reactions generating ATP and anabolic reactions
consuming it. It also serves as a carrier of phosphate groups in phosphorylation reactions.
A vitamin is an organic compound needed in small quantities that cannot be made in the cells. In human nutrition,
most vitamins function as coenzymes after modification; for example, all water-soluble vitamins are phosphorylated
Metabolism 240

or are coupled to nucleotides when they are used in cells.[16] Nicotinamide adenine dinucleotide (NADH), a
derivative of vitamin B3 (niacin), is an important coenzyme that acts as a hydrogen acceptor. Hundreds of separate
types of dehydrogenases remove electrons from their substrates and reduce NAD+ into NADH. This reduced form of
the coenzyme is then a substrate for any of the reductases in the cell that need to reduce their substrates.[17]
Nicotinamide adenine dinucleotide exists in two related forms in the cell, NADH and NADPH. The NAD+/NADH
form is more important in catabolic reactions, while NADP+/NADPH is used in anabolic reactions.

Minerals and cofactors


Inorganic elements play critical roles in
metabolism; some are abundant (e.g. sodium
and potassium) while others function at
minute concentrations. About 99% of a
mammal's mass is made up of the elements
carbon, nitrogen, calcium, sodium, chlorine,
potassium, hydrogen, phosphorus, oxygen
and sulfur.[19] Organic compounds (proteins,
lipids and carbohydrates) contain the
majority of the carbon and nitrogen; most of
the oxygen and hydrogen is present as
water.[19]

The abundant inorganic elements act as


ionic electrolytes. The most important ions
are sodium, potassium, calcium,
magnesium, chloride, phosphate and the
organic ion bicarbonate. The maintenance of
Structure of hemoglobin. The protein subunits are in red and blue, and the
[18] precise gradients across cell membranes
iron-containing heme groups in green. From PDB 1GZX .
maintains osmotic pressure and pH.[20] Ions
are also critical for nerve and muscle function, as action potentials in these tissues are produced by the exchange of
electrolytes between the extracellular fluid and the cytosol.[21] Electrolytes enter and leave cells through proteins in
the cell membrane called ion channels. For example, muscle contraction depends upon the movement of calcium,
sodium and potassium through ion channels in the cell membrane and T-tubules.[22]

Transition metals are usually present as trace elements in organisms, with zinc and iron being most abundant.[23][24]
These metals are used in some proteins as cofactors and are essential for the activity of enzymes such as catalase and
oxygen-carrier proteins such as hemoglobin.[25] Metal cofactors are bound tightly to specific sites in proteins;
although enzyme cofactors can be modified during catalysis, they always return to their original state by the end of
the reaction catalyzed. Metal micronutrients are taken up into organisms by specific transporters and bind to storage
proteins such as ferritin or metallothionein when not being used.[26][27]

Catabolism
Catabolism is the set of metabolic processes that break down large molecules. These include breaking down and
oxidizing food molecules. The purpose of the catabolic reactions is to provide the energy and components needed by
anabolic reactions. The exact nature of these catabolic reactions differ from organism to organism and organisms can
be classified based on their sources of energy and carbon (their primary nutritional groups), as shown in the table
below. Organic molecules are used as a source of energy by organotrophs, while lithotrophs use inorganic substrates
and phototrophs capture sunlight as chemical energy. However, all these different forms of metabolism depend on
Metabolism 241

redox reactions that involve the transfer of electrons from reduced donor molecules such as organic molecules,
water, ammonia, hydrogen sulfide or ferrous ions to acceptor molecules such as oxygen, nitrate or sulfate.[28] In
animals these reactions involve complex organic molecules being broken down to simpler molecules, such as carbon
dioxide and water. In photosynthetic organisms such as plants and cyanobacteria, these electron-transfer reactions do
not release energy, but are used as a way of storing energy absorbed from sunlight.[7]

Classification of organisms based on their metabolism


Energy source sunlight photo- -troph

Preformed molecules chemo-

Electron donor organic compound organo-

inorganic compound litho-

Carbon source organic compound hetero-

inorganic compound auto-

The most common set of catabolic reactions in animals can be separated into three main stages. In the first, large
organic molecules such as proteins, polysaccharides or lipids are digested into their smaller components outside
cells. Next, these smaller molecules are taken up by cells and converted to yet smaller molecules, usually acetyl
coenzyme A (acetyl-CoA), which releases some energy. Finally, the acetyl group on the CoA is oxidised to water
and carbon dioxide in the citric acid cycle and electron transport chain, releasing the energy that is stored by
reducing the coenzyme nicotinamide adenine dinucleotide (NAD+) into NADH.

Digestion
Macromolecules such as starch, cellulose or proteins cannot be rapidly taken up by cells and must be broken into
their smaller units before they can be used in cell metabolism. Several common classes of enzymes digest these
polymers. These digestive enzymes include proteases that digest proteins into amino acids, as well as glycoside
hydrolases that digest polysaccharides into monosaccharides.
Microbes simply secrete digestive enzymes into their surroundings,[29][30] while animals only secrete these enzymes
from specialized cells in their guts.[31] The amino acids or sugars released by these extracellular enzymes are then
pumped into cells by specific active transport proteins.[32][33]
Metabolism 242

Energy from organic compounds


Carbohydrate catabolism is the breakdown
of carbohydrates into smaller units.
Carbohydrates are usually taken into cells
once they have been digested into
monosaccharides.[34] Once inside, the major
route of breakdown is glycolysis, where
sugars such as glucose and fructose are
converted into pyruvate and some ATP is
generated.[35] Pyruvate is an intermediate in
several metabolic pathways, but the majority
is converted to acetyl-CoA and fed into the
citric acid cycle. Although some more ATP
is generated in the citric acid cycle, the most
important product is NADH, which is made
from NAD+ as the acetyl-CoA is oxidized.
This oxidation releases carbon dioxide as a
A simplified outline of the catabolism of proteins, carbohydrates and fats
waste product. In anaerobic conditions,
glycolysis produces lactate, through the
enzyme lactate dehydrogenase re-oxidizing NADH to NAD+ for re-use in glycolysis. An alternative route for
glucose breakdown is the pentose phosphate pathway, which reduces the coenzyme NADPH and produces pentose
sugars such as ribose, the sugar component of nucleic acids.

Fats are catabolised by hydrolysis to free fatty acids and glycerol. The glycerol enters glycolysis and the fatty acids
are broken down by beta oxidation to release acetyl-CoA, which then is fed into the citric acid cycle. Fatty acids
release more energy upon oxidation than carbohydrates because carbohydrates contain more oxygen in their
structures.
Amino acids are either used to synthesize proteins and other biomolecules, or oxidized to urea and carbon dioxide as
a source of energy.[36] The oxidation pathway starts with the removal of the amino group by a transaminase. The
amino group is fed into the urea cycle, leaving a deaminated carbon skeleton in the form of a keto acid. Several of
these keto acids are intermediates in the citric acid cycle, for example the deamination of glutamate forms
α-ketoglutarate.[37] The glucogenic amino acids can also be converted into glucose, through gluconeogenesis
(discussed below).[38]

Energy transformations

Oxidative phosphorylation
In oxidative phosphorylation, the electrons removed from organic molecules in areas such as the protagon acid cycle
are transferred to oxygen and the energy released is used to make ATP. This is done in eukaryotes by a series of
proteins in the membranes of mitochondria called the electron transport chain. In prokaryotes, these proteins are
found in the cell's inner membrane.[39] These proteins use the energy released from passing electrons from reduced
molecules like NADH onto oxygen to pump protons across a membrane.[40]
Metabolism 243

Pumping protons out of the mitochondria creates a proton


concentration difference across the membrane and generates
an electrochemical gradient.[41] This force drives protons back
into the mitochondrion through the base of an enzyme called
ATP synthase. The flow of protons makes the stalk subunit
rotate, causing the active site of the synthase domain to
change shape and phosphorylate adenosine diphosphate –
turning it into ATP.[15]

Energy from inorganic compounds


Chemolithotrophy is a type of metabolism found in
prokaryotes where energy is obtained from the oxidation of Mechanism of ATP synthase. ATP is shown in red, ADP and
[42] phosphate in pink and the rotating stalk subunit in black.
inorganic compounds. These organisms can use hydrogen,
reduced sulfur compounds (such as sulfide, hydrogen sulfide
and thiosulfate),[1] ferrous iron (FeII)[43] or ammonia[44] as sources of reducing power and they gain energy from the
oxidation of these compounds with electron acceptors such as oxygen or nitrite.[45] These microbial processes are
important in global biogeochemical cycles such as acetogenesis, nitrification and denitrification and are critical for
soil fertility.[46][47]

Energy from light


The energy in sunlight is captured by plants, cyanobacteria, purple bacteria, green sulfur bacteria and some protists.
This process is often coupled to the conversion of carbon dioxide into organic compounds, as part of photosynthesis,
which is discussed below. The energy capture and carbon fixation systems can however operate separately in
prokaryotes, as purple bacteria and green sulfur bacteria can use sunlight as a source of energy, while switching
between carbon fixation and the fermentation of organic compounds.[48][49]
In many organisms the capture of solar energy is similar in principle to oxidative phosphorylation, as it involves
energy being stored as a proton concentration gradient and this proton motive force then driving ATP synthesis.[15]
The electrons needed to drive this electron transport chain come from light-gathering proteins called photosynthetic
reaction centres or rhodopsins. Reaction centers are classed into two types depending on the type of photosynthetic
pigment present, with most photosynthetic bacteria only having one type, while plants and cyanobacteria have
two.[50]
In plants, algae, and cyanobacteria, photosystem II uses light energy to remove electrons from water, releasing
oxygen as a waste product. The electrons then flow to the cytochrome b6f complex, which uses their energy to pump
protons across the thylakoid membrane in the chloroplast.[7] These protons move back through the membrane as they
drive the ATP synthase, as before. The electrons then flow through photosystem I and can then either be used to
reduce the coenzyme NADP+, for use in the Calvin cycle, which is discussed below, or recycled for further ATP
generation.[51]

Anabolism
Anabolism is the set of constructive metabolic processes where the energy released by catabolism is used to
synthesize complex molecules. In general, the complex molecules that make up cellular structures are constructed
step-by-step from small and simple precursors. Anabolism involves three basic stages. Firstly, the production of
precursors such as amino acids, monosaccharides, isoprenoids and nucleotides, secondly, their activation into
reactive forms using energy from ATP, and thirdly, the assembly of these precursors into complex molecules such as
proteins, polysaccharides, lipids and nucleic acids.
Metabolism 244

Organisms differ in how many of the molecules in their cells they can construct for themselves. Autotrophs such as
plants can construct the complex organic molecules in cells such as polysaccharides and proteins from simple
molecules like carbon dioxide and water. Heterotrophs, on the other hand, require a source of more complex
substances, such as monosaccharides and amino acids, to produce these complex molecules. Organisms can be
further classified by ultimate source of their energy: photoautotrophs and photoheterotrophs obtain energy from
light, whereas chemoautotrophs and chemoheterotrophs obtain energy from inorganic oxidation reactions.

Carbon fixation
Photosynthesis is the synthesis of carbohydrates from sunlight and
carbon dioxide (CO2). In plants, cyanobacteria and algae, oxygenic
photosynthesis splits water, with oxygen produced as a waste product.
This process uses the ATP and NADPH produced by the
photosynthetic reaction centres, as described above, to convert CO2
into glycerate 3-phosphate, which can then be converted into glucose.
This carbon-fixation reaction is carried out by the enzyme RuBisCO as
part of the Calvin – Benson cycle.[52] Three types of photosynthesis
occur in plants, C3 carbon fixation, C4 carbon fixation and CAM
Plant cells (bounded by purple walls) filled with
photosynthesis. These differ by the route that carbon dioxide takes to
chloroplasts (green), which are the site of
the Calvin cycle, with C3 plants fixing CO2 directly, while C4 and photosynthesis
CAM photosynthesis incorporate the CO2 into other compounds first,
as adaptations to deal with intense sunlight and dry conditions.[53]

In photosynthetic prokaryotes the mechanisms of carbon fixation are more diverse. Here, carbon dioxide can be
fixed by the Calvin – Benson cycle, a reversed citric acid cycle,[54] or the carboxylation of acetyl-CoA.[55][56]
Prokaryotic chemoautotrophs also fix CO2 through the Calvin – Benson cycle, but use energy from inorganic
compounds to drive the reaction.[57]

Carbohydrates and glycans


In carbohydrate anabolism, simple organic acids can be converted into monosaccharides such as glucose and then
used to assemble polysaccharides such as starch. The generation of glucose from compounds like pyruvate, lactate,
glycerol, glycerate 3-phosphate and amino acids is called gluconeogenesis. Gluconeogenesis converts pyruvate to
glucose-6-phosphate through a series of intermediates, many of which are shared with glycolysis.[35] However, this
pathway is not simply glycolysis run in reverse, as several steps are catalyzed by non-glycolytic enzymes. This is
important as it allows the formation and breakdown of glucose to be regulated separately, and prevents both
pathways from running simultaneously in a futile cycle.[58][59]
Although fat is a common way of storing energy, in vertebrates such as humans the fatty acids in these stores cannot
be converted to glucose through gluconeogenesis as these organisms cannot convert acetyl-CoA into pyruvate; plants
do, but animals do not, have the necessary enzymatic machinery.[60] As a result, after long-term starvation,
vertebrates need to produce ketone bodies from fatty acids to replace glucose in tissues such as the brain that cannot
metabolize fatty acids.[61] In other organisms such as plants and bacteria, this metabolic problem is solved using the
glyoxylate cycle, which bypasses the decarboxylation step in the citric acid cycle and allows the transformation of
acetyl-CoA to oxaloacetate, where it can be used for the production of glucose.[60][62]
Polysaccharides and glycans are made by the sequential addition of monosaccharides by glycosyltransferase from a
reactive sugar-phosphate donor such as uridine diphosphate glucose (UDP-glucose) to an acceptor hydroxyl group
on the growing polysaccharide. As any of the hydroxyl groups on the ring of the substrate can be acceptors, the
polysaccharides produced can have straight or branched structures.[63] The polysaccharides produced can have
structural or metabolic functions themselves, or be transferred to lipids and proteins by enzymes called
Metabolism 245

oligosaccharyltransferases.[64][65]

Fatty acids, isoprenoids and steroids


Fatty acids are made by fatty acid
synthases that polymerize and then
reduce acetyl-CoA units. The acyl
chains in the fatty acids are extended
by a cycle of reactions that add the
acyl group, reduce it to an alcohol,
dehydrate it to an alkene group and
then reduce it again to an alkane group.
The enzymes of fatty acid biosynthesis
are divided into two groups, in animals
and fungi all these fatty acid synthase
reactions are carried out by a single
multifunctional type I protein,[66]
while in plant plastids and bacteria
separate type II enzymes perform each
step in the pathway.[67][68]

Terpenes and isoprenoids are a large


class of lipids that include the
carotenoids and form the largest class
of plant natural products.[69] These
compounds are made by the assembly
and modification of isoprene units
Simplified version of the steroid synthesis pathway with the intermediates isopentenyl
donated from the reactive precursors
pyrophosphate (IPP), dimethylallyl pyrophosphate (DMAPP), geranyl pyrophosphate
isopentenyl pyrophosphate and (GPP) and squalene shown. Some intermediates are omitted for clarity.
dimethylallyl pyrophosphate.[70] These
precursors can be made in different ways. In animals and archaea, the mevalonate pathway produces these
compounds from acetyl-CoA,[71] while in plants and bacteria the non-mevalonate pathway uses pyruvate and
glyceraldehyde 3-phosphate as substrates.[70][72] One important reaction that uses these activated isoprene donors is
steroid biosynthesis. Here, the isoprene units are joined together to make squalene and then folded up and formed
into a set of rings to make lanosterol.[73] Lanosterol can then be converted into other steroids such as cholesterol and
ergosterol.[73][74]

Proteins
Organisms vary in their ability to synthesize the 20 common amino acids. Most bacteria and plants can synthesize all
twenty, but mammals can only synthesize eleven nonessential amino acids, so nine essential amino acids must be
obtained from food.[7] Some simple parasites, such as the bacteria Mycoplasma pneumoniae, lack all amino acid
synthesis and take their amino acids directly from their hosts.[75] All amino acids are synthesized from intermediates
in glycolysis, the citric acid cycle, or the pentose phosphate pathway. Nitrogen is provided by glutamate and
glutamine. Amino acid synthesis depends on the formation of the appropriate alpha-keto acid, which is then
transaminated to form an amino acid.[76]
Amino acids are made into proteins by being joined together in a chain by peptide bonds. Each different protein has
a unique sequence of amino acid residues: this is its primary structure. Just as the letters of the alphabet can be
Metabolism 246

combined to form an almost endless variety of words, amino acids can be linked in varying sequences to form a huge
variety of proteins. Proteins are made from amino acids that have been activated by attachment to a transfer RNA
molecule through an ester bond. This aminoacyl-tRNA precursor is produced in an ATP-dependent reaction carried
out by an aminoacyl tRNA synthetase.[77] This aminoacyl-tRNA is then a substrate for the ribosome, which joins the
amino acid onto the elongating protein chain, using the sequence information in a messenger RNA.[78]

Nucleotide synthesis and salvage


Nucleotides are made from amino acids, carbon dioxide and formic acid in pathways that require large amounts of
metabolic energy.[79] Consequently, most organisms have efficient systems to salvage preformed nucleotides.[79][80]
Purines are synthesized as nucleosides (bases attached to ribose). Both adenine and guanine are made from the
precursor nucleoside inosine monophosphate, which is synthesized using atoms from the amino acids glycine,
glutamine, and aspartic acid, as well as formate transferred from the coenzyme tetrahydrofolate. Pyrimidines, on the
other hand, are synthesized from the base orotate, which is formed from glutamine and aspartate.[81]

Xenobiotics and redox metabolism


All organisms are constantly exposed to compounds that they cannot use as foods and would be harmful if they
accumulated in cells, as they have no metabolic function. These potentially damaging compounds are called
xenobiotics.[82] Xenobiotics such as synthetic drugs, natural poisons and antibiotics are detoxified by a set of
xenobiotic-metabolizing enzymes. In humans, these include cytochrome P450 oxidases,[83]
UDP-glucuronosyltransferases,[84] and glutathione S-transferases.[85] This system of enzymes acts in three stages to
firstly oxidize the xenobiotic (phase I) and then conjugate water-soluble groups onto the molecule (phase II). The
modified water-soluble xenobiotic can then be pumped out of cells and in multicellular organisms may be further
metabolized before being excreted (phase III). In ecology, these reactions are particularly important in microbial
biodegradation of pollutants and the bioremediation of contaminated land and oil spills.[86] Many of these microbial
reactions are shared with multicellular organisms, but due to the incredible diversity of types of microbes these
organisms are able to deal with a far wider range of xenobiotics than multicellular organisms, and can degrade even
persistent organic pollutants such as organochloride compounds.[87]
A related problem for aerobic organisms is oxidative stress.[88] Here, processes including oxidative phosphorylation
and the formation of disulfide bonds during protein folding produce reactive oxygen species such as hydrogen
peroxide.[89] These damaging oxidants are removed by antioxidant metabolites such as glutathione and enzymes
such as catalases and peroxidases.[90][91]

Thermodynamics of living organisms


Living organisms must obey the laws of thermodynamics, which describe the transfer of heat and work. The second
law of thermodynamics states that in any closed system, the amount of entropy (disorder) will tend to increase.
Although living organisms' amazing complexity appears to contradict this law, life is possible as all organisms are
open systems that exchange matter and energy with their surroundings. Thus living systems are not in equilibrium,
but instead are dissipative systems that maintain their state of high complexity by causing a larger increase in the
entropy of their environments.[92] The metabolism of a cell achieves this by coupling the spontaneous processes of
catabolism to the non-spontaneous processes of anabolism. In thermodynamic terms, metabolism maintains order by
creating disorder.[93]
Metabolism 247

Regulation and control


As the environments of most organisms are constantly changing, the reactions of metabolism must be finely
regulated to maintain a constant set of conditions within cells, a condition called homeostasis.[94][95] Metabolic
regulation also allows organisms to respond to signals and interact actively with their environments.[96] Two closely
linked concepts are important for understanding how metabolic pathways are controlled. Firstly, the regulation of an
enzyme in a pathway is how its activity is increased and decreased in response to signals. Secondly, the control
exerted by this enzyme is the effect that these changes in its activity have on the overall rate of the pathway (the flux
through the pathway).[97] For example, an enzyme may show large changes in activity (i.e. it is highly regulated) but
if these changes have little effect on the flux of a metabolic pathway, then this enzyme is not involved in the control
of the pathway.[98]
There are multiple levels of metabolic
regulation. In intrinsic regulation, the
metabolic pathway self-regulates to respond
to changes in the levels of substrates or
products; for example, a decrease in the
amount of product can increase the flux
through the pathway to compensate.[97] This
type of regulation often involves allosteric
regulation of the activities of multiple
enzymes in the pathway.[99] Extrinsic
control involves a cell in a multicellular
Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor
organism changing its metabolism in
(1), which in turn starts many protein activation cascades (2). These include:
response to signals from other cells. These translocation of Glut-4 transporter to the plasma membrane and influx of glucose
signals are usually in the form of soluble (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
messengers such as hormones and growth
factors and are detected by specific receptors on the cell surface.[100] These signals are then transmitted inside the
cell by second messenger systems that often involved the phosphorylation of proteins.[101]

A very well understood example of extrinsic control is the regulation of glucose metabolism by the hormone
insulin.[102] Insulin is produced in response to rises in blood glucose levels. Binding of the hormone to insulin
receptors on cells then activates a cascade of protein kinases that cause the cells to take up glucose and convert it into
storage molecules such as fatty acids and glycogen.[103] The metabolism of glycogen is controlled by activity of
phosphorylase, the enzyme that breaks down glycogen, and glycogen synthase, the enzyme that makes it. These
enzymes are regulated in a reciprocal fashion, with phosphorylation inhibiting glycogen synthase, but activating
phosphorylase. Insulin causes glycogen synthesis by activating protein phosphatases and producing a decrease in the
phosphorylation of these enzymes.[104]
Metabolism 248

Evolution
The central pathways of metabolism
described above, such as glycolysis
and the citric acid cycle, are present in
all three domains of living things and
were present in the last universal
ancestor.[3][105] This universal
ancestral cell was prokaryotic and
probably a methanogen that had
extensive amino acid, nucleotide,
carbohydrate and lipid
[106][107]
metabolism. The retention of
these ancient pathways during later
evolution may be the result of these
reactions being an optimal solution to
Evolutionary tree showing the common ancestry of organisms from all three domains of their particular metabolic problems,
life. Bacteria are colored blue, eukaryotes red, and archaea green. Relative positions of with pathways such as glycolysis and
some of the phyla included are shown around the tree.
the citric acid cycle producing their
end products highly efficiently and in a
[4][5]
minimal number of steps. Mutation changes that affect non-coding DNA segments may merely affect the
metabolic efficiency of the individual for whom the mutation occurs.[108] The first pathways of enzyme-based
metabolism may have been parts of purine nucleotide metabolism, with previous metabolic pathways being part of
the ancient RNA world.[109]

Many models have been proposed to describe the mechanisms by which novel metabolic pathways evolve. These
include the sequential addition of novel enzymes to a short ancestral pathway, the duplication and then divergence of
entire pathways as well as the recruitment of pre-existing enzymes and their assembly into a novel reaction
pathway.[110] The relative importance of these mechanisms is unclear, but genomic studies have shown that enzymes
in a pathway are likely to have a shared ancestry, suggesting that many pathways have evolved in a step-by-step
fashion with novel functions being created from pre-existing steps in the pathway.[111] An alternative model comes
from studies that trace the evolution of proteins' structures in metabolic networks, this has suggested that enzymes
are pervasively recruited, borrowing enzymes to perform similar functions in different metabolic pathways (evident
in the MANET database)[112] These recruitment processes result in an evolutionary enzymatic mosaic.[113] A third
possibility is that some parts of metabolism might exist as "modules" that can be reused in different pathways and
perform similar functions on different molecules.[114]

As well as the evolution of new metabolic pathways, evolution can also cause the loss of metabolic functions. For
example, in some parasites metabolic processes that are not essential for survival are lost and preformed amino acids,
nucleotides and carbohydrates may instead be scavenged from the host.[115] Similar reduced metabolic capabilities
are seen in endosymbiotic organisms.[116]
Metabolism 249

Investigation and manipulation


Classically, metabolism is studied by a
reductionist approach that focuses on a
single metabolic pathway. Particularly
valuable is the use of radioactive tracers at
the whole-organism, tissue and cellular
levels, which define the paths from
precursors to final products by identifying
radioactively labelled intermediates and
products.[117] The enzymes that catalyze
these chemical reactions can then be
purified and their kinetics and responses to
inhibitors investigated. A parallel approach
is to identify the small molecules in a cell or
tissue; the complete set of these molecules is
called the metabolome. Overall, these
studies give a good view of the structure and
function of simple metabolic pathways, but
are inadequate when applied to more
complex systems such as the metabolism of
a complete cell.[118]
Metabolic network of the Arabidopsis thaliana citric acid cycle. Enzymes and
metabolites are shown as red squares and the interactions between them as black
An idea of the complexity of the metabolic
lines.
networks in cells that contain thousands of
different enzymes is given by the figure
showing the interactions between just 43 proteins and 40 metabolites to the right: the sequences of genomes provide
lists containing anything up to 45,000 genes.[119] However, it is now possible to use this genomic data to reconstruct
complete networks of biochemical reactions and produce more holistic mathematical models that may explain and
predict their behavior.[120] These models are especially powerful when used to integrate the pathway and metabolite
data obtained through classical methods with data on gene expression from proteomic and DNA microarray
studies.[121] Using these techniques, a model of human metabolism has now been produced, which will guide future
drug discovery and biochemical research.[122] These models are now being used in network analysis, to classify
human diseases into groups that share common proteins or metabolites.[123][124]

Bacterial metabolic networks are a striking example of bow-tie[125][126][127] organization, an architecture able to
input a wide range of nutrients and produce a large variety of products and complex macromolecules using a
relatively few intermediate common currencies.
A major technological application of this information is metabolic engineering. Here, organisms such as yeast, plants
or bacteria are genetically modified to make them more useful in biotechnology and aid the production of drugs such
as antibiotics or industrial chemicals such as 1,3-propanediol and shikimic acid.[128] These genetic modifications
usually aim to reduce the amount of energy used to produce the product, increase yields and reduce the production of
wastes.[129]
Metabolism 250

History
The term metabolism is derived from the Greek Μεταβολισμός –
"Metabolismos" for "change", or "overthrow".[130] The history of the
scientific study of metabolism spans several centuries and has moved from
examining whole animals in early studies, to examining individual metabolic
reactions in modern biochemistry. The first controlled experiments in human
metabolism were published by Santorio Santorio in 1614 in his book Ars de
statica medicina.[131] He described how he weighed himself before and after
eating, sleep, working, sex, fasting, drinking, and excreting. He found that
most of the food he took in was lost through what he called "insensible
perspiration".

In these early studies, the mechanisms of these metabolic processes had not
been identified and a vital force was thought to animate living tissue.[132] In
the 19th century, when studying the fermentation of sugar to alcohol by yeast,
Louis Pasteur concluded that fermentation was catalyzed by substances
within the yeast cells he called "ferments". He wrote that "alcoholic Santorio Santorio in his steelyard
balance, from Ars de statica medicina,
fermentation is an act correlated with the life and organization of the yeast
first published 1614
cells, not with the death or putrefaction of the cells."[133] This discovery,
along with the publication by Friedrich Wöhler in 1828 of the chemical
synthesis of urea,[134] notable for being the first organic compound prepared from wholly inorganic precursors,
proved that the organic compounds and chemical reactions found in cells were no different in principle than any
other part of chemistry.

It was the discovery of enzymes at the beginning of the 20th century by Eduard Buchner that separated the study of
the chemical reactions of metabolism from the biological study of cells, and marked the beginnings of
biochemistry.[135] The mass of biochemical knowledge grew rapidly throughout the early 20th century. One of the
most prolific of these modern biochemists was Hans Krebs who made huge contributions to the study of
metabolism.[136] He discovered the urea cycle and later, working with Hans Kornberg, the citric acid cycle and the
glyoxylate cycle.[137][62] Modern biochemical research has been greatly aided by the development of new techniques
such as chromatography, X-ray diffraction, NMR spectroscopy, radioisotopic labelling, electron microscopy and
molecular dynamics simulations. These techniques have allowed the discovery and detailed analysis of the many
molecules and metabolic pathways in cells.

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Further reading
Introductory
• Rose, S. and Mileusnic, R., The Chemistry of Life. (Penguin Press Science, 1999), ISBN 0-14-027273-9
• Schneider, E. D. and Sagan, D., Into the Cool: Energy Flow, Thermodynamics, and Life. (University Of Chicago
Press, 2005), ISBN 0-226-73936-8
• Lane, N., Oxygen: The Molecule that Made the World. (Oxford University Press, USA, 2004), ISBN
0-19-860783-0
Advanced
• Price, N. and Stevens, L., Fundamentals of Enzymology: Cell and Molecular Biology of Catalytic Proteins.
(Oxford University Press, 1999), ISBN 0-19-850229-X
• Berg, J. Tymoczko, J. and Stryer, L., Biochemistry. (W. H. Freeman and Company, 2002), ISBN 0-7167-4955-6
Metabolism 256

• Cox, M. and Nelson, D. L., Lehninger Principles of Biochemistry. (Palgrave Macmillan, 2004), ISBN
0-7167-4339-6
• Brock, T. D. Madigan, M. T. Martinko, J. and Parker J., Brock's Biology of Microorganisms. (Benjamin
Cummings, 2002), ISBN 0-13-066271-2
• Da Silva, J.J.R.F. and Williams, R. J. P., The Biological Chemistry of the Elements: The Inorganic Chemistry of
Life. (Clarendon Press, 1991), ISBN 0-19-855598-9
• Nicholls, D. G. and Ferguson, S. J., Bioenergetics. (Academic Press Inc., 2002), ISBN 0-12-518121-3

External links
biochemical families: proteins (amino acids/intermediates) · nucleic acids (constituents/intermediates) · carbohydrates (glycoproteins, alcohols,
glycosides)
lipids (fatty acids/intermediates, phospholipids, steroids, sphingolipids, eicosanoids) · tetrapyrroles/intermediates

Microbial ecology
Microbial ecology is the ecology of microorganisms: their relationship with one another and with their environment.
It concerns the three major domains of life — Eukaryota, Archaea, and Bacteria — as well as viruses.[1]
Microorganisms, by their omnipresence, impact the entire biosphere. Microbial life plays a primary role in regulating
biogeochemical systems in virtually all of our planet's environments, including some of the most extreme, from
frozen environments and acidic lakes, to hydrothermal vents at the bottom of deepest oceans, and some of the most
familiar, such as the human small intestine.[2][3] As a consequence of the quantitative magnitude of microbial life
(Whitman and coworkers calculated 5 × 10 30 cells, eight orders of magnitude greater than the number of stars in the
observable universe [4][5] ) microbes, by virtue of their biomass alone, constitute the single largest carbon sink.[6]
Aside from carbon fixation, microorganisms’ key collective metabolic processes (including nitrogen fixation,
methane metabolism, and sulfur metabolism) control global biogeochemical cycling.[7] The immensity of
microorganisms’ production is such that, even in the total absence of eukaryotic life these processes would likely
continue unchanged.[8]

Symbiosis
Microbes, especially bacteria, often engage in symbiotic relationships (either positive or negative) with other
organisms, and these relationships affect the ecosystem. One example of these fundamental symbioses are
chloroplasts, which allow eukaryotes to conduct photosynthesis. Chloroplasts are considered to be endosymbiotic
cyanobacteria, a group of bacteria that are thought to be the origins of aerobic photosynthesis. Some theories state
that this invention coincides with a major shift in the early earth's atmosphere, from a reducing atmosphere to an
oxygen-rich atmosphere. Some theories go as far as saying that this shift in the balance of gases might have triggered
a global ice-age known as the Snowball Earth.
Microbial ecology 257

Roles
They are the backbone of all ecosystems, but even more so in the zones where light cannot approach and thus
photosynthesis cannot be the basic means to collect energy. In such zones, chemosynthetic microbes provide energy
and carbon to the other organisms.
Other microbes are decomposers, with the ability to recycle nutrients from other organisms' waste poducts. These
microbes play a vital role in biogeochemical cycles.[6] The nitrogen cycle, the phosphorus cycle and the carbon cycle
all depend on microorganisms in one way or another. For example, nitrogen which makes up 78% of the planet's
atmosphere is "indigestible" for most organisms, and the flow of nitrogen into the biosphere depends on a microbial
process called fixation.
Due to the high level of horizontal gene transfer among microbial communities,[9] microbial ecology is also of
importance to studies of evolution.[10]

Microbial resource management


Biotechnology may be used alongside microbial ecology to address a number of environmental and economic
challenges. For example, molecular techniques such as community fingerprinting can be used to track changes in
microbial communities over time or assess their biodiversity. Managing the carbon cycle to sequester carbon dioxide
and prevent excess methanogenesis is important in mitigating global warming, and the prospects of bioenergy are
being expanded by the development of microbial fuel cells. Microbial resource management advocates a more
progressive attitude towards disease, whereby biological control agents are favoured over attempts at eradication.
Fluxes in microbial communities has to be better characterized for this field's potential to be realised.[11] In addition,
there are also clinical implications, as marine microbial symbioses are a valuable source of existing and novel
antimicrobial agents, and thus offer another line of inquiry in the evolutionary arms race of antibiotic resistance, a
pressing concern for researchers.[12]

References
[1] Ogilvie, LA; Hirsch, PR (editor) (2012). Microbial Ecological Theory: Current Perspectives. Caister Academic Press.
ISBN 978-1-908230-09-6.
[2] Bowler, C.; D. M Karl, R. R Colwell (2009). "Microbial oceanography in a sea of opportunity". Nature 458 (7244): 180–184.(subscription
required)
[3] Konopka, Allan (2009-11). "What is microbial community ecology?" (http:/ / www. ncbi. nlm. nih. gov/ pubmed/ 19657372). The ISME
Journal 3 (11): 1223–1230. doi:10.1038/ismej.2009.88. ISSN 1751-7370. PMID 19657372. . Retrieved 2011-02-27.
[4] Whitman, W B; D C Coleman, W J Wiebe (1998-06-09). "Prokaryotes: the unseen majority". Proceedings of the National Academy of
Sciences of the United States of America 95 (12): 6578–6583. doi:10.1073/pnas.95.12.6578. ISSN 0027-8424. PMC 33863. PMID 9618454.
[5] "number of stars in the observable universe - Wolfram" (http:/ / www. wolframalpha. com/ input/ ?i=number+ of+ stars+ in+ the+
observable+ universe). . Retrieved 2011-11-22.
[6] Fenchel, Tom (1998). Bacterial biogeochemistry : the ecophysiology of mineral cycling (2nd ed. ed.). San Diego: Academic Press.
[7] DeLong, Edward F. (2009-05). "The microbial ocean from genomes to biomes". Nature 459 (7244): 200–206. doi:10.1038/nature08059.
ISSN 0028-0836. PMID 19444206.(subscription required)
[8] Lupp, Claudia (2009-05). "Microbial oceanography". Nature 459 (7244): 179. doi:10.1038/459179a.(subscription required)
[9] McDaniel, Lauren D.; Elizabeth Young, Jennifer Delaney, Fabian Ruhnau, Kim B. Ritchie, John H. Paul (2010-10-01). "High Frequency of
Horizontal Gene Transfer in the Oceans". Science 330 (6000): 50. doi:10.1126/science.1192243.(subscription required)
[10] Smets, B. F; T. Barkay (2005). "Horizontal gene transfer: perspectives at a crossroads of scientific disciplines". Nature Reviews
Microbiology 3 (9): 675–678.(subscription required)
[11] W. Verstraete (May 2007). "Microbial ecology and environmental biotechnology". The ISME Journal 1 (1): 4–8. doi:10.1038/ismej.2007.7.
PMID 18043608.(subscription required)
[12] Ott, J. (2005). "Marine Microbial Thiotrophic Ectosymbioses". Oceanography and marine biology. 42: 95–118.
Microbial ecology 258

External links
• International Society for Microbial Biology (http://www.microbes.org/)
• DeLong, Edward F. (2007-05-28). "Microbial Communities in Nature and Laboratory - Interview". Journal of
Visualized Experiments : JoVE (4). doi:10.3791/202. ISSN 1940-087X.

Microbial genetics
Microbial genetics is a subject area within microbiology and genetic engineering. It studies the genetics of very
small (micro) organisms. This involves the study of the genotype of microbial species and also the expression system
in the form of phenotypes.It also involves the study of genetic processes taking place in these micro organisms i.e.,
recombination etc.

Microbiology
Microbiology (from Greek μῑκρος, mīkros, "small"; βίος, bios, "life";
and -λογία, -logia) is the study of microscopic organisms, which are
defined as any living organism that is either a single cell (unicellular),
a cell cluster, or has no cells at all (acellular).[1] This includes
eukaryotes, such as fungi and protists, and prokaryotes. Viruses[2] and
prions, though not strictly classed as living organisms, are also studied.
Microbiology typically includes the study of the immune system, or
immunology. Generally, immune systems interact with pathogenic
microbes; these two disciplines often intersect which is why many
An agar plate streaked with microorganisms
colleges offer a paired degree such as "Microbiology and
Immunology".

Microbiology is a broad term which includes virology, mycology, parasitology, bacteriology, immunology and other
branches. A microbiologist is a specialist in microbiology and these related topics.
Microbiological procedures usually must be aseptic, and use a variety of tools such as light microscopes with a
combination of stains and dyes.The most commonly used stains are called basic dyes, and are composed of
positively charged molecules. Two types of basic dyes are simple stains and differential stains. Simple stains consist
of one dye and identify the shape and multicell arrangement of bacteria. Methylene blue, carbolfuchsin, safranin, and
crystal violet are some of the most commonly used stains. Differential stains on the other hand, use two or more dyes
and help us to distinguish between two or more organisms or two or different parts of the organism. Types of
differential stains are gram, Ziehl-Neelsen acid fast, negative, flagella, and endospore. Specific constraints apply to
particular fields of microbiology, such as parasitology, which heavily utilizes the light microscopy, whereas
microscopy's utility in bacteriology is limited due to the similarity is many cells physiology. Indeed, most means of
differentiating bacteria is based on growth or biochemical reactions. Virology has very little need for light
microscopes, relying on almost entirely molecular means. Mycology relies on all technologies the most evenly, from
macroscopy to molecular techniques.
Microbiology is actively researched, and the field is advancing continuously. It is estimated that only about one
percent of the microorganisms present in a given environmental sample are culturable[3] and the number of bacterial
cells and species on Earth is still not possible to be determined, recent estimates indicate that it can be extremely
high (5 Exp 30 cells on Earth, unknown number of species). Although microbes were directly observed over three
hundred years ago, the precise determination, quantitation and description of its functions is far to be complete,
Microbiology 259

given the overwhelming diversity detected by genetic and culture-independent means.

History

Ancient
The existence of microorganisms was hypothesized for many centuries before their actual discovery. The existence
of unseen microbiological life was postulated by Jainism which is based on Mahavira’s teachings as early as 6th
century BCE.[4] Paul Dundas notes that Mahavira asserted existence of unseen microbiological creatures living in
earth, water, air and fire.[5] Jain scriptures also describe nigodas which are sub-microscopic creatures living in large
clusters and having a very short life and are said to pervade each and every part of the universe, even in tissues of
plants and flesh of animals.[6] The Roman Marcus Terentius Varro made references to microbes when he warned
against locating a homestead in the vicinity of swamps "because there are bred certain minute creatures which cannot
be seen by the eyes, which float in the air and enter the body through the mouth and nose and there by cause serious
diseases."[7]
In 1546 Girolamo Fracastoro proposed that epidemic diseases were caused by transferable seedlike entities that
could transmit infection by direct or indirect contact, or vehicle transmission.[8]
However, early claims about the existence of microorganisms were speculative, and not based on microscopic
observation. Actual observation and discovery of microbes had to await the invention of the microscope in the 17th
century.

Modern
In 1676, Anton van Leeuwenhoek observed bacteria and other
microorganisms, using a single-lens microscope of his own design.[1]
While Van Leeuwenhoek is often cited as the first to observe microbes,
Robert Hooke made the first recorded microscopic observation, of the
fruiting bodies of molds, in 1665.[9] The first observation of microbes
using a microscope is generally credited to the Dutch draper and
haberdasher, Antonie van Leeuwenhoek, who lived for most of his life
in Delft, Holland. It has, however, been suggested that a Jesuit priest
called Athanasius Kircher was the first to observe micro-organisms.[10]
He was among the first to design magic lanterns for projection
purposes, so he must have been well acquainted with the properties of
lenses.[10] One of his books contains a chapter in Latin, which reads in
translation – ‘Concerning the wonderful structure of things in nature,
investigated by Microscope. Here, he wrote ‘who would believe that Anton van Leeuwenhoek, is considered to be the
first to observe microorganisms using a
vinegar and milk abound with an innumerable multitude of worms.’ He
microscope.
also noted that putrid material is full of innumerable creeping
animalcule. These observations antedate Robert Hooke’s Micrographia
by nearly 20 years and were published some 29 years before van Leeuwenhoek saw protozoa and 37 years before he
described having seen bacteria.[10]
Microbiology 260

The field of bacteriology (later a subdiscipline of microbiology) was


founded in the 19th century by Ferdinand Cohn, a botanist whose
studies on algae and photosynthetic bacteria led him to describe several
bacteria including Bacillus and Beggiatoa. Cohn was also the first to
formulate a scheme for the taxonomic classification of bacteria and
discover spores.[11] Louis Pasteur and Robert Koch were
contemporaries of Cohn’s and are often considered to be the father of
microbiology[10] and medical microbiology, respectively.[12] Pasteur is
most famous for his series of experiments designed to disprove the
then widely held theory of spontaneous generation, thereby solidifying
microbiology’s identity as a biological science.[13] Pasteur also
designed methods for food preservation (pasteurization) and vaccines
against several diseases such as anthrax, fowl cholera and rabies.[1]
Innovative laboratory glassware and experimental
Koch is best known for his contributions to the germ theory of disease,
methods developed by Louis Pasteur and other proving that specific diseases were caused by specific pathogenic
biologists contributed to the young field of micro-organisms. He developed a series of criteria that have become
bacteriology in the late 19th century.
known as the Koch's postulates. Koch was one of the first scientists to
focus on the isolation of bacteria in pure culture resulting in his
description of several novel bacteria including Mycobacterium tuberculosis, the causative agent of tuberculosis.[1]

While Pasteur and Koch are often considered the founders of microbiology, their work did not accurately reflect the
true diversity of the microbial world because of their exclusive focus on micro-organisms having direct medical
relevance. It was not until the late 19th century and the work of Martinus Beijerinck and Sergei Winogradsky, the
founders of general microbiology (an older term encompassing aspects of microbial physiology, diversity and
ecology), that the true breadth of microbiology was revealed.[1] Beijerinck made two major contributions to
microbiology: the discovery of viruses and the development of enrichment culture techniques.[14] While his work on
the Tobacco Mosaic Virus established the basic principles of virology, it was his development of enrichment
culturing that had the most immediate impact on microbiology by allowing for the cultivation of a wide range of
microbes with wildly different physiologies. Winogradsky was the first to develop the concept of chemolithotrophy
and to thereby reveal the essential role played by micro-organisms in geochemical processes.[15] He was responsible
for the first isolation and description of both nitrifying and nitrogen-fixing bacteria.[1]

Branches
The branches of microbiology can be classified into pure and applied sciences.[16] Microbiology can be also
classified based on taxonomy, in the cases of bacteriology, mycology, protozoology, and phycology. There is
considerable overlap between the specific branches of microbiology with each other and with other disciplines.

Pure microbiology

Taxonomic arrangement
• Bacteriology: The study of bacteria.
• Mycology: The study of fungi.
• Protozoology: The study of protozoa.
• Phycology (or algology): The study of algae.
• Parasitology: The study of parasites.
• Immunology: The study of the immune system.
• Virology: The study of the viruses.
Microbiology 261

• Nematology:The study of the nematodes

Integrative arrangement
• Microbial cytology: The study of microscopic and submicroscopic details of microorganisms.
• Microbial physiology: The study of how the microbial cell functions biochemically. Includes the study of
microbial growth, microbial metabolism and microbial cell structure.
• Microbial ecology: The relationship between microorganisms and their environment.
• Microbial genetics: The study of how genes are organized and regulated in microbes in relation to their cellular
functions. Closely related to the field of molecular biology.
• Cellular microbiology: A discipline bridging microbiology and cell biology.
• Evolutionary microbiology: The study of the evolution of microbes. This field can be subdivided into:
• Microbial taxonomy: The naming and classification of microorganisms.
• Microbial systematics: The study of the diversity and genetic relationship of microorganisms.
• Generation microbiology: The study of those microorganisms that have the same characters as their parents.
• Systems microbiology: A discipline bridging systems biology and microbiology.
• Molecular microbiology: The study of the molecular principles of the physiological processes in microorganisms.

Other
• Nano microbiology: The study of those microorganisms on nano level.
• Exo microbiology (or Astro microbiology): The study of microorganisms in outer space.
• Weapon microbiology: The study of those microorganisms which are using in weapon industries.

Applied microbiology
• Medical microbiology: The study of the pathogenic microbes and the role of microbes in human illness. Includes
the study of microbial pathogenesis and epidemiology and is related to the study of disease pathology and
immunology.
• Pharmaceutical microbiology: The study of microorganisms that are related to the production of antibiotics,
enzymes, vitamins,vaccines, and other pharmaceutical products and that cause pharmaceutical contamination and
spoil.
• Industrial microbiology: The exploitation of microbes for use in industrial processes. Examples include industrial
fermentation and wastewater treatment. Closely linked to the biotechnology industry. This field also includes
brewing, an important application of microbiology.
• Microbial biotechnology: The manipulation of microorganisms at the genetic and molecular level to generate
useful products.
• Food microbiology and Dairy microbiology: The study of microorganisms causing food spoilage and foodborne
illness. Using microorganisms to produce foods, for example by fermentation.
• Agricultural microbiology: The study of agriculturally relevant microorganisms. This field can be further
classified into the following:
• Plant microbiology and Plant pathology: The study of the interactions between microorganisms and plants and
plant pathogens.
• Soil microbiology: The study of those microorganisms that are found in soil.
• Veterinary microbiology: The study of the role in microbes in veterinary medicine or animal taxonomy.
• Environmental microbiology: The study of the function and diversity of microbes in their natural environments.
This involves the characterization of key bacterial habitats such as the rhizosphere and phyllosphere, soil and
groundwater ecosystems, open oceans or extreme environments (extremophiles). This field includes other
branches of microbiology such as:
Microbiology 262

• Microbial ecology
• Microbially-mediated nutrient cycling
• Geomicrobiology
• Microbial diversity
• Bioremediation
• Water microbiology (or Aquatic microbiology): The study of those microorganisms that are found in water.
• Aeromicrobiology (or Air microbiology): The study of airborne microorganisms.
• Epidemiology: The study of the incidence, spread, and control of disease.

Benefits
Whilst there are undoubtedly some who fear all microbes due to the
association of some microbes with various human illnesses, many
microbes are also responsible for numerous beneficial processes such
as industrial fermentation (e.g. the production of alcohol, vinegar and
dairy products), antibiotic production and as vehicles for cloning in
more complex organisms such as plants. Scientists have also exploited
their knowledge of microbes to produce biotechnologically important
enzymes such as Taq polymerase, reporter genes for use in other
genetic systems and novel molecular biology techniques such as the Fermenting tanks with yeast being used to brew
beer
yeast two-hybrid system.

Bacteria can be used for the industrial production of amino acids. Corynebacterium glutamicum is one of the most
important bacterial species with an annual production of more than two million tons of amino acids, mainly
L-glutamate and L-lysine.[17]
A variety of biopolymers, such as polysaccharides, polyesters, and polyamides, are produced by microorganisms.
Microorganisms are used for the biotechnological production of biopolymers with tailored properties suitable for
high-value medical application such as tissue engineering and drug delivery. Microorganisms are used for the
biosynthesis of xanthan, alginate, cellulose, cyanophycin, poly(gamma-glutamic acid), levan, hyaluronic acid,
organic acids, oligosaccharides and polysaccharide, and polyhydroxyalkanoates.[18]
Microorganisms are beneficial for microbial biodegradation or bioremediation of domestic, agricultural and
industrial wastes and subsurface pollution in soils, sediments and marine environments. The ability of each
microorganism to degrade toxic waste depends on the nature of each contaminant. Since sites typically have multiple
pollutant types, the most effective approach to microbial biodegradation is to use a mixture of bacterial species and
strains, each specific to the biodegradation of one or more types of contaminants.[19]
There are also various claims concerning the contributions to human and animal health by consuming probiotics
(bacteria potentially beneficial to the digestive system) and/or prebiotics (substances consumed to promote the
growth of probiotic microorganisms).[20]
Recent research has suggested that microorganisms could be useful in the treatment of cancer. Various strains of
non-pathogenic clostridia can infiltrate and replicate within solid tumors. Clostridial vectors can be safely
administered and their potential to deliver therapeutic proteins has been demonstrated in a variety of preclinical
models.[21]
Microbiology 263

References
[1] Madigan M, Martinko J (editors) (2006). Brock Biology of Microorganisms (13th ed.). Pearson Education. p. 1096. ISBN 0-321-73551-X.
[2] Rice G (2007-03-27). "Are Viruses Alive?" (http:/ / serc. carleton. edu/ microbelife/ yellowstone/ viruslive. html). . Retrieved 2007-07-23.
[3] Nitesh RAI, Ludwig W, Schleifer KH (2011). "Phylogenetic identification and in situ detection of individual microbial cells without
cultivation". Microbiology Rev. 59 (1): 143–169. PMC 239358. PMID 7535888.
[4] Mahavira is dated 599 BC - 527 BC. See. Dundas, Paul; John Hinnels ed. (2002). The Jain. London: Routledge. ISBN 0-415-26606-8. p. 24
[5] Dundas, Paul (2002) p. 88
[6] *Jaini, Padmanabh (1998). The Jaina Path of Purification. New Delhi: Motilal Banarsidass. ISBN 81-208-1578-5. p. 109
[7] Varro on Agriculture 1, xii Loeb.
[8] Fracastoro, Girolamo (1546), De Contagione et Contagiosis Morbis transl. Wilmer Cave Wright (1930). New York: G.P. Putnam's
[9] Gest H (2005). "The remarkable vision of Robert Hooke (1635-1703): first observer of the microbial world". Perspect. Biol. Med. 48 (2):
266–72. doi:10.1353/pbm.2005.0053. PMID 15834198.
[10] Wainwright, Milton (2003). An Alternative View of the Early History of Microbiology. "Advances in Applied Microbiology Volume 52".
Advances in applied microbiology. Advances in Applied Microbiology 52: 333–55. doi:10.1016/S0065-2164(03)01013-X.
ISBN 978-0-12-002654-8. PMID 12964250.
[11] Drews G (1999). "Ferdinand Cohn, among the Founder of Microbiology". ASM News 65 (8): 547.
[12] Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
[13] Bordenave G (2003). "Louis Pasteur (1822-1895)". Microbes Infect. 5 (6): 553–60. doi:10.1016/S1286-4579(03)00075-3. PMID 12758285.
[14] Johnson J (2001) [1998]. "Martinus Willem Beijerinck" (http:/ / www. apsnet. org/ Education/ feature/ TMV/ intro. html). APSnet. American
Phytopathological Society. . Retrieved May 2, 2010.
[15] Paustian T, Roberts G (2009). "Beijerinck and Winogradsky Initiate the Field of Environmental Microbiology" (http:/ / www.
microbiologytext. com/ index. php?module=Book& func=displayarticle& art_id=32). Through the Microscope: A Look at All Things Small
(3rd ed.). Textbook Consortia. § 1–14. . Retrieved May 2, 2010.
[16] Pharmaceutical Microbiology Principles and Applications (http:/ / books. google. com/ books?id=VN9Oj2MKTkQC& pg=SA1-PA1).
Nirali Prakashan. pp. 1.1–1.2. ISBN 978-81-85790-61-9. . Retrieved 18 June 2011.
[17] Burkovski A (editor). (2008). Corynebacteria: Genomics and Molecular Biology (http:/ / www. horizonpress. com/ cory). Caister Academic
Press. . .
[18] Rehm BHA (editor). (2008). Microbial Production of Biopolymers and Polymer Precursors: Applications and Perspectives (http:/ / www.
horizonpress. com/ biopolymers). Caister Academic Press. . .
[19] Diaz E (editor). (2008). Microbial Biodegradation: Genomics and Molecular Biology (http:/ / www. horizonpress. com/ biod) (1st ed.).
Caister Academic Press. . .
[20] Tannock GW (editor). (2005). Probiotics and Prebiotics: Scientific Aspects (http:/ / www. horizonpress. com/ pro3). Caister Academic
Press. . .
[21] Mengesha et al. (2009). "Clostridia in Anti-tumor Therapy". Clostridia: Molecular Biology in the Post-genomic Era. Caister Academic
Press. ISBN 978-1-904455-38-7.

External links
• Microbiology (http://www.bbc.co.uk/programmes/b007753d) on In Our Time at the BBC. ( listen now (http:/
/www.bbc.co.uk/iplayer/console/b007753d/In_Our_Time_Microbiology))
• Bacteriology Made Easy | Medchrome (http://medchrome.com/basic-science/microbiology/bacteriology-easy/
)
• Online lectures in microbiology (http://media.med.sc.edu/microbiology2007/) University of South Carolina
• Microbiology Online (http://www.ocean.edu/academics/programs_of_study/science/MicrobiologyOnline.
htm)
• Online Microbiology textbook (http://www.microbiologytext.com/index.php?module=Book&func=toc&
book_id=4)
• Online Medical Microbiology textbook (http://www.microbiologybook.org/)
• Institute of Microbiology of the Swiss Federal Institute of Technology (http://www.micro.biol.ethz.ch/)
• Annual Review of Microbiology (http://arjournals.annualreviews.org/loi/micro/)
Mitochondrion 264

Mitochondrion
In cell biology, a mitochondrion
(plural mitochondria) is a
membrane-enclosed organelle found in
most eukaryotic cells.[1] These
organelles range from 0.5 to
1.0 micrometer (μm) in diameter.
Mitochondria are sometimes described
as "cellular power plants" because they
generate most of the cell's supply of
adenosine triphosphate (ATP), used as
a source of chemical energy.[2] In
addition to supplying cellular energy,
mitochondria are involved in a range Two mitochondria from mammalian lung tissue displaying their
matrix and membranes as shown by electron microscopy
of other processes, such as signaling,
cellular differentiation, cell death, as
well as the control of the cell cycle and
cell growth.[3] Mitochondria have been
implicated in several human diseases,
including mitochondrial disorders[4]
and cardiac dysfunction,[5] and may
play a role in the aging process. The
word mitochondrion comes from the
Greek μίτος mitos, thread, + χονδρίον
chondrion, granule.

Several characteristics make


mitochondria unique. The number of
mitochondria in a cell varies widely by
Schematic of typical animal cell, showing subcellular components. Organelles: (1)
organism and tissue type. Many cells
Nucleolus (2) Nucleus (3) Ribosomes (little dots) (4) Vesicle (5) Rough endoplasmic
have only a single mitochondrion, reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) Smooth ER (9) Mitochondria
whereas others can contain several (10) Vacuole (11) Cytosol (12) Lysosome (13) Centrioles within Centrosome
[6][7]
thousand mitochondria. The
organelle is composed of compartments that carry out specialized functions. These compartments or regions include
the outer membrane, the intermembrane space, the inner membrane, and the cristae and matrix. Mitochondrial
proteins vary depending on the tissue and the species. In humans, 615 distinct types of proteins have been identified
from cardiac mitochondria,[8] whereas in Murinae (rats), 940 proteins encoded by distinct genes have been
reported.[9] The mitochondrial proteome is thought to be dynamically regulated.[10] Although most of a cell's DNA is
contained in the cell nucleus, the mitochondrion has its own independent genome. Further, its DNA shows
substantial similarity to bacterial genomes.[11]

History
The first observations of intracellular structures that probably represent mitochondria were published in the
1840s.[12] Richard Altmann, in 1894, established them as cell organelles and called them 'bioblasts'.[12] The term
'mitochondria' itself was coined by Carl Benda in 1898.[12] Friedrich Meves, in 1904, made the first recorded
Mitochondrion 265

observation of mitochondria in plants (Nymphea).[12] B. F. Kingsbury, in 1912, first related them with cell
respiration, but almost exclusively based on morphological observations.[12] Philip Siekevitz, in 1957, dubbed them
'the powerhouse of the cell'.[13]

Structure
A mitochondrion contains outer and
inner membranes composed of
phospholipid bilayers and proteins.[6]
The two membranes, however, have
different properties. Because of this
double-membraned organization, there
are five distinct compartments within
the mitochondrion. They are:

1. the outer mitochondrial membrane,


2. the intermembrane space (the space
between the outer and inner
membranes),
3. the inner mitochondrial membrane,
4. the cristae space (formed by
infoldings of the inner membrane), and
5. the matrix (space within the inner membrane).

Outer membrane
The outer mitochondrial membrane, which encloses the entire organelle, has a protein-to-phospholipid ratio similar
to that of the eukaryotic plasma membrane (about 1:1 by weight). It contains large numbers of integral proteins
called porins. These porins form channels that allow molecules 5000 Daltons or less in molecular weight to freely
diffuse from one side of the membrane to the other.[6] Larger proteins can enter the mitochondrion if a signaling
sequence at their N-terminus binds to a large multisubunit protein called translocase of the outer membrane, which
then actively moves them across the membrane.[14] Disruption of the outer membrane permits proteins in the
intermembrane space to leak into the cytosol, leading to certain cell death.[15] The mitochondrial outer membrane
can associate with the endoplasmic reticulum (ER) membrane, in a structure called MAM (mitochondria-associated
ER-membrane). This is important in the ER-mitochondria calcium signaling and involved in the transfer of lipids
between the ER and mitochondria.[16]

Intermembrane space
The intermembrane space is the space between the outer membrane and the inner membrane. Because the outer
membrane is freely permeable to small molecules, the concentrations of small molecules such as ions and sugars in
the intermembrane space is the same as the cytosol.[6] However, large proteins must have a specific signaling
sequence to be transported across the outer membrane, so the protein composition of this space is different from the
protein composition of the cytosol. One protein that is localized to the intermembrane space in this way is
cytochrome c.[15]
Mitochondrion 266

Inner membrane
The inner mitochondrial membrane contains proteins with five types of functions:[6]
1. Those that perform the redox reactions of oxidative phosphorylation
2. ATP synthase, which generates ATP in the matrix
3. Specific transport proteins that regulate metabolite passage into and out of the matrix
4. Protein import machinery.
5. Mitochondria fusion and fission protein
It contains more than 151 different polypeptides, and has a very high protein-to-phospholipid ratio (more than 3:1 by
weight, which is about 1 protein for 15 phospholipids). The inner membrane is home to around 1/5 of the total
protein in a mitochondrion.[6] In addition, the inner membrane is rich in an unusual phospholipid, cardiolipin. This
phospholipid was originally discovered in cow hearts in 1942, and is usually characteristic of mitochondrial and
bacterial plasma membranes.[17] Cardiolipin contains four fatty acids rather than two, and may help to make the
inner membrane impermeable.[6] Unlike the outer membrane, the inner membrane doesn't contain porins, and is
highly impermeable to all molecules. Almost all ions and molecules require special membrane transporters to enter
or exit the matrix. Proteins are ferried into the matrix via the translocase of the inner membrane (TIM) complex or
via Oxa1.[14] In addition, there is a membrane potential across the inner membrane, formed by the action of the
enzymes of the electron transport chain.

Cristae

The inner mitochondrial membrane is


compartmentalized into numerous cristae, which
expand the surface area of the inner mitochondrial
membrane, enhancing its ability to produce ATP. For
typical liver mitochondria, the area of the inner
membrane is about five times as great as the outer
membrane. This ratio is variable and mitochondria
from cells that have a greater demand for ATP, such as
muscle cells, contain even more cristae. These folds are
studded with small round bodies known as F1 particles
or oxysomes. These are not simple random folds but
Cross-sectional image of cristae in rat liver mitochondrion to
rather invaginations of the inner membrane, which can demonstrate the likely 3D structure and relationship to the inner
affect overall chemiosmotic function.[18] membrane.

One recent mathematical modeling study has suggested


that the optical properties of the cristae in filamentous mitochondria may affect the generation and propagation of
light within the tissue.[19]

Matrix
The matrix is the space enclosed by the inner membrane. It contains about 2/3 of the total protein in a
mitochondrion.[6] The matrix is important in the production of ATP with the aid of the ATP synthase contained in
the inner membrane. The matrix contains a highly-concentrated mixture of hundreds of enzymes, special
mitochondrial ribosomes, tRNA, and several copies of the mitochondrial DNA genome. Of the enzymes, the major
functions include oxidation of pyruvate and fatty acids, and the citric acid cycle.[6]
Mitochondria have their own genetic material, and the machinery to manufacture their own RNAs and proteins (see:
protein biosynthesis). A published human mitochondrial DNA sequence revealed 16,569 base pairs encoding 37 total
genes: 22 tRNA, 2 rRNA, and 13 peptide genes.[20] The 13 mitochondrial peptides in humans are integrated into the
Mitochondrion 267

inner mitochondrial membrane, along with proteins encoded by genes that reside in the host cell's nucleus.

Mitochondria-associated ER membrane (MAM)


The mitochondria-associated ER membrane (MAM) is another structural element that is increasingly recognized for
its critical role in cellular physiology and homeostasis. Once considered a technical snag in cell fractionation
techniques, the alleged ER vesicle contaminants that invariably appeared in the mitochondrial fraction have been
re-identified as membranous structures derived from the MAM—the interface between mitochondria and the ER.[21]
Physical coupling between these two organelles had previously been observed in electron micrographs and has more
recently been probed with fluorescence microscopy.[21] Such studies estimate that at the MAM, which may comprise
up to 20% of the mitochondrial outer membrane, the ER and mitochondria are separated by a mere 10-25 nm and
held together by protein tethering complexes.[21][22][23]
Purified MAM from subcellular fractionation has shown to be enriched in enzymes involved in phospholipid
exchange, in addition to channels associated with Ca2+ signaling.[21][23] These hints of a prominent role for the
MAM in the regulation of cellular lipid stores and signal transduction have been borne out, with significant
implications for mitochondrial-associated cellular phenomena, as discussed below. Not only has the MAM provided
insight into the mechanistic basis underlying such physiological processes as intrinsic apoptosis and the propagation
of calcium signaling, but it also favors a more refined view of the mitochondria. Though often seen as static, isolated
‘powerhouses’ hijacked for cellular metabolism through an ancient endosymbiotic event, the evolution of the MAM
underscores the extent to which mitochondria have been integrated into overall cellular physiology, with intimate
physical and functional coupling to the endomembrane system.

Phospholipid transfer
The MAM is enriched in enzymes involved in lipid biosynthesis, such as phosphatidylserine synthase on the ER face
and phosphatidylserine decarboxylase on the mitochondrial face.[24][25] Because mitochondria are dynamic
organelles constantly undergoing fission and fusion events, they require a constant and well-regulated supply of
phospholipids for membrane integrity.[26][27] But mitochondria are not only a destination for the phospholipids they
finish synthesis of; rather, this organelle also plays a role in inter-organelle trafficking of the intermediates and
products of phospholipid biosynthetic pathways, ceramide and cholesterol metabolism, and glycosphingolipid
anabolism.[25][27]
Such trafficking capacity depends on the MAM, which has been shown to facilitate transfer of lipid intermediates
between organelles.[24] In contrast to the standard vesicular mechanism of lipid transfer, evidence indicates that the
physical proximity of the ER and mitochondrial membranes at the MAM allows for lipid flipping between opposed
bilayers.[27] Despite this unusual and seemingly energetically unfavorable mechanism, such transport does not
require ATP.[27] Instead, it has been shown to be dependent on a multiprotein tethering structure termed the
ER-mitochondria encounter structure, or ERMES, although it remains unclear whether this structure directly
mediates lipid transfer or is required to keep the membranes in sufficiently close proximity to lower the energy
barrier for lipid flipping.[27][28]
The MAM may also be part of the secretory pathway, in addition to its role in intracellular lipid trafficking. In
particular, the MAM appears to be an intermediate destination between the rough ER and the Golgi in the pathway
that leads to very-low-density lipoprotein, or VLDL, assembly and secretion.[25][29] The MAM thus serves as a
critical metabolic and trafficking hub in lipid metabolism.
Mitochondrion 268

Calcium signaling
A critical role for the ER in calcium signaling was acknowledged before such a role for the mitochondria was widely
accepted, in part because the low affinity of Ca2+ channels localized to the outer mitochondrial membrane seemed to
fly in the face of this organelle’s purported responsiveness to changes in intracellular Ca2+ flux.[21] But the presence
of the MAM resolves this apparent contradiction: the close physical association between the two organelles results in
Ca2+ microdomains at contact points that facilitate efficient Ca2+ transmission from the ER to the mitochondria.[21]
Transmission occurs in response to so-called “Ca2+ puffs” generated by spontaneous clustering and activation of
IP3R, a canonical ER membrane Ca2+ channel.[21][22]
The fate of these puffs—in particular, whether they remain restricted to isolated locales or integrated into Ca2+
waves for propagation throughout the cell—is determined in large part by MAM dynamics. Although reuptake of
Ca2+ by the ER (concomitant with its release) modulates the intensity of the puffs, thus insulating mitochondria to a
certain degree from high Ca2+ exposure, the MAM often serves as a firewall that essentially buffers Ca2+ puffs by
acting as a sink into which free ions released into the cytosol can be funneled.[21][30][31] This Ca2+ tunneling occurs
through the low-affinity Ca2+ receptor VDAC1, which recently has been shown to be physically tethered to the IP3R
clusters on the ER membrane and enriched at the MAM.[21][22][32] The ability of mitochondria to serve as a Ca2+
sink is a result of the electrochemical gradient generated during oxidative phosphorylation, which makes tunneling
of the cation an exergonic process.[32]
But transmission of Ca2+ is not unidirectional; rather, it is a two-way street. The properties of the Ca2+ pump SERCA
and the channel IP3R present on the ER membrane facilitate feedback regulation coordinated by MAM function. In
particular, clearance of Ca2+ by the MAM allows for spatio-temporal patterning of Ca2+ signaling because Ca2+
alters IP3R activity in a biphasic manner.[21] SERCA is likewise affected by mitochondrial feedback: uptake of Ca2+
by the MAM stimulates ATP production, thus providing energy that enables SERCA to reload the ER with Ca2+ for
continued Ca2+ efflux at the MAM.[30][32] Thus, the MAM is not a passive buffer for Ca2+ puffs; rather it helps
modulate further Ca2+ signaling through feedback loops that affect ER dynamics.
Regulating ER release of Ca2+ at the MAM is especially critical because only a certain window of Ca2+ uptake
sustains the mitochondria, and consequently the cell, at homeostasis. Sufficient intraorganelle Ca2+ signaling is
required to stimulate metabolism by activating dehydrogenase enzymes critical to flux through the citric acid
cycle.[33] However, once Ca2+ signaling in the mitochondria passes a certain threshold, it stimulates the intrinsic
pathway of apoptosis in part by collapsing the mitochondrial membrane potential required for metabolism.[21]
Studies examining the role of pro- and anti-apoptotic factors support this model; for example, the anti-apoptotic
factor Bcl-2 has been shown to interact with IP3Rs to reduce Ca2+ filling of the ER, leading to reduced efflux at the
MAM and preventing collapse of the mitochondrial membrane potential post-apoptotic stimuli.[21] Given the need
for such fine regulation of Ca2+ signaling, it is perhaps unsurprising that dysregulated mitochondrial Ca2+ has been
implicated in several neurodegenerative diseases, while the catalogue of tumor suppressors includes a few that are
enriched at the MAM.[32]

Molecular basis for tethering


Recently advances in the identification of the tethers between the mitochondrial and ER membranes suggest that the
scaffolding function of the molecular elements involved is secondary to other, non-structural functions. ERMES, a
multiprotein complex of interacting ER- and mitochondrial-resident membrane proteins, is required for lipid transfer
at the MAM and exemplifies this principle. One of its components, for example, is also a constituent of the protein
complex required for insertion of transmembrane beta-barrel proteins into the lipid bilayer.[27] Other proteins
implicated in scaffolding likewise have functions independent of structural tethering at the MAM; for example,
ER-resident and mitochondrial-resident mitofusins form heterocomplexes that regulate the number of inter-organelle
contact sites, although mitofusins were first identified for their role in fission and fusion events between individual
mitochondria.[21] Glucose-related protein 75 (grp75) is another dual-function protein. In addition to the matrix pool
Mitochondrion 269

of grp75, a portion serves as a chaperone that physically links the mitochondrial and ER Ca2+ channels VDAC and
IP3R for efficient Ca2+ transmission at the MAM.[21][22] Another prominent tether is Sigma-1R, another chaperone
whose stabilization of ER-resident IP3R has been proposed to preserve communication at the MAM during the
metabolic stress response.[21][32]

Perspective

The MAM is a critical signaling, metabolic, and trafficking hub in the


cell that allows for the integration of ER and mitochondrial physiology.
Coupling between these organelles is not simply structural but
functional as well and critical for overall cellular physiology and
homeostasis. The MAM thus offers a perspective on mitochondria that
diverges from the traditional view of this organelle as a static, isolated
unit appropriated for its metabolic capacity by the cell. Instead, this
mitochondrial-ER interface emphasizes the integration of the
mitochondria, the product of an endosymbiotic event, into diverse
cellular processes.
Model of the multimeric tethering complex,
ERMES.

Organization and distribution


Mitochondria are found in nearly all eukaryotes. They vary in number and location according to cell type. A single
mitochondrion is often found in unicellular organisms. Conversely, numerous mitochondria are found in human liver
cells, with about 1000–2000 mitochondria per cell, making up 1/5 of the cell volume.[6] The mitochondrial content
of otherwise similar cells can vary substantially in size and membrane potential,[34] with differences arising from
sources including uneven partitioning at cell divisions, leading to extrinsic differences in ATP levels and
downstream cellular processes.[35] The mitochondria can be found nestled between myofibrils of muscle or wrapped
around the sperm flagellum.[6] Often they form a complex 3D branching network inside the cell with the
cytoskeleton. The association with the cytoskeleton determines mitochondrial shape, which can affect the function as
well.[36] Recent evidence suggests that vimentin, one of the components of the cytoskeleton, is critical to the
association with the cytoskeleton.[37]

Function
The most prominent roles of mitochondria are to produce the energy currency of the cell, ATP (i.e., phosphorylation
of ADP), through respiration, and to regulate cellular metabolism.[7] The central set of reactions involved in ATP
production are collectively known as the citric acid cycle, or the Krebs Cycle. However, the mitochondrion has many
other functions in addition to the production of ATP.

Energy conversion
A dominant role for the mitochondria is the production of ATP, as reflected by the large number of proteins in the
inner membrane for this task. This is done by oxidizing the major products of glucose, pyruvate, and NADH, which
are produced in the cytosol.[7] This process of cellular respiration, also known as aerobic respiration, is dependent on
the presence of oxygen. When oxygen is limited, the glycolytic products will be metabolized by anaerobic
fermentation, a process that is independent of the mitochondria.[7] The production of ATP from glucose has an
approximately 13-times higher yield during aerobic respiration compared to fermentation.[38] Recently it has been
Mitochondrion 270

shown that plant mitochondria can produce a limited amount of ATP without oxygen by using the alternate substrate
nitrite.[39]

Pyruvate and the citric acid cycle


Each pyruvate molecule produced by glycolysis is actively transported across the inner mitochondrial membrane,
and into the matrix where it is oxidized and combined with coenzyme A to form CO2, acetyl-CoA, and NADH.[7]
The acetyl-CoA is the primary substrate to enter the citric acid cycle, also known as the tricarboxylic acid (TCA)
cycle or Krebs cycle. The enzymes of the citric acid cycle are located in the mitochondrial matrix, with the exception
of succinate dehydrogenase, which is bound to the inner mitochondrial membrane as part of Complex II.[40] The
citric acid cycle oxidizes the acetyl-CoA to carbon dioxide, and, in the process, produces reduced cofactors (three
molecules of NADH and one molecule of FADH2) that are a source of electrons for the electron transport chain, and
a molecule of GTP (that is readily converted to an ATP).[7]

NADH and FADH2: the electron transport chain

The redox energy from NADH and FADH2


is transferred to oxygen (O2) in several steps
via the electron transport chain. These
energy-rich molecules are produced within
the matrix via the citric acid cycle but are
also produced in the cytoplasm by
glycolysis. Reducing equivalents from the
cytoplasm can be imported via the
malate-aspartate shuttle system of antiporter
proteins or feed into the electron transport
chain using a glycerol phosphate shuttle.[7] Diagram of the electron transport chain in the mitonchondrial intermembrane space
Protein complexes in the inner membrane
(NADH dehydrogenase, cytochrome c reductase, and cytochrome c oxidase) perform the transfer and the
incremental release of energy is used to pump protons (H+) into the intermembrane space. This process is efficient,
but a small percentage of electrons may prematurely reduce oxygen, forming reactive oxygen species such as
superoxide.[7] This can cause oxidative stress in the mitochondria and may contribute to the decline in mitochondrial
function associated with the aging process.[41]

As the proton concentration increases in the intermembrane space, a strong electrochemical gradient is established
across the inner membrane. The protons can return to the matrix through the ATP synthase complex, and their
potential energy is used to synthesize ATP from ADP and inorganic phosphate (Pi).[7] This process is called
chemiosmosis, and was first described by Peter Mitchell[42][43] who was awarded the 1978 Nobel Prize in Chemistry
for his work. Later, part of the 1997 Nobel Prize in Chemistry was awarded to Paul D. Boyer and John E. Walker for
their clarification of the working mechanism of ATP synthase.[44]

Heat production
Under certain conditions, protons can re-enter the mitochondrial matrix without contributing to ATP synthesis. This
process is known as proton leak or mitochondrial uncoupling and is due to the facilitated diffusion of protons into
the matrix. The process results in the unharnessed potential energy of the proton electrochemical gradient being
released as heat.[7] The process is mediated by a proton channel called thermogenin, or UCP1.[45] Thermogenin is a
33kDa protein first discovered in 1973.[46] Thermogenin is primarily found in brown adipose tissue, or brown fat,
and is responsible for non-shivering thermogenesis. Brown adipose tissue is found in mammals, and is at its highest
levels in early life and in hibernating animals. In humans, brown adipose tissue is present at birth and decreases with
Mitochondrion 271

age.[45]

Storage of calcium ions


The concentrations of free calcium in the
cell can regulate an array of reactions and is
important for signal transduction in the cell.
Mitochondria can transiently store calcium,
a contributing process for the cell's
homeostasis of calcium.[47] In fact, their
ability to rapidly take in calcium for later
release makes them very good "cytosolic
buffers" for calcium.[48][49][50] The
endoplasmic reticulum (ER) is the most
Mitochondria (M) within a chondrocyte stained for calcium as shown by electron
significant storage site of calcium, and there
microscopy.
is a significant interplay between the
mitochondrion and ER with regard to
calcium.[51] The calcium is taken up into the matrix by a calcium uniporter on the inner mitochondrial membrane.[52]
It is primarily driven by the mitochondrial membrane potential.[47] Release of this calcium back into the cell's
interior can occur via a sodium-calcium exchange protein or via "calcium-induced-calcium-release" pathways.[52]
This can initiate calcium spikes or calcium waves with large changes in the membrane potential. These can activate a
series of second messenger system proteins that can coordinate processes such as neurotransmitter release in nerve
cells and release of hormones in endocrine cells.

Ca2+ influx to the mitochondrial matrix has recently been implicated as a mechanism to regulate respiratory
bioenergetics by allowing the electrochemical potential across the membrane to transiently "pulse" from
ΔΨ-dominated to pH-dominated, facilitating a reduction of oxidative stress.[53]

Additional functions
Mitochondria play a central role in many other metabolic tasks, such as:
• Regulation of the membrane potential[7]
• Apoptosis-programmed cell death[54]
• Calcium signaling (including calcium-evoked apoptosis)[55]
• Regulation of cellular metabolism[56]
• Certain heme synthesis reactions[57] (see also: porphyrin)
• Steroid synthesis.[48]
Some mitochondrial functions are performed only in specific types of cells. For example, mitochondria in liver cells
contain enzymes that allow them to detoxify ammonia, a waste product of protein metabolism. A mutation in the
genes regulating any of these functions can result in mitochondrial diseases.

Cellular proliferation regulation


The relationship between cellular proliferation and mitochondria has been investigated using cervical cancer Hela
cells. Tumor cells require an ample amount of ATP (Adenosine triphosphate) in order to synthesize bioactive
compounds such as lipids, proteins, and nucleotides for rapid cell proliferation.[58] The majority of ATP in tumor
cells is generated via the Oxidative Phosphorylation pathway (OxPhos).[59] Interference with OxPhos have shown to
cause cell cycle arrest suggesting that mitochondria plays a role in cell proliferation.[59] Mitochondrial ATP
production is also vital for cell division in addition to other basic functions in the cell including the regulation of cell
Mitochondrion 272

volume, solute concentration, and cellular architecture.[60][61][62] ATP levels differ at various stages of the cell cycle
suggesting that there is a relationship between the abundance of ATP and the cell's ability to enter a new cell cyle.[63]
ATP’s role in the basic functions of the cell make the cell cycle sensitive to changes in the availability of
mitochondrial derived ATP.[63] The variation in ATP levels at different stages of the cell cycle support the
hypothesis that mitochondria plays an important role in cell cycle regulation.[63] Although the specific mechanisms
between mitochondria and the cell cycle regulation is not well understood, studies have shown that low energy cell
cycle checkpoints monitor the energy capability before committing to another round of cell division.[64]

Origin
Mitochondria have many features in common with prokaryotes. As a result, they are thought to be originally derived
from endosymbiotic prokaryotes.
A mitochondrion contains DNA, which is organized as several copies of a single, circular chromosome. This
mitochondrial chromosome contains genes for redox proteins such as those of the respiratory chain. The CoRR
hypothesis proposes that this co-location is required for redox regulation. The mitochondrial genome codes for some
RNAs of ribosomes, and the twenty-two tRNAs necessary for the translation of messenger RNAs into protein. The
circular structure is also found in prokaryotes, and the similarity is extended by the fact that mitochondrial DNA is
organized with a variant genetic code similar to that of Proteobacteria.[65] This suggests that their ancestor, the
so-called proto-mitochondrion, was a member of the Proteobacteria.[65] In particular, the proto-mitochondrion was
probably closely related to the rickettsia.[66] However, the exact relationship of the ancestor of mitochondria to the
alpha-proteobacteria and whether the mitochondrion was formed at the same time or after the nucleus, remains
controversial.[67]
A recent study[68] by researchers of the University of Hawaiʻi at Mānoa and the Oregon State University indicates
that the SAR11 clade of bacteria shares a relatively recent common ancestor with the mitochondria existing in most
eukaryotic cells.

Phylogeny of Rickettsiales

Other alphaproteobacteria Rhodospirillales, Sphingomonadales, Rhodobacteraceae, Rhizobiales, etc.

SAR11 clade Pelagibacter ubique

Mitochondria

Ehrlichia

Anaplasma
Rickettsiales Anaplasmataceae

Wolbachia

Neorickettsia

Rickettsiaceae Rickettsia
Mitochondrion 273

[69]
Robust phylogeny of Rickettsiales from Williams et al. (2007)

The ribosomes coded for by the mitochondrial DNA are similar to those from bacteria in size and structure.[70] They
closely resemble the bacterial 70S ribosome and not the 80S cytoplasmic ribosomes, which are coded for by nuclear
DNA.
The endosymbiotic relationship of mitochondria with their host cells was popularized by Lynn Margulis.[71] The
endosymbiotic hypothesis suggests that mitochondria descended from bacteria that somehow survived endocytosis
by another cell, and became incorporated into the cytoplasm. The ability of these bacteria to conduct respiration in
host cells that had relied on glycolysis and fermentation would have provided a considerable evolutionary advantage.
In a similar manner, host cells with symbiotic bacteria capable of photosynthesis would have had an advantage. The
incorporation of symbiotes would have increased the number of environments in which the cells could survive. This
symbiotic relationship probably developed 1.7[72] to 2[73] billion years ago.
A few groups of unicellular eukaryotes lack mitochondria: the microsporidians, metamonads, and archamoebae.[74]
These groups appear as the most primitive eukaryotes on phylogenetic trees constructed using rRNA information,
which once suggested that they appeared before the origin of mitochondria. However, this is now known to be an
artifact of long-branch attraction—they are derived groups and retain genes or organelles derived from mitochondria
(e.g., mitosomes and hydrogenosomes).[1]

Genome
The human mitochondrial genome is a circular DNA molecule of about
16 kilobases.[75] It encodes 37 genes: 13 for subunits of respiratory
complexes I, III, IV and V, 22 for mitochondrial tRNA (for the 20
standard amino acids, plus an extra gene for leucine and serine), and 2
for rRNA.[75] One mitochondrion can contain two to ten copies of its
DNA.[76]

As in prokaryotes, there is a very high proportion of coding DNA and


an absence of repeats. Mitochondrial genes are transcribed as
multigenic transcripts, which are cleaved and polyadenylated to yield
mature mRNAs. Not all proteins necessary for mitochondrial function Mitochondrial DNA.

are encoded by the mitochondrial genome; most are coded by genes in


the cell nucleus and the corresponding proteins are imported into the mitochondrion.[20] The exact number of genes
encoded by the nucleus and the mitochondrial genome differs between species. In general, mitochondrial genomes
are circular, although exceptions have been reported.[77] In general, mitochondrial DNA lacks introns, as is the case
in the human mitochondrial genome;[20] however, introns have been observed in some eukaryotic mitochondrial
DNA,[78] such as that of yeast[79] and protists,[80] including Dictyostelium discoideum.[81]

In animals the mitochondrial genome is typically a single circular chromosome that is approximately 16-kb long and
has 37 genes. The genes, while highly conserved, may vary in location. Curiously, this pattern is not found in the
human body louse (Pediculus humanus). Instead this mitochondrial genome is arranged in 18 minicircular
chromosomes, each of which is 3–4 kb long and has one to three genes.[82] This pattern is also found in other
sucking lice, but not in chewing lice. Recombination has been shown to occur between the minichromosomes. The
reason for this difference is not known.
While slight variations on the standard code had been predicted earlier,[83] none was discovered until 1979, when
researchers studying human mitochondrial genes determined that they used an alternative code.[84] Many slight
variants have been discovered since,[85] including various alternative mitochondrial codes.[86] Further, the AUA,
AUC, and AUU codons are all allowable start codons.
Mitochondrion 274

Exceptions to the universal genetic code (UGC) in mitochondria[6]


Organism Codon Standard Mitochondria

Mammals AGA, AGG Arginine Stop codon

Invertebrates AGA, AGG Arginine Serine

Fungi CUA Leucine Threonine

All of the above AUA Isoleucine Methionine

UGA Stop codon Tryptophan

Some of these differences should be regarded as pseudo-changes in the genetic code due to the phenomenon of RNA
editing, which is common in mitochondria. In higher plants, it was thought that CGG encoded for tryptophan and not
arginine; however, the codon in the processed RNA was discovered to be the UGG codon, consistent with the
universal genetic code for tryptophan.[87] Of note, the arthropod mitochondrial genetic code has undergone parallel
evolution within a phylum, with some organisms uniquely translating AGG to lysine.[88]
Mitochondrial genomes have far fewer genes than the bacteria from which they are thought to be descended.
Although some have been lost altogether, many have been transferred to the nucleus, such as the respiratory complex
II protein subunits.[75] This is thought to be relatively common over evolutionary time. A few organisms, such as the
Cryptosporidium, actually have mitochondria that lack any DNA, presumably because all their genes have been lost
or transferred.[89] In Cryptosporidium, the mitochondria have an altered ATP generation system that renders the
parasite resistant to many classical mitochondrial inhibitors such as cyanide, azide, and atovaquone.[89]

Replication and inheritance


Mitochondria divide by binary fission similar to bacterial cell division; unlike bacteria, however, mitochondria can
also fuse with other mitochondria.[75][90] The regulation of this division differs between eukaryotes. In many
single-celled eukaryotes, their growth and division is linked to the cell cycle. For example, a single mitochondrion
may divide synchronously with the nucleus. This division and segregation process must be tightly controlled so that
each daughter cell receives at least one mitochondrion. In other eukaryotes (in mammals for example), mitochondria
may replicate their DNA and divide mainly in response to the energy needs of the cell, rather than in phase with the
cell cycle. When the energy needs of a cell are high, mitochondria grow and divide. When the energy use is low,
mitochondria are destroyed or become inactive. In such examples, and in contrast to the situation in many single
celled eukaryotes, mitochondria are apparently randomly distributed to the daughter cells during the division of the
cytoplasm. Understanding of mitochondrial dynamics, which is described as the balance between mitochondrial
fusion and fission, has revealed that functional and structural alterations in mitochondrial morphology are important
factors in pathologies associated with several disease conditions.[91]
An individual's mitochondrial genes are not inherited by the same mechanism as nuclear genes. At fertilization of an
egg cell by a sperm, the egg nucleus and sperm nucleus each contribute equally to the genetic makeup of the zygote
nucleus. In contrast, the mitochondria, and therefore the mitochondrial DNA, usually comes from the egg only. The
sperm's mitochondria enter the egg but do not contribute genetic information to the embryo.[92] Instead, paternal
mitochondria are marked with ubiquitin to select them for later destruction inside the embryo.[93] The egg cell
contains relatively few mitochondria, but it is these mitochondria that survive and divide to populate the cells of the
adult organism. Mitochondria are, therefore, in most cases inherited down the female line, known as maternal
inheritance. This mode is seen in most organisms including all animals. However, mitochondria in some species can
sometimes be inherited paternally. This is the norm among certain coniferous plants, although not in pine trees and
yew trees.[94] It has been suggested that it occurs at a very low level in humans.[95]
Uniparental inheritance leads to little opportunity for genetic recombination between different lineages of
mitochondria, although a single mitochondrion can contain 2–10 copies of its DNA.[76] For this reason,
Mitochondrion 275

mitochondrial DNA usually is thought to reproduce by binary fission. What recombination does take place maintains
genetic integrity rather than maintaining diversity. However, there are studies showing evidence of recombination in
mitochondrial DNA. It is clear that the enzymes necessary for recombination are present in mammalian cells.[96]
Further, evidence suggests that animal mitochondria can undergo recombination.[97] The data are a bit more
controversial in humans, although indirect evidence of recombination exists.[98][99] If recombination does not occur,
the whole mitochondrial DNA sequence represents a single haplotype, which makes it useful for studying the
evolutionary history of populations.

Population genetic studies


The near-absence of genetic recombination in mitochondrial DNA makes it a useful source of information for
scientists involved in population genetics and evolutionary biology.[100] Because all the mitochondrial DNA is
inherited as a single unit, or haplotype, the relationships between mitochondrial DNA from different individuals can
be represented as a gene tree. Patterns in these gene trees can be used to infer the evolutionary history of populations.
The classic example of this is in human evolutionary genetics, where the molecular clock can be used to provide a
recent date for mitochondrial Eve.[101][102] This is often interpreted as strong support for a recent modern human
expansion out of Africa.[103] Another human example is the sequencing of mitochondrial DNA from Neanderthal
bones. The relatively large evolutionary distance between the mitochondrial DNA sequences of Neanderthals and
living humans has been interpreted as evidence for lack of interbreeding between Neanderthals and
anatomically-modern humans.[104]
However, mitochondrial DNA reflects the history of only females in a population and so may not represent the
history of the population as a whole. This can be partially overcome by the use of paternal genetic sequences, such as
the non-recombining region of the Y-chromosome.[103] In a broader sense, only studies that also include nuclear
DNA can provide a comprehensive evolutionary history of a population.[105]

Dysfunction and disease

Mitochondrial diseases
With their central place in cell metabolism, damage — and subsequent dysfunction — in mitochondria is an
important factor in a wide range of human diseases. Mitochondrial disorders often present themselves as
neurological disorders, but can manifest as myopathy, diabetes, multiple endocrinopathy, or a variety of other
systemic manifestations.[106] Diseases caused by mutation in the mtDNA include Kearns-Sayre syndrome, MELAS
syndrome and Leber's hereditary optic neuropathy.[107] In the vast majority of cases, these diseases are transmitted
by a female to her children, as the zygote derives its mitochondria and hence its mtDNA from the ovum. Diseases
such as Kearns-Sayre syndrome, Pearson's syndrome, and progressive external ophthalmoplegia are thought to be
due to large-scale mtDNA rearrangements, whereas other diseases such as MELAS syndrome, Leber's hereditary
optic neuropathy, myoclonic epilepsy with ragged red fibers (MERRF), and others are due to point mutations in
mtDNA.[106]
In other diseases, defects in nuclear genes lead to dysfunction of mitochondrial proteins. This is the case in
Friedreich's ataxia, hereditary spastic paraplegia, and Wilson's disease.[108] These diseases are inherited in a
dominance relationship, as applies to most other genetic diseases. A variety of disorders can be caused by nuclear
mutations of oxidative phosphorylation enzymes, such as coenzyme Q10 deficiency and Barth syndrome.[106]
Environmental influences may interact with hereditary predispositions and cause mitochondrial disease. For
example, there may be a link between pesticide exposure and the later onset of Parkinson's disease.[109][110]
Other pathologies with etiology involving mitochondrial dysfunction include schizophrenia, bipolar disorder,
dementia, Alzheimer's disease,[111] Parkinson's disease, epilepsy, stroke, cardiovascular disease, retinitis pigmentosa,
and diabetes mellitus.[112][113] A common thread thought to link these seemingly-unrelated conditions is cellular
Mitochondrion 276

damage causing oxidative stress. How exactly mitochondrial dysfunction fits into the etiology of these pathologies is
yet to be elucidated.
Mitochondria-mediated oxidative stress plays a role in cardiomyopathy in Type 2 diabetics. Increased fatty acid
delivery to the heart increases fatty acid uptake by cardiomyocytes, resulting in increased fatty acid oxidation in
these cells. This process increases the reducing equivalents available to the electron transport chain of the
mitochondria, ultimately increasing reactive oxygen species (ROS) production. ROS increases uncoupling proteins
(UCPs) and potentiate proton leakage through the adenine nucleotide translocator (ANT), the combination of which
uncouples the mitochondria. Uncoupling then increases oxygen consumption by the mitochondria, compounding the
increase in fatty acid oxiation. This creates a vicious cycle of uncoupling; furthermore, even though oxygen
consumption increases, ATP synthesis does not increase proportionally because the mitochondria is uncoupled. Less
ATP availability ultimately results in an energy deficit presenting as reduced cardiac efficiency and contractile
dysfunction. To compound the problem, impaired sarcoplasmic reticulum calcium release and reduced mitochondrial
reuptake limits peak cytosolic levels of the important signaling ion during muscle contraction. The decreased
intra-mitochondrial calcium concentration increases dehydrogenase activation and ATP synthesis. So in addition to
lower ATP synthesis due to fatty acid oxidation, ATP synthesis is impaired by poor calcium signaling as well,
causing cardiac problems for diabetics.[114]

Possible relationships to aging


Given the role of mitochondria as the cell's powerhouse, there may be some leakage of the high-energy electrons in
the respiratory chain to form reactive oxygen species. This was thought to result in significant oxidative stress in the
mitochondria with high mutation rates of mitochondrial DNA (mtDNA).[115] Hypothesized links between aging and
oxidative stress are not new and were proposed over 50 years ago.[116] A vicious cycle was thought to occur, as
oxidative stress leads to mitochondrial DNA mutations, which can lead to enzymatic abnormalities and further
oxidative stress. However, recent measurements of the rate of accumulation of mutation observed in mitochondrial
DNA[117] were estimated to be 1 mutation every 7884 years (10^-7 to 10^-9 per base per year, dating back to the
most recent common ancestor of humans and apes), consistent with other estimates of mutation rates of autosomal
dna ( 10^-8 per base per generation[118])
A number of changes can occur to mitochondria during the aging process.[119] Tissues from elderly patients show a
decrease in enzymatic activity of the proteins of the respiratory chain.[120] However, mutated mtDNA can only be
found in about 0.2% of very old cells.[121] Large deletions in the mitochondrial genome have been hypothesized to
lead to high levels of oxidative stress and neuronal death in Parkinson's disease.[122] However, there is much debate
over whether mitochondrial changes are causes of aging or merely characteristics of aging. One notable study in
mice demonstrated shortened lifespan but no increase in reactive oxygen species despite increasing mitochondrial
DNA mutations.[123] However, it has to be noted that aging non-mutant mice do not seem to accumulate a great
number of mutations in mitochondrial DNA imposing a cloud of doubt on the involvement of mitochondrial DNA
mutations in "natural" aging. As a result, the exact relationships between mitochondria, oxidative stress, and aging
have not yet been settled.
Mitochondrion 277

In popular culture
In Madeleine L'Engle's A Wind in the Door, the Farandolae are fictional creatures that live inside mitochondria, and
do circular "dances" around their "trees of origin".

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[100] Castro JA, Picornell A, Ramon M (1998). "Mitochondrial DNA: a tool for populational genetics studies". Int Microbiol. 1 (4): 327–32.
PMID 10943382.
[101] Cann RL, Stoneking M, Wilson AC (1987 January). "Mitochondrial DNA and human evolution". Nature. 325 (6099): 31–36.
doi:10.1038/325031a0. PMID 3025745.
[102] Torroni A, Achilli A, Macaulay V, Richards M, Bandelt HJ (2006). "Harvesting the fruit of the human mtDNA tree". Trends Genet. 22 (6):
339–45. doi:10.1016/j.tig.2006.04.001. PMID 16678300.
[103] Garrigan D, Hammer MF (2006). "Reconstructing human origins in the genomic era". Nat. Rev. Genet. 7 (9): 669–80.
doi:10.1038/nrg1941. PMID 16921345.
[104] Krings M, Stone A, Schmitz RW, Krainitzki H, Stoneking M, Pääbo S (1997). "Neandertal DNA sequences and the origin of modern
humans". Cell 90 (1): 19–30. doi:10.1016/S0092-8674(00)80310-4. PMID 9230299.
[105] Harding RM, Fullerton SM, Griffiths RC, Bond J, Cox MJ, Schneider JA, Moulin DS, Clegg JB (1997 April). "Archaic African and Asian
lineages in the genetic ancestry of modern humans". Am J Hum Genet. 60 (4): 772–89. PMC 1712470. PMID 9106523.
[106] Zeviani M, Di Donato S (2004). "Mitochondrial disorders". Brain. 127 (Pt 10): 2153–2172. doi:10.1093/brain/awh259. PMID 15358637.
[107] Taylor RW, Turnbull DM (2005). "MITOCHONDRIAL DNA MUTATIONS IN HUMAN DISEASE". Nat. Rev. Genet. 6 (5): 389–402.
doi:10.1038/nrg1606. PMC 1762815. PMID 15861210.
[108] Chinnery PF, Schon EA (2003). "Mitochondria". J. Neurol. Neurosurg. Psychiatr. 74 (9): 1188–99. doi:10.1136/jnnp.74.9.1188.
PMC 1738655. PMID 12933917.
[109] Sherer TB, Betarbet R, Greenamyre JT (2002). "Environment, mitochondria, and Parkinson's disease". The Neuroscientist. 8 (3): 192–7.
doi:10.1177/1073858402008003004. PMID 12061498.
[110] Gomez C, Bandez MJ, Navarro A (2007). "Pesticides and impairment of mitochondrial function in relation with the parkinsonian
syndrome". Front. Biosci. 12: 1079–93. doi:10.2741/2128. PMID 17127363.
[111] Lim YA et al. (2010). "Abeta and human amylin share a common toxicity pathway via mitochondrial dysfunction". Proteomics 10 (8):
1621–33. doi:10.1002/pmic.200900651. PMID 20186753.
[112] Schapira AH (2006). "Mitochondrial disease". Lancet 368 (9529): 70–82. doi:10.1016/S0140-6736(06)68970-8. PMID 16815381.
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[113] Pieczenik SR, Neustadt J (2007). "Mitochondrial dysfunction and molecular pathways of disease". Exp. Mol. Pathol. 83 (1): 84–92.
doi:10.1016/j.yexmp.2006.09.008. PMID 17239370.
[114] Bugger H, Abel ED (2010). "Mitochondria in the diabetic heart". Cardiovascular Research 88 (2): 229–240. doi:10.1093/cvr/cvq239.
[115] Richter C, Park J, Ames BN (1988 September). "Normal oxidative damage to mitochondrial and nuclear DNA is extensive". PNAS 85 (17):
6465–6467. doi:10.1073/pnas.85.17.6465. PMC 281993. PMID 3413108.
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pmc/ articles/ PMC2694979/ ?tool=pubmed) Am J Hum Genet. 2009 June 12; 84(6): 740–759.
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156/ 1/ 297. full) Genetics, Vol. 156, 297-304, September 2000
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[121] de Grey, Aubrey (Fall 2004). " Mitochondrial Mutations in Mammalian Aging: An Over-Hasty About-Turn? (http:/ / www. mprize. com/
files/ sens/ polg-PP. pdf)" Rejuvenation Res. 7 (3): 171–4. doi:10.1089/rej.2004.7.171. PMID 15588517.
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515–517. doi:10.1038/ng1769. PMID 16604074.
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doi:10.1073/pnas.0508886102. PMC 1312403. PMID 16332961.

External links
• Mitochondria Atlas (http://www.uni-mainz.de/FB/Medizin/Anatomie/workshop/EM/EMMitoE.html) at
University of Mainz
• Mitochondria Research Portal (http://www.mitochondrial.net) at mitochondrial.net
• Mitochondria: Architecture dictates function (http://www.cytochemistry.net/Cell-biology/mitoch1.htm) at
cytochemistry.net
• Mitochondria links (http://bama.ua.edu/~hsmithso/class/bsc_495/mito-plastids/mito_web.html) at
University of Alabama
• MIP (http://www.mitophysiology.org/) Mitochondrial Physiology Society
• 3D structures of proteins from inner mitochondrial membrane (http://opm.phar.umich.edu/localization.
php?localization=Mitochondrial inner membrane) at University of Michigan
• 3D structures of proteins associated with outer mitochondrial membrane (http://opm.phar.umich.edu/
localization.php?localization=Mitochondrial outer membrane) at University of Michigan
• Mitochondrial Protein Partnership (http://www.mitoproteins.org) at University of Wisconsin
• Mitochondrion - Cell Centered Database (http://ccdb.ucsd.edu/sand/main?stype=lite&
keyword=mitochondrion&Submit=Go&event=display&start=1)
• Mitochondrion Reconstructed by Electron Tomography (http://www.sci.sdsu.edu/TFrey/MitoMovie.htm) at
San Diego State University
• Video Clip of Rat-liver Mitochondrion from Cryo-electron Tomography (http://www.wadsworth.org/databank/
electron/cryomito_dis2.html)
 This article incorporates public domain material from the NCBI document "Science Primer" (http:/ / www. ncbi.
nlm.nih.gov/About/primer/index.html).
Molecular microbiology 282

Molecular microbiology
Molecular microbiology is the branch of microbiology devoted to the study of the molecular principles of the
physiological processes involved in the life cycle of prokaryotic and eukaryotic microorganisms such as bacteria,
viruses, unicellular algae, fungi, and protozoa. This includes gene expression and regulation, genetic transfer, the
synthesis of macromolecules, sub-cellular organization, cell to cell communication, and molecular aspects of
pathogenicity and virulence.
Molecular microbiology is primarily involved in the interactions between the various cell systems of microorganisms
including the interrelationship of DNA, RNA and protein biosynthesis and the manner in which these interactions are
regulated.

Bacteria
Mainly because of their relative simplicity, ease of manipulation and growth in vitro, and importance in medicine,
bacteria were instrumental in the development of molecular biology. The complete genome sequence for a large
number of bacterial species is now available. A list of sequenced prokaryotic genomes is available. Molecular
microbiology techniques are currently being used in the development of new genetically engineered vaccines, in
bioremediation,[1] biotechnology, food microbiology,[2] probiotic research,[3] antibacterial development[4] and
environmental microbiology.[5]
Many bacteria have become model organisms for molecular studies.
Molecular techniques have had a direct influence on the clinical practice of medical microbiology. In many cases
where traditional phenotypic methods of microbial identification and typing are insufficient or time-consuming,
molecular techniques can provide rapid and accurate data, potentially improving clinical outcomes. Specific
examples include:
• 16s rRNA sequencing to provide bacterial identifications
• Pulsed Field Gel Electrophoresis for strain typing of epidemiologically related organisms.
• Direct detection of genes related to resistance mechanisms, such as mecA gene in Staphylococcus aureus

Gene expression and regulation


Bacteria have evolved abilities to regulate gene expression in response to signals in the intracellular and extracellular
environment. Key to this are the diverse macromolecules (proteins or RNA) that sense change through direct
interactions with chemical or physical stimuli.[6]

Bacterial pathogenesis
New infectious diseases are emerging and bacteria-induced illnesses, such as tuberculosis, whooping cough and
typhoid fever, are still a major cause of global mortality. In recent decades the development of molecular biology
and genetic tools has led to extensive studies on the molecular and cellular aspects of the virulence properties of
pathogenic bacteria.[7]
Molecular microbiology 283

Bacterial glycomics
Glycans play diverse roles in bacterial physiology. Progress in the study of bacterial glycomics is advancing rapidly
due to improvements in analytical methodologies and the development of new and innovative approaches for glycan
isolation, characterization and synthesis. Research in bacterial glycomics could lead to the development of novel
drugs, bioactive glycans and glycoconjugate vaccines.[8]

Horizontal gene transfer


Horizontal gene transfer (HGT) is a highly significant phenomenon amongst single-celled organisms. The evolution
of bacteria and archaea often results from the acquisition of new genes through horizontal transfer rather than by
modification of vertically inherited genes. Horizontal or lateral gene transfer is a major factor in the spread of
bacterial antibiotic resistance and other adaptive traits of microorganisms and is particularly significant in microbial
communities. HGT may also play a substantial role in the emergence of novel infections and opportunistic
pathogens.[9]

Viruses
Viruses are important pathogens of humans and animals.[10] Their genomes are relatively small. For these reasons
they were among the first organisms to be fully sequenced. The complete DNA sequence of the Epstein-Barr virus
was completed in 1984.[11][12] Bluetongue virus (BTV) has been in the forefront of molecular studies for last three
decades and now represents one of the best understood viruses at the molecular and structural levels.[13][14] Other
viruses such as Papillomavirus,[15] Coronavirus,[16] Caliciviruses,[17] Paramyxoviruses[18] and Influenza virus[19][20]
have also been extensively studied at the molecular level.
Bacterial viruses, or bacteriophages, are estimated to be the most widely distributed and diverse entities in the
biosphere. Bacteriophages, or "phage", have been fundamental in the development of the science of molecular
biology and became "model organisms" for probing the basic chemistry of life.[21] The first DNA-genome project to
be completed was the phage Φ-X174 in 1977. Φ29 phage, a phage of Bacillus, is a paradigm for the study of several
molecular mechanisms of general biological processes, including DNA replication and regulation of
transcription.[21][22]

Gene Therapy
Some viruses are used as vectors for gene therapy. Virus vectors have been developed that mediate stable genetic
modification of treated cells by chromosomal integration of the transferred vector genomes. Gammaretroviral and
lentiviral vectors, for example, can be utilized in clinical gene therapy aimed at the long-term correction of genetic
defects, e.g., in stem and progenitor cells. Gammaretroviral and lentiviral vectors have so far been used in more than
300 clinical trials, addressing treatment options for various diseases.[23][24]
Molecular microbiology 284

RNAi and viruses


The new technology of RNAi is emerging as a powerful modality for battling some of the most notoriously
challenging viral clinical targets. In particular, this technology is being developed as a new therapeutic tool for
fighting specific viruses, including human immunodeficiency virus (HIV), hepatitis C virus (HCV) and respiratory
viruses.[25]

Fungi
Yeasts and molds are eukaryotic microorganisms classified in the kingdom Fungi.

Neurospora
Neurospora is the leading model for the study of the genomics and molecular biology of filamentous fungi. The ease
of culture, amenability to genetic and molecular genetic analysis, and the close correlation between genetic and
biochemical traits are some of its advantages. Research with Neurospora has provided insights unachievable from
work with simpler systems and difficult to extract from more complicated ones. The application of modern high
throughput analyses had led to increased information on the genomics and molecular biology of Neurospora in
recent years.[26]

Technology
Polymerase chain reaction[27][28][29] (PCR) is used in microbiology to amplify (replicate many times) a single DNA
sequence. If required, the sequence can also be altered in predetermined ways. Real-time PCR [30] is used for the
rapid detection of microorganisms and is currently employed in diagnostic clinical microbiology laboratories,
environmental analysis, food microbiology, and many other fields.[31] The closely related technique of quantitative
PCR (qPCR) permits the quantitative measurement of DNA or RNA molecules and is used to estimate the densities
of the reference pathogens in food, water and environmental samples. qPCR provides both specificity and
quantification of target microorganisms.[29]
Loop-mediated isothermal amplification (LAMP) is a relatively new DNA amplification technique that is simple,
rugged and low cost. In LAMP, the target sequence is amplified at a constant temperature using either two or three
sets of primers and a polymerase with high strand displacement activity. LAMP is used in organizations engaged in
combating infectious diseases such as tuberculosis, malaria, and sleeping sickness in developing regions and has
been proposed for the detection of waterborne pathogens.[5]
Gel electrophoresis is used routinely in microbiology to separate DNA, RNA, or protein molecules using an electric
field by virtue of their size, shape or electric charge.
Southern blotting, northern blotting, western blotting and Eastern blotting are molecular techniques for detecting the
presence of microbial DNA sequences (Southern), RNA sequences (northern), protein molecules (western) or protein
modifications (Eastern).
DNA microarrays are used in microbiology as the modern alternative to the "blotting" techniques. Microarrays
permit the exploration of thousands of sequences at one time. This technique is used in molecular microbiology to
detect the presence of pathogens in a sample (air, water, organ tissue, etc.). It is also used to determine the genetic
differences between two microbial strains.[32]
DNA sequencing and genomics have been used for many decades in molecular microbiology studies. Due to their
relatively small size, virus and bacterial genomes were the first to be completely analysed by DNA sequencing. A
huge range of sequence and genomic data is now available for a number of species and strains of microorganisms.
Lab-on-a-chip (LOC) devices integrate and scale down laboratory functions and processes to a miniaturized chip
format. Many LOC devices are used in a wide array of biomedical and other analytical applications including rapid
Molecular microbiology 285

pathogen detection, clinical diagnosis, forensic science, electrophoresis, flow cytometry, blood chemistry analysis,
protein and DNA analysis. LOC devices can be fabricated from many types of material including various polymers,
glass, or silicon, or combinations of these materials. A broad variety of fabrication technologies are used for LOC
device fabrication. LOC systems have several common features including microfluidics and sensing capabilities.
Microfluidics deals with fluid flow in tiny channels using flow control devices (e.g. channels, pumps, mixers and
valves). Sensing capabilities, usually optical or electrochemical sensors, can also be integrated into the chip.[32][33]
RNA interference (RNAi) was discovered as a cellular gene regulation mechanism in 1998, but several RNAi-based
applications for gene silencing have already made it into clinical trials. RNA interference (RNAi) technology has
formed the basis of novel tools for biological research and drug discovery.[25][34]
Nanotechnology, the engineering and art of manipulating matter at the nanoscale (1-100 nm), offers the potential of
novel nanomaterials with applications in microbiology, in particular environmental microbiology.[35]

References
[1] Diaz E (editor). (2008). Microbial Biodegradation: Genomics and Molecular Biology. Caister Academic Press. ISBN 978-1-904455-17-2.
[2] Fratamico PM and Bayles DO (editor). (2005). Foodborne Pathogens: Microbiology and Molecular Biology. Caister Academic Press.
ISBN 978-1-904455-00-4.
[3] Mayo, B; van Sinderen, D (editor) (2010). Bifidobacteria: Genomics and Molecular Aspects. Caister Academic Press.
ISBN 978-1-904455-68-4.
[4] Miller, AA; Miller, PF (editor) (2011). Emerging Trends in Antibacterial Discovery: Answering the Call to Arms. Caister Academic Press.
ISBN 978-1-904455-89-9.
[5] Sen, K; Ashbolt, NK (editor) (2010). Environmental Microbiology: Current Technology and Water Applications. Caister Academic Press.
ISBN 978-1-904455-70-7.
[6] Spiro, S; Dixon, R (editor) (2010). Sensory Mechanisms in Bacteria: Molecular Aspects of Signal Recognition. Caister Academic Press.
ISBN 978-1-904455-69-1.
[7] Locht, C; Simonet, M (editor) (2012). Bacterial Pathogenesis: Molecular and Cellular Mechanisms. Caister Academic Press.
ISBN 978-1-904455-91-2.
[8] Reid, CW; Twine, SM; Reid, AN (editor) (2012). Bacterial Glycomics: Current Research, Technology and Applications. Caister Academic
Press. ISBN 978-1-904455-95-0.
[9] Francino, MP (editor) (2012). Horizontal Gene Transfer in Microorganisms. Caister Academic Press. ISBN 978-1-908230-10-2.
[10] Mettenleiter TC and Sobrino F (editors). (2008). Animal Viruses: Molecular Biology. Caister Academic Press. ISBN 978-1-904455-22-6.
[11] Baer et al. (1984). "DNA sequence and expression of the B95-8 Epstein—Barr virus genome". Nature 310 (5974): 207–211.
doi:10.1038/310207a0. PMID 6087149.
[12] Robertson ES (editor). (2005). Epstein-Barr Virus. Caister Academic Press. ISBN 978-1-904455-03-5.
[13] Roy P (2008). "Molecular Dissection of Bluetongue Virus". Animal Viruses: Molecular Biology. Caister Academic Press.
ISBN 978-1-904455-22-6.
[14] Roy P (2008). "Structure and Function of Bluetongue Virus and its Proteins". Segmented Double-stranded RNA Viruses: Structure and
Molecular Biology. Caister Academic Press. ISBN 978-1-904455-21-9.
[15] Campo MS (editor). (2006). Papillomavirus Research: From Natural History To Vaccines and Beyond. Caister Academic Press.
ISBN 978-1-904455-04-2.
[16] Thiel V (editor). (2007). Coronaviruses: Molecular and Cellular Biology. Caister Academic Press. ISBN 978-1-904455-16-5.
[17] Hansman, GS (editor) (2010). Caliciviruses: Molecular and Cellular Virology. Caister Academic Press. ISBN 978-1-904455-63-9.
[18] Samal, SK (editor) (2011). The Biology of Paramyxoviruses. Caister Academic Press. ISBN 978-1-904455-85-1.
[19] Kawaoka Y (editor). (2006). Influenza Virology: Current Topics. Caister Academic Press. ISBN 978-1-904455-06-6.
[20] Wang, Q; Tao, YJ (editors) (2010). Influenza: Molecular Virology. Caister Academic Press. ISBN 978-1-904455-57-8.
[21] Mc Grath S and van Sinderen D (editors). (2007). Bacteriophage: Genetics and Molecular Biology. Caister Academic Press.
ISBN 978-1-904455-14-1.
[22] Graumann P (editor). (2007). Bacillus: Cellular and Molecular Biology. Caister Academic Press. ISBN 978-1-904455-12-7.
[23] Kurth, R; Bannert, N (editors) (2010). Retroviruses: Molecular Biology, Genomics and Pathogenesis. Caister Academic Press.
ISBN 978-1-904455-55-4.
[24] Desport, M (editors) (2010). Lentiviruses and Macrophages: Molecular and Cellular Interactions. Caister Academic Press.
ISBN 978-1-904455-60-8.
[25] Martinez, MA (editor) (2010). RNA Interference and Viruses: Current Innovations and Future Trends. Caister Academic Press.
ISBN 978-1-904455-56-1.
[26] Kasbekar, DP; McCluskey, K (editor) (2013). Neurospora: Genomics and Molecular Biology. Caister Academic Press.
ISBN 978-1-908230-12-6.
Molecular microbiology 286

[27] Logan J, Edwards K, Saunders N (editors) (2009). Real-Time PCR: Current Technology and Applications. Caister Academic Press.
ISBN 978-1-904455-39-4.
[28] Kennedy, S; Oswald, N (editor) (2011). PCR Troubleshooting and Optimization: The Essential Guide. Caister Academic Press.
ISBN 978-1-904455-72-1.
[29] Filion, M (editor) (2012). Quantitative Real-time PCR in Applied Microbiology. Caister Academic Press. ISBN 978-1-908230-01-0.
[30] http:/ / www. horizonpress. com/ pcr
[31] Mackay IM (editor). (2007). Real-Time PCR in Microbiology: From Diagnosis to Characterization. Caister Academic Press.
ISBN 978-1-904455-18-9.
[32] Herold, KE; Rasooly, A (editor) (2009). Lab-on-a-Chip Technology: Biomolecular Separation and Analysis. Caister Academic Press.
ISBN 978-1-904455-47-9.
[33] Herold, KE; Rasooly, A (editor) (2009). Lab-on-a-Chip Technology: Fabrication and Microfluidics. Caister Academic Press.
ISBN 978-1-904455-46-2.
[34] Morris, KV (editor) (2008). RNA and the Regulation of Gene Expression: A Hidden Layer of Complexity. Caister Academic Press.
ISBN 978-1-904455-25-7.
[35] Cloete, TE (editor) (2010). Nanotechnology in Water Treatment Applications. Caister Academic Press. ISBN 978-1-904455-66-0.

External links
• Microbiology (http://www.horizonpress.com/gateway/micro.html)
• University of Washington Medicine | Molecular Microbiology Division (http://depts.washington.edu/
molmicdx/)
• John Innes Centre | Molecular Microbiology Department (http://www.jic.ac.uk/corporate/
science-departments/mol-micro.htm)

Morphology (biology)
In biology, morphology is a branch of bioscience
dealing with the study of the form and structure of
organisms and their specific structural
[1][2][3][4][5][6][7]
features.
This includes aspects of the outward appearance
(shape, structure, colour, pattern)[8] as well as the form
and structure of the internal parts like bones and
organs. This is in contrast to physiology, which deals
primarily with function. Morphology is a branch of life
science dealing with the study of gross structure of an
organism or Taxon and its component parts.

Term
The word "morphology" is from the Greek μορφή,
morphé = form and λόγος, lógos = word, study,
research. The biological concept of morphology was
developed by Johann Wolfgang von Goethe (1790) and Morphology of a male Caprella mutica
independently by the German anatomist and
physiologist Karl Friedrich Burdach (1800).

In English-speaking countries, the term "molecular morphology" has been used for some time for describing the
structure of compound molecules, such as polymers. [9] and RNA. The term "gross morphology" refers to the
collective structures or an organism as a whole as a general description of the form and structure of an organism,
Morphology (biology) 287

taking into account all of its structures without specifying an individual structure.

Branches of morphology
• Comparative Morphology is analysis of the patterns of the locus of structures within the body plan of an
organism, and forms the basis of taxonomical categorization.
• Functional Morphology is the study of the relationship between the structure and function of morphological
features.
• Experimental Morphology is the study of the effects of external factors upon the morphology of organisms under
experimental conditions, such as the effect of genetic mutation.
The field of morphology is divided into two distinct branches.
• "Anatomy" is the study of the form and structure of internal features of an organism.
• "Eidonomy" is the study of the form and structure of the external features of an organism.

Morphology and classification


Most taxa differ morphologically from other taxa. Typically, closely related taxa differ much less than more distantly
related ones, but there are exceptions to this. Cryptic species are species which look very similar, or perhaps even
outwardly identical, but are reproductively isolated. Conversely, sometimes unrelated taxa acquire a similar
appearance as a result of convergent evolution or even mimicry. A further problem with relying on morphological
data is that what may appear, morphologically speaking, to be two distinct species, may in fact be shown by DNA
analysis to be a single species. The significance of these differences can be examined through the use of allometric
engineering in which one or both species are manipulated to phenocopy the other species.

References
[1] "Morphology" (http:/ / www. askoxford. com/ concise_oed/ morphology?view=uk). http:/ / www. askoxford. com. . Retrieved 2010-06-24.
[2] "Morphology" (http:/ / www. merriam-webster. com/ medical/ morphology). Merriam Webster.com. . Retrieved 2010-06-24.
[3] "Morphology" (http:/ / dictionary. cambridge. org/ dictionary/ british/ morphology). dictionary.cambridge.org. . Retrieved 2010-06-24.
[4] "Morphology" (http:/ / encarta. msn. com/ encnet/ features/ dictionary/ DictionaryResults. aspx?lextype=3& search=morphology).
encarta.msn.com. . Retrieved 2010-06-24.
[5] "Morphology" (http:/ / www. medterms. com/ script/ main/ art. asp?articlekey=4432lextype=3& search=morphology). www.medterms.com. .
Retrieved 2010-06-24.
[6] "Morphology" (http:/ / dictionary. reference. com/ browse/ morphology). dictionary.reference.com. . Retrieved 2010-06-24.
[7] "Morphology" (http:/ / www. dictionary. net/ morphology). http:/ / www. dictionary. net/ . . Retrieved 2010-06-24.
[8] "morphology" (http:/ / www. britannica. com/ EBchecked/ topic/ 392797/ morphology). Encyclopædia Britannica. . Retrieved 2009-04-09.
[9] "Polymer Morphology" (http:/ / www. eng. uc. edu/ ~gbeaucag/ Classes/ Morphology. html). http:/ / www. ceas. uc. edu/ . . Retrieved
2010-06-24.
Mucin 288

Mucin
Mucins are a family of high molecular weight, heavily
glycosylated proteins (glycoconjugates) produced by
epithelial tissues in most metazoans.[1] Mucins' key
characteristic is their ability to form gels; therefore they
are a key component in most gel-like secretions,
serving functions from lubrication to cell signalling to
forming chemical barriers.[1] They often take an
inhibitory role.[1] Some mucins are associated with
controlling mineralization, including nacre formation in
molluscs,[2] calcification in echinoderms[3] and bone
formation in vertebrates.[4] They bind to pathogens as
part of the immune system. Overexpression of the
mucin proteins, especially MUC1 is associated with
many types of cancer.[5] Micrograph showing cells with prominent mucin-containing
intracytoplasmic vacuoles. Pap stain.
Although some mucins are membrane-bound due to the
presence of a hydrophobic membrane-spanning domain that favors retention in the plasma membrane, most mucins
are secreted onto mucosal surfaces or secreted to become a component of saliva.

Genes
At least 19 human mucin genes have been distinguished by cDNA cloning — MUC1, MUC2, MUC3A, MUC3B,
MUC4, MUC5AC, MUC5B, MUC6, MUC7, MUC8, MUC12, MUC13, MUC15, MUC16, MUC17, MUC19, and
MUC20.[6]
The major secreted airway mucins are MUC5AC and MUC5B, while MUC2 is secreted mostly in the intestine but
also in the airway.

Protein structure
Mature mucins are composed of two distinct regions:
• The amino- and carboxy-terminal regions are very lightly glycosylated, but rich in cysteines. The cysteine
residues participate in establishing disulfide linkages within and among mucin monomers.
• A large central region formed of multiple tandem repeats of 10 to 80 residue sequences in which up to half of the
amino acids are serine or threonine. This area becomes saturated with hundreds of O-linked oligosaccharides.
N-linked oligosaccharides are also found on mucins, but in less abundance than O-linked sugars.
Mucin 289

Glycosylation and aggregation


Mucin genes encode mucin monomers that are synthesized as rod-shape apomucin cores that are post-translationally
modified by exceptionally abundant glycosylation.
The dense "sugar coating" of mucins gives them considerable water-holding capacity and also makes them resistant
to proteolysis, which may be important in maintaining mucosal barriers.
Mucins are secreted as massive aggregates of proteins with molecular masses of roughly 1 to 10 million Da. Within
these aggregates, monomers are linked to one another mostly by non-covalent interactions, although intermolecular
disulfide bonds may also play a role in this process.

Secretion
Upon stimulation, MARCKS (myristylated alanine-rich C kinase substrate) protein coordinates the secretion of
mucin from mucin filled vesicles within the specialized epithelial cells.[7] Fusion of the vesicles to the plasma
membrane causes release of the mucin, which as it exchanges Ca2+ for Na+ expands up to 600 fold. The result is a
viscoelastic product of interwoven molecules which, combined with other secretions (e.g., from the airway
epithelium and the submucosal glands in the respiratory system), is called mucus.[8] [9]

Clinical significance
Increased mucin production occurs in many adenocarcinomas, including cancers of the pancreas, lung, breast, ovary,
colon and other tissues. Mucins are also overexpressed in lung diseases such as asthma, bronchitis, COPD or cystic
fibrosis. Two membrane mucins, MUC1 and MUC4 have been extensively studied in relation to their pathological
implication in the disease process.[10][11][12] Mucins are under investigation as possible diagnostic markers for
malignancies and other disease processes in which they are most commonly over- or mis-expressed.
Abnormal deposits of mucin are responsible for the non-pitting facial edema seen in untreated hypothryoidism. This
edema is seen in the pretibial area as well.[13]

References
[1] Marin, F.; Luquet, G.; Marie, B.; Medakovic, D. (2007). "Molluscan Shell Proteins: Primary Structure, Origin, and Evolution". Current
Topics in Developmental Biology Volume 80. Current Topics in Developmental Biology. 80. pp. 209. doi:10.1016/S0070-2153(07)80006-8.
ISBN 9780123739148.
[2] Marin, F.; Corstjens, P.; De Gaulejac, B.; De Vrind-De Jong, E.; Westbroek, P. (2000). "Mucins and molluscan calcification. Molecular
characterization of mucoperlin, a novel mucin-like protein from the nacreous shell layer of the fan mussel Pinna nobilis (Bivalvia,
pteriomorphia)". The Journal of Biological Chemistry 275 (27): 20667–20675. doi:10.1074/jbc.M003006200. PMID 10770949.
[3] Boskey, A. (2003). "Biomineralization: an Overview". Connective Tissue Research 44 (1): 5–9. doi:10.1080/713713622. PMID 12952166.
[4] RJ Midura, VC Hascall (1996). "Bone sialoprotein–a mucin in disguise?". Glycobiology 6 (7): 677–81. doi:10.1093/glycob/6.7.677.
PMID 8953277.
[5] Niv Y (April 2008). "MUC1 and colorectal cancer pathophysiology considerations". World J. Gastroenterol. 14 (14): 2139–41.
doi:10.3748/wjg.14.2139. PMC 2703837. PMID 18407586.
[6] Perez-Vilar, J; Hill, RL (2004). "Mucin Family of Glycoproteins". Encyclopedia of Biological Chemistry (Lennarz & Lane, EDs.) (Oxford:
Academic Press/Elsevier) 2: 758–764.
[7] Li, Y; Martin, LD; Spizz, G; Adler, KB (November 2, 2001). "MARCKS protein is a key molecule regulating mucin secretion by human
airway epithelial cells in vitro". J Biol Chem 276 (44): 40982–90. doi:10.1074/jbc.M105614200. PMID 11533058.
[8] Rogers, DF (September 2007). "Physiology of airway mucus secretion and pathophysiology of hypersecretion". Respir Care 52 (9):
1134–1146. PMID 17716382.
[9] Perez-Vilar, J (20087). "Mucin granule intraluminal organization". Am J Respir Cell Mol Biol 36 (2): 183–190.
doi:10.1165/rcmb.2006-0291TR. PMC 2176109. PMID 16960124.
[10] Singh AP, Moniaux N, Chauhan SC, Meza JL, Batra SK (January 2004). "Inhibition of MUC4 expression suppresses pancreatic tumor cell
growth and metastasis.". Cancer Research 64 (2): 622–30. doi:10.1158/0008-5472.CAN-03-2636. PMID 14744777.
[11] Singh Ajay P., Chauhan Subhash C., Bafna Sangeeta, Johansson Sonny L., Smith Lynette M., Moniaux Nicolas, Lin Ming-Fong, Batra
Surinder K. (March 2006). "Aberrant expression of transmembrane mucins, MUC1 and MUC4, in human prostate carcinomas". The Prostate
Mucin 290

66 (4): 421–429. doi:10.1002/pros.20372. PMID 16302265.


[12] Singh A. P., Chaturvedi P., Batra S. K. (January 2007). "Emerging Roles of MUC4 in Cancer: A Novel Target for Diagnosis and Therapy".
Cancer Research 67 (2): 433–436. doi:10.1158/0008-5472.CAN-06-3114. PMID 17234748.
[13] Hanberg, Allen "Medical Surgical Nursing: clinical management for positive outcomes" Black and Hawk (Eds.). ElSevier 2009.

• Ali M, Hutton D, Wilson J, Pearson J (September 2005). "Major Secretory Mucin Expression in Chronic
Sinusitis". Otolaryngology - Head and Neck Surgery 133 (3): 423–428. doi:10.1016/j.otohns.2005.06.005.
PMID 16143194.

External links
• Mucins (http://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=Mucins) at the US National
Library of Medicine Medical Subject Headings (MeSH)
• " Mucin (http://web.archive.org/web/20090616022448/http://www.mercksource.com/pp/us/cns/
cns_hl_dorlands_split.jsp?pg=/ppdocs/us/common/dorlands/dorland/five/000067870.htm)" at Dorland's
Medical Dictionary

Mycology
Mycology (from the Greek μύκης, mukēs, meaning "fungus") is the
branch of biology concerned with the study of fungi, including their
genetic and biochemical properties, their taxonomy and their use to
humans as a source for tinder, medicinals (e.g., penicillin), food (e.g.,
beer, wine, cheese, edible mushrooms) and entheogens, as well as their
dangers, such as poisoning or infection.

From mycology arose the field of phytopathology, the study of plant


diseases, and the two disciplines remain closely related because the
vast majority of "plant" pathogens are fungi. A biologist who studies
Mushrooms are a kind of fungal reproductive
mycology is called a mycologist. structure

Historically, mycology was a branch of botany because, although fungi


are evolutionarily more closely related to animals than to plants, this was not recognized until a few decades ago.
Pioneer mycologists included Elias Magnus Fries, Christian Hendrik Persoon, Anton de Bary and Lewis David von
Schweinitz.
Many fungi produce toxins, antibiotics and other secondary metabolites. For example the cosmopolitan (worldwide)
genus Fusarium and their toxins associated with fatal outbreaks of alimentary toxic aleukia in humans were
extensively studied by Abraham Joffe.
Fungi are fundamental for life on earth in their roles as symbionts, e.g. in the form of mycorrhizae, insect symbionts
and lichens. Many fungi are able to break down complex organic biomolecules such as lignin, the more durable
component of wood, and pollutants such as xenobiotics, petroleum, and polycyclic aromatic hydrocarbons. By
decomposing these molecules, fungi play a critical role in the global carbon cycle.
Fungi and other organisms traditionally recognized as fungi, such as oomycetes and myxomycetes (slime molds),
often are economically and socially important as some cause diseases of animals (such as histoplasmosis) as well as
plants (such as Dutch elm disease and Rice blast).
Field meetings to find interesting species of fungi are known as 'forays', after the first such meeting organized by the
Woolhope Naturalists' Field Club in 1868 and entitled "a foray among the fungi."
Mycology 291

Some fungi can cause disease in humans or other organisms. The study of pathogenic fungi is referred to as medical
mycology.[1]

History
Humans probably started collecting mushrooms as food in Prehistoric times. Mushrooms were first written about in
the works of Euripides (480-406 B.C.). The Greek philosopher Theophrastos of Eressos (371-288 B.C.) was perhaps
the first to try to systematically classify plants; mushrooms were considered to be plants that were missing certain
organs. It was later Pliny the elder (23–79 A.D.), who wrote about truffles in his encyclopedia Naturalis historia.
The Middle Ages saw little advancement in the body of knowledge about fungi. Rather, the invention of the printing
press allowed some authors to disseminate superstitions and misconceptions about the fungi that had been
perpetuated by the classical authors.[2]


Fungi and truffles are neither herbs, nor roots, nor flowers, nor seeds, but merely the superfluous moisture or earth, of trees, or rotten


wood, and of other rotting things. This is plain from the fact that all fungi and truffles, especially those that are used for eating, grow most
commonly in thundery and wet weather.

[3]
—Jerome Bock (Hieronymus Tragus), 1552

The start of the modern age of mycology begins with Pier Antonio Micheli's 1737 publication of Nova plantarum
genera.[4] Published in Florence, this seminal work laid the foundations for the systematic classification of grasses,
mosses and fungi. The term mycology and the complementary mycologist were first used in 1836 by M.J.
Berkeley.[5]

Medicinal mycology
For centuries, certain mushrooms have been documented as a folk medicine in China, Japan, and Russia.[6] Although
the use of mushrooms in folk medicine is largely centered on the Asian continent, people in other parts of the world
like the Middle East, Poland and Belarus have been documented using mushrooms for medicinal purposes.[7][8]
Certain mushrooms, especially polypores like Reishi were thought to be able to benefit a wide variety of health
ailments. Medicinal mushroom research in the United States is currently active, with studies taking place at City of
Hope National Medical Center,[9][10] as well as the Memorial Sloan–Kettering Cancer Center.[11]
Current research focuses on mushrooms that may have hypoglycemic activity, anti-cancer activity, anti-pathogenic
activity, and immune system enhancing activity. Recent research has found that the oyster mushroom naturally
contains the cholesterol-lowering drug lovastatin,[12] mushrooms produce large amounts of vitamin D when exposed
to UV light,[13] and that certain fungi may be a future source of taxol.[14] To date, penicillin, lovastatin, ciclosporin,
griseofulvin, cephalosporin, ergometrine, and statins are the most famous pharmaceuticals which have been isolated
from the fungi kingdom.
Mycology 292

Notes
[1] San-Blas G; Calderone RA (editors). (2008). Pathogenic Fungi (http:/ / www. horizonpress. com/ pat2). Caister Academic Press. . .
[2] Ainsworth, p. 13.
[3] De stirpium maxime earum quae in Germania nostra nascuntur, usitatis nomenclaturis. Strasbourg. In Ainsworth, p. 13, quoting Buller,
AHR. (1915). Micheli and the discovery of reproduction in fungi. Transactions of the royal Society of Canada, series 3 9: 1–25.
[4] Ainsworth, p. 4.
[5] Ainsworth, p. 2.
[6] Smith JE, Rowan NJ, Sullivan R (May 2002). "Medicinal Mushrooms: Their therapeutic properties and current medical usage with special
emphasis on cancer treatments" (http:/ / sci. cancerresearchuk. org/ labs/ med_mush/ med_mush. html). Cancer Research UK. p. 5. .
[7] Sarfaraz Khan Marwat, Mir Ajab Khan, Muhammad Aslam Khan, Mushtaq Ahmad, Muhammad Zafar, Fazal-ur-Rehman and Shazia Sultana
(2009). "Vegetables mentioned in the Holy Qura’n and Ahadith and their ethnomedicinal studies in Dera Ismail Khan, N.W.F.P., Pakistan"
(http:/ / scialert. net/ fulltext/ ?doi=pjn. 2009. 530. 538). Pakistan Journal of Nutrition 8 (5): 530–538. . Sahih Muslim, Book 23, Chapter 27,
Hadiths
[8] Shashkina MIa, Shashkin PN, Sergeev AV (October 2006). "[Chemical and medicobiological properties of Chaga (review)]".
Farmatsevtychnyĭ zhurnal 40 (10). doi:10.1007/s11094-006-0194-4.
[9] Di Rado, Alicia (July 2008). "A salad fixin' with medical benefits?" (http:/ / www. cityofhope. org/ about/ publications/ eHope/
2008-vol-7-num-7-july-29/ Pages/ a-salad-fixin-with-medical-benefits. aspx). EHope (City of Hope National Medical Center) 7 (7). .
[10] Di Rado, Alicia (November 2008). "Can a mushroom help fight lung cancer?" (http:/ / www. cityofhope. org/ about/ publications/ eHope/
2008-vol-7-num-11-november-26/ Pages/ can-a-mushroom-help-fight-lung-cancer. aspx). EHope (City of Hope National Medical Center) 7
(11). .
[11] Deng G, Lin H, Seidman A (September 2009). "A phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in
breast cancer patients: immunological effects". Journal of Cancer Research and Clinical Oncology 135 (9): 1215–21.
doi:10.1007/s00432-009-0562-z. PMID 19253021.
[12] Gunde-Cimerman N, Cimerman A. (Mar 1995), "Pleurotus fruiting bodies contain the inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A
reductase-lovastatin.", Exp Mycol. 19 (1): 1–6, doi:10.1006/emyc.1995.1001, ISSN 0147-5975, PMID 7614366
[13] Bowerman, Susan (March 31, 2008), "If mushrooms see the light" (http:/ / articles. latimes. com/ 2008/ mar/ 31/ health/ he-eat31), The Los
Angeles Times,
[14] Ji, Y; Bi; Yan; Zhu (Jan 2006), "Taxol-producing fungi: a new approach to industrial production of taxol" (http:/ / toxnet. nlm. nih. gov/
cgi-bin/ sis/ search/ r?dbs+ hsdb:@term+ @rn+ 33069-62-4) (Free full text), Sheng wu gong cheng xue bao = Chinese journal of
biotechnology 22 (1): 1–6, ISSN 1000-3061, PMID 16572833,

References
Ainsworth, G. C. (1976). Introduction to the History of Mycology. Cambridge, UK: Cambridge University Press.
ISBN 0-521-21013-5.

External links
• Professional organizations
• BMS: British Mycological Society (http://www.britmycolsoc.org.uk/) (United Kingdom)
• MSA: Mycological Society of America (http://www.msafungi.org) (North America)
• Amateur organizations
• Mycological Society of San Francisco (http://www.mssf.org/)
• North American Mycological Association (http://namyco.org/clubs/index.html/) (list of amateur
organizations in North America)
• Puget Sound Mycological Society (http://psms.org/)
• Oregon Mycological Society (http://www.wildmushrooms.org/)
• Miscellaneous links
• Online lectures in mycology (http://media.med.sc.edu/microbiology2007/) University of South Carolina
• The WWW Virtual Library: Mycology (http://mycology.cornell.edu/)
• MykoWeb links page (http://www.mykoweb.com/links.html)
• Mycological Glossary at the Illinois Mycological Association (http://www.mushroomthejournal.com/
greatlakesdata/Terms/TermsFrame.html)
Mycology 293

• FUNGI Magazine (http://www.fungimag.com/) for professionals and amateurs - largest circulating U.S.
publication concerning all things mycological]
• Fungal Cell Biology Group (http://129.215.156.68/index.html) at University of Edinburgh, UK.
• Mycological Marvels (http://exhibits.mannlib.cornell.edu/mycological/) Cornell University, Mann Library

Myofibril
Myofibril

1. Axon
2. Neuromuscular junction
3. Muscle fiber
4. Myofibril

Latin myofibrilla

MeSH [1]
Myofibrils

Code [2]
TH H2.00.05.0.00007

A myofibril (also known as a muscle fibril)


is a basic rod-like unit of a muscle.[3]
Muscles are composed of tubular cells
called myocytes, also known as muscle
fibers, and these cells in turn contain many
chains of myofibrils.
A diagram of the structure of a Myofibril
Myofibrils are composed of long proteins
such as actin, myosin, and titin, and other
proteins that hold them together. These proteins are organized into thin filaments and thick filaments, which repeat
along the length of the myofibril in sections called sarcomeres. Muscles contract by sliding the thin (actin) and thick
(myosin) filaments along each other.
Actomyosin motors are important in muscle contraction (relying in this case on "classical myosins") as well as other
processes like retraction of membrane blebs, filiopod
Myofibril 294

retraction, and uropodium advancement


(relying in this case on "nonclassical
myosins").

Structure
The filaments of myofibrils, myofilaments,
consist of two types, thick and thin:

Sliding filament model of muscle contraction

• Thin filaments consist primarily of the protein actin, coiled with nebulin filaments.
• Thick filaments consist primarily of the protein myosin, held in place by titin filaments.
The protein complex composed of actin and myosin is sometimes referred to as "actomyosin."
In striated muscle, such as skeletal and cardiac muscle, the actin and myosin filaments each have a specific and
constant length on the order of a few micrometers, far less than the length of the elongated muscle cell (a few
millimeters in the case of human skeletal muscle cells). The filaments are organized into repeated subunits along the
length of the myofibril. These subunits are called sarcomeres. The muscle cell is nearly filled with myofibrils
running parallel to each other on the long axis of the cell. The sarcomeric subunits of one myofibril are in nearly
perfect alignment with those of the myofibrils next to it. This alignment gives rise to certain optical properties which
cause the cell to appear striped or striated. In smooth muscle cells, this alignment is absent, hence there are no
apparent striations and the cells are called smooth.

Appearance
The names of the various sub-regions of the sarcomere are based on their relatively lighter or darker appearance
when viewed through the light microscope. Each sarcomere is delimited by two very dark colored bands called
Z-discs or Z-lines (from the German zwischen meaning between). These Z-discs are dense protein discs that do not
easily allow the passage of light. The T-tubule is present in this area. The area between the Z-discs is further divided
into two lighter colored bands at either end called the I-bands, and a darker, grayish band in the middle called the A
band.
The I bands appear lighter because these regions of the sarcomere mainly contain the thin actin filaments, whose
smaller diameter allows the passage of light between them. The A band, on the other hand, contains mostly myosin
filaments whose larger diameter restricts the passage of light. A stands for anisotropic and I for isotropic, referring to
the optical properties of living muscle as demonstrated with polarized light microscopy.
The parts of the A band that abut the I bands are occupied by the both actin and myosin filaments (where they
interdigitate as described above). Also within the A band is a relatively brighter central region called the H-zone
(from the German helle, meaning bright) in which there is no actin/myosin overlap when the muscle is in a relaxed
state. Finally, the A band is bisected by a dark central line called the M-line (from the German mittel meaning
middle).
Myofibril 295

Action
The myosin heads form cross bridges with the Actin filaments, this is where they carry out a 'rowing' action along
the actin. when the muscle fibre is relaxed (before contraction) the myosin head has ADP + pi bound to it.
When a nerve impluse arrives, Ca2+ ions cause troponin to change shape, this moves the troponin+tropomyosin
complex away from the myosin binding site.
The Myosin head can now bind to the actin filament and tilts it through 45 degree angle so the actin is pulled along,
the myosin head tilts the ADP+pi are released allowing ATP to attach to the myosin head.
The myosin head hydrolyses the ATP to ADP+Pi (presence of Ca2+ ions activate the myosins ATPase) the energy
produced by this is used to detach the myosin head from the actin
The myosin head now flips back to the cocked position and is ready to bind to the actin again. And once the muscle
relaxes the troponin and tropomyosin complex covers the myosin binding site once more.
When a muscle contracts, the actin is pulled along myosin toward the center of the sarcomere until the actin and
myosin filaments are completely overlapped. The H zone becomes smaller and smaller due to the increasing overlap
of actin and myosin filaments, and the muscle shortens. Thus when the muscle is fully contracted, the H zone is no
longer visible (as in the bottom diagram, left). Note that the actin and myosin filaments themselves do not change
length, but instead slide past each other. This is known as the sliding filament theory of muscle contraction.

References
[1] http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Myofibrils
[2] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTH/ THh200. html
[3] McCracken, Thomas (1999). New Atlas of Human Anatomy. China: Metro Books. pp. 1-120. ISBN 1-5866-3097-0.

External links
• Nismat (http://www.nismat.org/physcor/muscle.html)
• MsJensen (http://msjensen.cehd.umn.edu/1135/Links/Animations/Flash/0008-swf_sarcomere_shor.swf)
(animation of sarcomeres contraction)
Nerve 296

Nerve
A nerve is an enclosed, cable-like bundle of axons (the long, slender
projections of neurons) in the peripheral nervous system. A nerve
provides a common pathway for the electrochemical nerve impulses
that are transmitted along each of the axons to peripheral organs.
In the central nervous system, the analogous structures are known as
tracts.[1][2] Neurons are sometimes called nerve cells, though this
term is potentially misleading since many neurons do not form
nerves, and nerves also include non-neuronal Schwann cells that
coat the axons in myelin.
Each nerve is a cordlike structure that contains many axons. These
axons are often referred to as "fibres". Within a nerve, each axon is
surrounded by a layer of connective tissue called the endoneurium.
The axons are bundled together into groups called fascicles, and
each fascicle is wrapped in a layer of connective tissue called the
perineurium. Finally, the entire nerve is wrapped in a layer of
connective tissue called the epineurium.

Anatomy
Nerves are categorized into three groups based on the direction that
signals are conducted:
• Afferent nerves conduct signals from sensory neurons to the
Nerves (yellow)
central nervous system, for example from the mechanoreceptors
in skin.
• Efferent nerves conduct signals from the central nervous system along motor neurons to their target muscles and
glands.
• Mixed nerves contain both afferent and efferent axons, and thus conduct both incoming sensory information and
outgoing muscle commands in the same bundle.
Nerves can be categorized into two groups based on where they connect to the central nervous system:
• Spinal nerves innervate much of the body, and connect through the spinal column to the spinal cord. They are
given letter-number designations according to the vertebra through which they connect to the spinal column.
• Cranial nerves innervate parts of the head, and connect directly to the brain (especially to the brainstem). They
are typically assigned Roman numerals from 1 to 12, although cranial nerve zero is sometimes included. In
addition, cranial nerves have descriptive names.
Nerve 297

Each nerve is covered externally by a dense sheath of connective


tissue, the epineurium. Underlying this is a layer of flat cells, the
perineurium, which forms a complete sleeve around a bundle of axons.
Perineurial septae extend into the nerve and subdivide it into several
bundles of fibers. Surrounding each such fiber is the endoneurium.
This forms an unbroken tube which extends from the surface of the
spinal cord to the level at which the axon synapses with its muscle
fibers, or ends in sensory receptors. The endoneurium consists of an
inner sleeve of material called the glycocalyx and an outer, delicate,
meshwork of collagen fibers. Nerves are bundled along with blood Cross-section of a nerve

vessels, since the neurons of a nerve have fairly high energy


requirements. Within the endoneurium, the individual nerve fibers are surrounded by a low protein liquid called
endoneurial fluid. The endoneurium has properties analogous to the blood–brain barrier, in that it prevents certain
molecules from crossing from the blood into the endoneurial fluid. In this respect, endoneurial fluid is similar to
cerebro-spinal fluid in the central nervous system. During the development of nerve edema from nerve irritation or
(injury), the amount of endoneurial fluid may increase at the site of irritation. This increase in fluid can be visualized
using magnetic resonance neurography, and thus MR neurography can identify nerve irritation and/or injury.

Physiology
A nerve conveys information in the form of electrochemical impulses (known as nerve impulses or action potentials)
carried by the individual neurons that make up the nerve. These impulses are extremely fast, with some myelinated
neurons conducting at speeds up to 120 m/s. The impulses travel from one neuron to another by crossing a synapse,
the message is converted from electrical to chemical and then back to electrical.[1][2]
Nerves can be categorized into two groups based on function:
• Sensory nerves conduct sensory information from their receptors to the central nervous system, where the
information is then processed. Thus they are synonymous with afferent nerves.
• Motor nerves conduct signals from the central nervous system to muscles. Thus they are synonymous with
efferent nerves.[1][2]

Clinical importance
Damage to nerves can be caused by physical injury or swelling (e.g.
carpal tunnel syndrome), autoimmune diseases (e.g. Guillain-Barré
syndrome), infection (neuritis), diabetes or failure of the blood vessels
surrounding the nerve. A pinched nerve occurs when pressure is placed
on a nerve, usually from swelling due to an injury or pregnancy. Nerve
damage or pinched nerves are usually accompanied by pain, numbness,
weakness, or paralysis. Patients may feel these symptoms in areas far
from the actual site of damage, a phenomenon called referred pain.
Referred pain occurs because when a nerve is damaged, signalling is Micrograph demonstrating perineural spread of
prostate cancer. H&E stain.
defective from all parts of the area from which the nerve receives
input, not just the site of the damage. Neurologists usually diagnose
disorders of the nerves by a physical examination, including the testing of reflexes, walking and other directed
movements, muscle weakness, proprioception, and the sense of touch. This initial exam can be followed with tests
such as nerve conduction study and electromyography (EMG).
Nerve 298

Cancer
Cancer can spread along nerves; this is known as perineural spread and often is associated with a worse prognosis.

Growth and stimulation


Nerve growth normally ends in adolescence, but can be re-stimulated with a molecular mechanism known as "Notch
signaling."[3]

References
[1] Purves D, Augustine GJ, Fitzppatrick D et al. (2008). Neuroscience (4th ed.). Sinauer Associates. pp. 11–20. ISBN 978-0-87893-697-7.
[2] Marieb EN, Hoehn K (2007). Human Anatomy & Physiology (7th ed.). Pearson. pp. 388–602. ISBN 0-8053-5909-5.
[3] Yale Study Shows Way To Re-Stimulate Brain Cell Growth ScienceDaily (http:/ / www. sciencedaily. com/ releases/ 1999/ 10/
991022005127. htm) (Oct. 22, 1999) — Results Could Boost Understanding Of Alzheimer's, Other Brain Disorders

Nissl body
A Nissl body (or Nissl granule or tigroid body) is a large
granular body found in neurons. These granules are rough
endoplasmic reticulum (with free ribosomes) and are the site of
protein synthesis. It was named after Franz Nissl, German
neurologist (1860-1919)[1].
Nissl bodies can be demonstrated by a method of selective staining
developed by Nissl (Nissl staining), using an aniline stain to label
extranuclear RNA granules. This staining method is useful to
localize the perikaryon, cell body, as it can be seen in the Soma
Image of a Nissl-stained histological section through
(biology) and dendrites of neurons, though not in the axon or axon
the rodent hippocampus showing various classes of
hillock. Due to RNA's basophilic (lat. "base-loving") properties it cells (neurons and glia).
is stained blue by this method.

Nissl bodies show changes under various physiological conditions


and in pathological conditions they may dissolve and disappear
(chromatolysis).
They are thought to be involved in the synthesis of
neurotransmitters such as acetylcholine.

References
[1] [ synd/2902 (http:/ / www. whonamedit. com/ synd. cfm/ 2902. html) at Who
Named It? "Nissl's substance"]. Retrieved 2009-02-25.

Motor nerve cell from ventral horn of medulla spinalis


External links of rabbit. The angular ande spindle-shaped Nissl bodies
are well shown.
• Nissl+Bodies (http://www.nlm.nih.gov/cgi/mesh/2011/
MB_cgi?mode=&term=Nissl+Bodies) at the US National
Library of Medicine Medical Subject Headings (MeSH)
• BU Histology Learning System: 04103loa (http://www.bu.edu/histology/p/04103loa.htm) - "Nervous Tissue
and Neuromuscular Junction: spinal cord, cell bodies of anterior horn cells"
Nissl body 299

• Anatomy at MUN nerve/nerve97 (http://www.med.mun.ca/anatomyts/nerve/nerve97.htm) (halfway down


page)
• Histology at anhb.uwa.edu.au (http://www.lab.anhb.uwa.edu.au/mb140/CorePages/Nervous/Nervous.htm)
• Tissues containing Nissl bodies at harvard.edu (http://www.hms.harvard.edu/societies/castle/Room166/
bodyblock/histology/)

Nucleic acid
Nucleic acids are biological molecules
essential for known forms of life on this
planet; they include DNA (deoxyribonucleic
acid) and RNA (ribonucleic acid). Together
with proteins, nucleic acids are the most
important biological macromolecules; each
is found in abundance in all living things,
where they function in encoding,
transmitting and expressing genetic
information.

Nucleic acids were discovered by Friedrich


Miescher in 1869.[1] Experimental studies of
nucleic acids constitute a major part of
modern biological and medical research, and
form a foundation for genome and forensic
science, as well as the biotechnology and
pharmaceutical industries.[2][3][4]

Occurrence and A comparison of the two principal nucleic acids: RNA (left) and DNA (right),
showing the helices and nucleobases each employs.
nomenclature[5]
The term nucleic acid is the overall name for DNA and RNA, members of a family of biopolymers,[6] and is
synonymous with polynucleotide. Nucleic acids were named for their initial discovery within the nucleus, and for the
presence of phosphate groups (related to phosphoric acid). Although first discovered within the nucleus of
eukaryotic cells, nucleic acids are now known to be found in all life forms, including within bacteria, archaea,
mitochondria, chloroplasts, viruses and viroids. All living cells and organelles contain both DNA and RNA, while
viruses contain either DNA or RNA, but usually not both.[7] The basic component of biological nucleic acids is the
nucleotide, each of which contains a pentose sugar (ribose or deoxyribose), a phosphate group, and a nucleobase.
Nucleic acids are also generated within the laboratory, through the use of enzymes[8] (DNA and RNA polymerases)
and by solid-phase chemical synthesis. The chemical methods also enable the generation of altered nucleic acids that
are not found in nature,[9] for example peptide nucleic acids.
Nucleic acid 300

Molecular composition and size[10]


Nucleic acids can vary in size, but are generally very large molecules. Indeed, DNA molecules are probably the
largest individual molecules known. Well-studied biological nucleic acid molecules range in size from 21
nucleotides (small interfering RNA) to large chromosomes (human chromosome 1 is a single molecule that contains
247 million base pairs[11]).
In most cases, naturally occurring DNA molecules are double-stranded and RNA molecules are single-stranded.
There are numerous exceptions, however—some viruses have genomes made of double-stranded RNA and other
viruses have single-stranded DNA genomes, and, in some circumstances, nucleic acid structures with three or four
strands can form.
Nucleic acids are linear polymers (chains) of nucleotides. Each nucleotide consists of three components: a purine or
pyrimidine nucleobase (sometimes termed nitrogenous base or simply base), a pentose sugar, and a phosphate
group. The substructure consisting of a nucleobase plus sugar is termed a nucleoside. Nucleic acid types differ in the
structure of the sugar in their nucleotides - DNA contains 2'-deoxyribose while RNA contains ribose (where the only
difference is the presence of a hydroxyl group). Also, the nucleobases found in the two nucleic acid types are
different: adenine, cytosine, and guanine are found in both RNA and DNA, while thymine occurs in DNA and uracil
occurs in RNA.
The sugars and phosphates in nucleic acids are connected to each other in an alternating chain (sugar-phosphate
backbone) through phosphodiester linkages.[10] In conventional nomenclature, the carbons to which the phosphate
groups attach are the 3'-end and the 5'-end carbons of the sugar. This gives nucleic acids directionality, and the ends
of nucleic acid molecules are referred to as 5'-end and 3'-end. The nucleobases are joined to the sugars via an
N-glycosidic linkage involving a nucleobase ring nitrogen (N-1 for pyrimidines and N-9 for purines) and the 1'
carbon of the pentose sugar ring.
Non-standard nucleosides are also found in both RNA and DNA and usually arise from modification of the standard
nucleosides within the DNA molecule or the primary (initial) RNA transcript. Transfer RNA (tRNA) molecules
contain a particularly large number of modified nucleosides.[12]

Topology
Double-stranded nucleic acids are made up of complementary sequences, in which extensive Watson-Crick base
pairing results in the a highly repeated and quite uniform double-helical three-dimensional structure.[13] In contrast,
single-stranded RNA and DNA molecules are not constrained to a regular double helix, and can adopt highly
complex three-dimensional structures that are based on short stretches of intramolecular base-paired sequences that
include both Watson-Crick and noncanonical base pairs, as well as a wide range of complex tertiary interactions.[14]
Nucleic acid molecules are usually unbranched, and may occur as linear and circular molecules. For example,
bacterial chromosomes, plasmids, mitochondrial DNA and chloroplast DNA are usually circular double-stranded
DNA molecules, while chromosomes of the eukaryotic nucleus are usually linear double-stranded DNA
molecules.[7] Most RNA molecules are linear, single-stranded molecules, but both circular and branched molecules
can result from RNA splicing reactions.[5]

Nucleic acid sequences


One DNA or RNA molecule differs from another primarily in the sequence of nucleotides. Nucleotide sequences are
of great importance in biology, since they carry the ultimate instructions that encode all biological molecules,
molecular assemblies, subcellular and cellular structures, organs and organisms, and directly enable cognition,
memory and behavior (See: Genetics). Enormous efforts have gone into the development of experimental methods to
determine the nucleotide sequence of biological DNA and RNA molecules,[15][16] and today hundreds of millions of
nucleotides are sequenced daily at genome centers and smaller laboratories worldwide.
Nucleic acid 301

Types of nucleic acids

Deoxyribonucleic acid
Deoxyribonucleic acid (i/diˌɒksiˌraɪbɵ.njuːˌkleɪ.ɨk ˈæsɪd/; DNA) is a nucleic acid containing the genetic instructions
used in the development and functioning of all known living organisms (with the exception of RNA viruses). The
DNA segments carrying this genetic information are called genes. Likewise, other DNA sequences have structural
purposes, or are involved in regulating the use of this genetic information. Along with RNA and proteins, DNA is
one of the three major macromolecules that are essential for all known forms of life. DNA consists of two long
polymers of simple units called nucleotides, with backbones made of sugars and phosphate groups joined by ester
bonds. These two strands run in opposite directions to each other and are therefore anti-parallel. Attached to each
sugar is one of four types of molecules called nucleobases (informally, bases). It is the sequence of these four
nucleobases along the backbone that encodes information. This information is read using the genetic code, which
specifies the sequence of the amino acids within proteins. The code is read by copying stretches of DNA into the
related nucleic acid RNA in a process called transcription. Within cells DNA is organized into long structures called
chromosomes. During cell division these chromosomes are duplicated in the process of DNA replication, providing
each cell its own complete set of chromosomes. Eukaryotic organisms (animals, plants, fungi, and protists) store
most of their DNA inside the cell nucleus and some of their DNA in organelles, such as mitochondria or
chloroplasts.[1] In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm. Within the
chromosomes, chromatin proteins such as histones compact and organize DNA. These compact structures guide the
interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.

Ribonucleic acid
Ribonucleic acid (RNA) functions in converting genetic information from genes into the amino acid sequences of
proteins. The three universal types of RNA include transfer RNA (tRNA), messenger RNA (mRNA), and ribosomal
RNA (rRNA). Messenger RNA acts to carry genetic sequence information between DNA and ribosomes, directing
protein synthesis. Ribosomal RNA is a major component of the ribosome, and catalyzes peptide bond formation.
Transfer RNA serves as the carrier molecule for amino acids to be used in protein synthesis, and is responsible for
decoding the mRNA. In addition, many other classes of RNA are now known.

Artificial nucleic acid analogs


Artificial nucleic acid analogs have been designed and synthesized by chemists, and include peptide nucleic acid,
morpholino- and locked nucleic acid, as well as glycol nucleic acid and threose nucleic acid. Each of these is
distinguished from naturally-occurring DNA or RNA by changes to the backbone of the molecule.

References
[1] Dahm, R (Jan 2008). "Discovering DNA: Friedrich Miescher and the early years of nucleic acid research". Human Genetics 122 (6): 565–81.
doi:10.1007/s00439-007-0433-0. ISSN 0340-6717. PMID 17901982.
[2] International Human Genome Sequencing Consortium (2001). "Initial sequencing and analysis of the human genome." (http:/ / www. nature.
com/ nature/ journal/ v409/ n6822/ pdf/ 409860a0. pdf) (PDF). Nature 409 (6822): 860–921. doi:10.1038/35057062. PMID 11237011. .
[3] Venter, JC, et al. (2001). "The sequence of the human genome." (http:/ / www. sciencemag. org/ cgi/ reprint/ 291/ 5507/ 1304. pdf) (PDF).
Science 291 (5507): 1304–1351. doi:10.1126/science.1058040. PMID 11181995. .
[4] Budowle B, van Daal A (April 2009). "Extracting evidence from forensic DNA analyses: future molecular biology directions".
BioTechniques 46 (5): 339–40, 342–50. doi:10.2144/000113136. PMID 19480629.
[5] Alberts, Bruce (2008). Molecular biology of the cell. New York: Garland Science. ISBN 0-8153-4105-9.
[6] Elson D (1965). "Metabolism of nucleic acids (macromolecular DNA and RNA)". Annu. Rev. Biochem. 34: 449–86.
doi:10.1146/annurev.bi.34.070165.002313. PMID 14321176.
[7] Brock, Thomas D.; Madigan, Michael T. (2009). Brock biology of microorganisms. Pearson / Benjamin Cummings. ISBN 0-321-53615-0.
[8] Mullis, Kary B. The Polymerase Chain Reaction (Nobel Lecture). 1993. (retrieved December 1, 2010) http:/ / nobelprize. org/ nobel_prizes/
chemistry/ laureates/ 1993/ mullis-lecture. html
Nucleic acid 302

[9] Verma S, Eckstein F (1998). "Modified oligonucleotides: synthesis and strategy for users". Annu. Rev. Biochem. 67: 99–134.
doi:10.1146/annurev.biochem.67.1.99. PMID 9759484.
[10] Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2007). Biochemistry. San Francisco: W.H. Freeman. ISBN 0-7167-6766-X.
[11] Gregory SG, Barlow KF, McLay KE, et al. (May 2006). "The DNA sequence and biological annotation of human chromosome 1". Nature
441 (7091): 315–21. doi:10.1038/nature04727. PMID 16710414.
[12] Rich A, RajBhandary UL (1976). "Transfer RNA: molecular structure, sequence, and properties". Annu. Rev. Biochem. 45: 805–60.
doi:10.1146/annurev.bi.45.070176.004105. PMID 60910.
[13] Watson JD, Crick FH (April 1953). "Molecular structure of nucleic acids; a structure for deoxyribose nucleic acid". Nature 171 (4356):
737–8. Bibcode 1953Natur.171..737W. doi:10.1038/171737a0. PMID 13054692.
[14] Ferré-D'Amaré AR, Doudna JA (1999). "RNA folds: insights from recent crystal structures". Annu Rev Biophys Biomol Struct 28: 57–73.
doi:10.1146/annurev.biophys.28.1.57. PMID 10410795.
[15] Gilbert, Walter G. 1980. DNA Sequencing and Gene Structure (Nobel Lecture) http:/ / nobelprize. org/ nobel_prizes/ chemistry/ laureates/
1980/ gilbert-lecture. html
[16] Sanger, Frederick. 1980. Determination of Nucleotide Sequences in DNA (Nobel Lecture) http:/ / nobelprize. org/ nobel_prizes/ chemistry/
laureates/ 1980/ sanger-lecture. html

Further reading
• Wolfram Saenger, Principles of Nucleic Acid Structure, 1984, Springer-Verlag New York Inc.
• Bruce Alberts, Alexander Johnson, Julian Lewis, Martin Raff, Keith Roberts, and Peter Walter Molecular Biology
of the Cell, 2007, ISBN 978-0-8153-4105-5. Fourth edition is available online through the NCBI Bookshelf: link
(http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=mboc4)
• Jeremy M Berg, John L Tymoczko, and Lubert Stryer, Biochemistry 5th edition, 2002, W H Freeman. Available
online through the NCBI Bookshelf: link (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=stryer)
• Astrid Sigel, Helmut Sigel and Roland K. O. Sigel, ed. (2012). Interplay between Metal Ions and Nucleic Acids.
Metal Ions in Life Sciences. 10. Springer. doi:10.1007/978-94-007-2172-2. ISBN 978-94-007-2171-5.

External links
• Interview with Aaron Klug, Nobel Laureate for structural elucidation of biologically important nucleic-acid
protein complexes (http://www.vega.org.uk/video/programme/122) provided by the Vega Science Trust.
• Nucleic Acids Research (Journal) (http://nar.oxfordjournals.org/)
• Nucleic Acids Book (free online book on the chemistry and biology of nucleic acids) (http://www.atdbio.com/
nucleic-acids-book)
Organelle 303

Organelle
Organelle
Latin organella

Code TH H1.00.01.0.00009 [1]

In cell biology, an organelle (


 /ɔrɡəˈnɛl/) is a specialized subunit
within a cell that has a specific
function, and is usually separately
enclosed within its own lipid bilayer.
The name organelle comes from the
idea that these structures are to cells
what an organ is to the body (hence the
name organelle, the suffix -elle being a
diminutive). Organelles are identified
by microscopy, and can also be
purified by cell fractionation. There are
many types of organelles, particularly Schematic of typical animal cell, showing subcellular components. Organelles: (1)
in eukaryotic cells. Prokaryotes were Nucleolus (2) Nucleus (3) Ribosomes (little dots) (4) Vesicle (5) Rough endoplasmic
reticulum (ER) (6) Golgi apparatus (7) Cytoskeleton (8) Smooth ER (9) Mitochondria
once thought not to have organelles,
(10) Vacuole (11) Cytosol (12) Lysosome (13) Centrioles within Centrosome
but some examples have now been
identified.[2]

History and terminology


In biology organs are defined as confined functional units within an organism.[3] The analogy of bodily organs to
microscopic cellular substructures is obvious, as from even early works, authors of respective textbooks rarely
elaborate on the distinction between the two.
Credited as the first[4][5][6] to use a diminutive of organ (i.e. little organ) for cellular structures was German zoologist
Karl August Möbius (1884), who used the term "organula" [7] (plural form of organulum, the diminutive of latin
organum). From the context, it is clear that he referred to reproduction related structures of protists. In a footnote,
which was published as a correction in the next issue of the journal, he justified his suggestion to call organs of
unicellular organisms "organella" since they are only differently formed parts of one cell, in contrast to multicellular
organs of multicellular organisms. Thus, the original definition was limited to structures of unicellular organisms.

It would take several years before organulum, or the later term organelle, became accepted and expanded in meaning
to include subcellular structures in multicellular organisms. Books around 1900 from Valentin Häcker,[8] Edmund
Wilson[9] and Oscar Hertwig[10] still referred to cellular organs. Later, both terms came to be used side by side:
Bengt Lidforss wrote 1915 (in German) about "Organs or Organells".[11]
Around 1920, the term organelle was used to describe propulsion structures ("motor organelle complex", i.e., flagella
and their anchoring)[12] and other protist structures, such as ciliates.[13] Alfred Kühn wrote about centrioles as
division organelles, although he stated that, for Vahlkampfias, the alternative 'organelle' or 'product of structural
build-up' had not yet been decided, without explaining the difference between the alternatives.[14]
Organelle 304

In his 1953 textbook, Max Hartmann used the term for extracellular (pellicula, shells, cell walls) and intracellular
skeletons of protists.[15]
Later, the now-widely-used[16][17][18][19] definition of organelle emerged, after which only cellular structures with
surrounding membrane had been considered organelles. However, the more original definition of subcellular
functional unit in general still coexists.[20][21]
In 1978, Albert Frey-Wyssling suggested that the term organelle should refer only to structures that convert energy,
such as centrosomes, ribosomes, and nucleoli.[22][23] This new definition, however, did not win wide recognition.

Examples
While most cell biologists consider the term organelle to be synonymous with "cell compartment", other cell
biologists choose to limit the term organelle to include only those that are DNA-containing, having originated from
formerly-autonomous microscopic organisms acquired via endosymbiosis.[24][25][26]
Under this definition, there would only be two broad classes of organelles (i.e. those that contain their own DNA,
and have originated from endosymbiotic bacteria):
• mitochondria (in almost all eukaryotes)
• plastids[27] (e.g. in plants, algae,and some protists).
Other organelles are also suggested to have endosymbiotic origins, but do not contain their own DNA (notably the
flagellum - see evolution of flagella).
Under the more restricted definition of membrane-bound structures, some parts of the cell do not qualify as
organelles. Nevertheless, the use of organelle to refer to non-membrane bound structures such as ribosomes is
common.[28] This has led some texts to delineate between membrane-bound and non-membrane bound
organelles.[29] These structures are large assemblies of macromolecules that carry out particular and specialized
functions, but they lack membrane boundaries. Such cell structures include:
• ribosome
• cytoskeleton
• flagellum
• centriole and microtubule-organizing center (MTOC)
• proteasome.

Eukaryotic organelles
Eukaryotes are one of the structurally complex cell type, and by definition are in part organized by smaller interior
compartments, that are themselves enclosed by lipid membranes that resemble the outermost cell membrane. The
larger organelles, such as the nucleus and vacuoles, are easily visible with the light microscope. They were among
the first biological discoveries made after the invention of the microscope.
Not all eukaryotic cells have each of the organelles listed below. Exceptional organisms have cells which do not
include some organelles that might otherwise be considered universal to eukaryotes (such as mitochondria).[30] There
are also occasional exceptions to the number of membranes surrounding organelles, listed in the tables below (e.g.,
some that are listed as double-membrane are sometimes found with single or triple membranes). In addition, the
number of individual organelles of each type found in a given cell varies depending upon the function of that cell.
Organelle 305

Major eukaryotic organelles


Organelle Main function Structure Organisms Notes

chloroplast photosynthesis, traps energy from sunlight double-membrane plants, protists has some genes; theorized to be engulfed
(plastid) compartment (rare kleptoplastic by the ancestral eukaryotic cell
organisms) (endosymbiosis)

endoplasmic translation and folding of new proteins single-membrane all eukaryotes rough endoplasmic reticulum is covered
reticulum (rough endoplasmic reticulum), expression compartment with ribosomes, has folds that are flat
of lipids (smooth endoplasmic reticulum) sacs; smooth endoplasmic reticulum has
folds that are tubular

Golgi sorting, packaging, processing and single-membrane all eukaryotes cis-face (convex) nearest to rough
apparatus modification of proteins compartment endoplasmic reticulum; trans-face
(concave) farthest from rough
endoplasmic reticulum

mitochondria energy production from the oxidation of double-membrane most eukaryotes has some DNA; theorized to be engulfed
glucose substances and the release of compartment by an ancestral eukaryotic cell
adenosine triphosphate (endosymbiosis)

vacuole storage,transportation, helps maintain single-membrane eukaryotes


homeostasis compartment

nucleus DNA maintenance, controls all activities double-membrane most eukaryotes contains bulk of genome
of the cell, RNA transcription compartment

Mitochondria and chloroplasts, which have double-membranes and their own DNA, are believed to have originated
from incompletely consumed or invading prokaryotic organisms, which were adopted as a part of the invaded cell.
This idea is supported in the Endosymbiotic theory.

Minor eukaryotic organelles and cell components


Organelle/Macromolecule Main function Structure Organisms

acrosome helps spermatoza fuse with ovum single-membrane many animals


compartment

autophagosome vesicle which sequesters cytoplasmic material double-membrane all eukaryotic cells
and organelles for degradation compartment

centriole anchor for cytoskeleton, helps in cell division Microtubule protein animals
by forming spindle fibers

cilium Microtubule protein animals, protists, few plants


movement in or of external medium; "critical
[31]
developmental signaling pathway".

eyespot apparatus detects light, allowing phototaxis to take place green algae and other unicellular
photosynthetic organisms such as
euglenids

glycosome carries out glycolysis single-membrane Some protozoa, such as Trypanosomes.


compartment

glyoxysome conversion of fat into sugars single-membrane plants


compartment

hydrogenosome energy & hydrogen production double-membrane a few unicellular eukaryotes


compartment

lysosome breakdown of large molecules (e.g., proteins + single-membrane most eukaryotes


polysaccharides) compartment
Organelle 306

melanosome pigment storage single-membrane animals


compartment

mitosome probably plays a role in Fe-S cluster assembly double-membrane a few unicellular eukaryotes which lack
compartment mitochondria

myofibril myocyte contraction bundled filaments animals

nucleolus ribosome production protein-DNA-RNA most eukaryotes

parenthesome not characterized not characterized fungi

peroxisome breakdown of metabolic hydrogen peroxide single-membrane all eukaryotes


compartment

proteasome degradation of unneeded or damaged proteins very large protein All eukaryotes, all archaea, some bacteria
by proteolysis complex

ribosome translation of RNA into proteins RNA-protein eukaryotes, prokaryotes

vesicle material transport single-membrane all eukaryotes


compartment

Other related structures:


• cytosol
• endomembrane system
• nucleosome
• microtubule
• cell membrane

Prokaryotic organelles
Prokaryotes are not as structurally
complex as eukaryotes, and were once
thought not to have any internal
structures enclosed by lipid
membranes. In the past, they were
often viewed as having little internal
organization; but, slowly, details are (A) Electron micrograph of Halothiobacillus neapolitanus cells, arrows highlight
emerging about prokaryotic internal carboxysomes. (B) Image of intact carboxysomes isolated from H. neapolitanus. Scale
[32]
bars are 100 nm.
structures. An early false turn was the
idea developed in the 1970s that
bacteria might contain membrane folds termed mesosomes, but these were later shown to be artifacts produced by
the chemicals used to prepare the cells for electron microscopy.[33]

However, more recent research has revealed that at least some prokaryotes have microcompartments such as
carboxysomes. These subcellular compartments are 100 - 200 nm in diameter and are enclosed by a shell of
proteins.[2] Even more striking is the description of membrane-bound magnetosomes in bacteria,[34][35] as well as the
nucleus-like structures of the Planctomycetes that are surrounded by lipid membranes.[36]
Organelle 307

Prokaryotic organelles and cell components


Organelle/Macromolecule Main function Structure Organisms

carboxysome carbon fixation protein-shell compartment some bacteria

chlorosome photosynthesis light harvesting complex green sulfur bacteria

flagellum movement in external medium protein filament some prokaryotes and eukaryotes

magnetosome magnetic orientation inorganic crystal, lipid membrane magnetotactic bacteria

nucleoid DNA maintenance, transcription to RNA DNA-protein prokaryotes

plasmid DNA exchange circular DNA some bacteria

ribosome translation of RNA into proteins RNA-protein eukaryotes, prokaryotes

thylakoid photosynthesis photosystem proteins and pigments mostly cyanobacteria

Proteins and organelles


The function of a protein is closely correlated with the organelle in which it resides. Some methods were proposed
for predicting the organelle in which an uncharacterized protein is located according to its amino acid
composition[37][38] and some methods were based on pseudo amino acid composition.[39][40][41][42]

References
[1] http:/ / www. unifr. ch/ ifaa/ Public/ EntryPage/ ViewTH/ THh100. html
[2] Kerfeld, Ca; Sawaya, Mr; Tanaka, S; Nguyen, Cv; Phillips, M; Beeby, M; Yeates, To (August 2005). "Protein structures forming the shell of
primitive bacterial organelles.". Science 309 (5736): 936–8. Bibcode 2005Sci...309..936K. doi:10.1126/science.1113397. PMID 16081736.
[3] Lynsey Peterson (2010-04-17). "Mastering the Parts of a Cell" (http:/ / www. lessonplanet. com/ directory_articles/ biology_lesson_plans/
19_April_2010/ 363/ mastering_the_parts_of_a_cell). Lesson Planet. . Retrieved 2010-04-19.
[4] Bütschli, O. (1888). Dr. H. G. Bronn's Klassen u. Ordnungen des Thier-Reichs wissenschaftlich dargestellt in Wort und Bild. Erster Band.
Protozoa. Dritte Abtheilung: Infusoria und System der Radiolaria.. pp. 1412. "Die Vacuolen sind demnach in strengem Sinne keine
beständigen Organe oder O r g a n u l a (wie Möbius die Organe der Einzelligen im Gegensatz zu denen der Vielzelligen zu nennen
vorschlug)."
[5] Amer. Naturalist. 23, 1889, S. 183: „It may possibly be of advantage to use the word organula here instead of organ, following a suggestion
by Möbius. Functionally-differentiated multicellular aggregates in multicellular forms or metazoa are in this sense organs, while, for
functionally-differentiated portions of unicellular organisms or for such differentiated portions of the unicellular germ-elements of metazoa,
the diminutive organula is appropriate.“ Cited after : Oxford English Dictionary online, entry for „organelle“.
[6] 'Journal de l'anatomie et de la physiologie normales et pathologiques de l'homme et des animaux' at Google Books (http:/ / books. google.
com/ books?id=yAQwAAAAIAAJ& q=Organulum+ OR+ Organula+ OR+ Organella+ date:1800-1900& dq=Organulum+ OR+ Organula+
OR+ Organella+ date:1800-1900& as_brr=0& pgis=1)
[7] Möbius, K. (September 1884). "Das Sterben der einzelligen und der vielzelligen Tiere. Vergleichend betrachtet" (http:/ / www. dietzellab. de/
goodies/ history/ ). Biologisches Centralblatt 4 (13,14): 389–392, 448. . "Während die Fortpflanzungszellen der vielzelligen Tiere unthätig
fortleben bis sie sich loslösen, wandern und entwickeln, treten die einzelligen Tiere auch durch die an der Fortpflanzung beteiligten
Leibesmasse in Verkehr mit der Außenwelt und viele bilden sich dafür auch besondere Organula". Footnote on p. 448: "Die Organe der
Heteroplastiden bestehen aus vereinigten Zellen. Da die Organe der Monoplastiden nur verschieden ausgebildete Teile e i n e r Zelle sind
schlage ich vor, sie „Organula“ zu nennen"
[8] Häcker, Valentin (1899). Zellen- und Befruchtungslehre. Jena: Verlag von Gustav Fisher.
[9] Wilson, Edmund B. (1900). The cell in Development and Inheritance (second ed.). New York: The Macmillan Company.
[10] Hertwig, Oscar (1906). Allgemeine Biologie. Zweite Auflage des Lehrbuchs "Die Zelle und die Gewebe". Jena: Verlag von Gustav Fischer.
[11] Lidforss, B. (1915). "Protoplasma". In Paul Hinneberg. Allgemeine Biologie. Leipzig, Berlin: Verlag von B.G.Teubner. pp. 227 (218–264).
"Eine Neubildung dieser Organe oder Organellen findet wenigstens bei höheren Pflanzen nicht statt"
[12] Kofoid CA, Swezy O (1919). "Flagellate Affinities of Trichonympha". Proc. Natl. Acad. Sci. U.S.A. 5 (1): 9–16.
Bibcode 1919PNAS....5....9K. doi:10.1073/pnas.5.1.9. PMC 1091514. PMID 16576345.
[13] Cl. Hamburger, Handwörterbuch der Naturw. Bd. V, .S. 435. Infusorien. cited after Petersen, Hans (May 1919). "Über den Begriff des
Lebens und die Stufen der biologischen Begriffsbildung". Archiv für Entwicklungsmechanik der Organismen (now: Development Genes and
Evolution) 45 (3): 423–442. doi:10.1007/BF02554406. ISSN 1432-041X.
Organelle 308

[14] Kühn, Alfred (1920). "Untersuchungen zur kausalen Analyse der Zellteilung. I. Teil: Zur Morphologie und Physiologie der Kernteilung von
Vahlkampfia bistadialis". Archiv für Entwicklungsmechanik der Organismen (now: Development Genes and Evolution) 46 (2–3): 259–327.
doi:10.1007/BF02554424. "die Alternative: Organell oder Produkt der Strukturbildung"
[15] Hartmann, Max (1953). Allgemeine Biologie (4. Aufl. ed.). Stuttgart: Gustav Fisher Verlag.
[16] Nultsch, Allgemeine Botanik, 11. Aufl. 2001, Thieme Verlag
[17] Wehner/Gehring, Zoologies, 23. Aufl. 1995, Thieme Verlag
[18] Alberts, Bruce et al. (2002). The Molecular Biology of the Cell, 4th ed., Garland Science, 2002, ISBN 0-8153-3218-1. online via
"NCBI-Bookshelf" (http:/ / www. ncbi. nlm. nih. gov/ entrez/ query. fcgi?db=Books& itool=toolbar)
[19] Brock, Mikrobiologie, 2. korrigierter Nachdruck (2003), der 1. Aufl. von 2001
[20] Strasburgers Lehrbuch der Botanik für Hochschulen, 35. Aufl. (2002), S. 42
[21] Alliegro MC, Alliegro MA, Palazzo RE (June 2006). "Centrosome-associated RNA in surf clam oocytes". Proc. Nat. Acad. Sci. USA 103
(24): 9037–9038. Bibcode 2006PNAS..103.9034A. doi:10.1073/pnas.0602859103. PMC 1482561. PMID 16754862.
[22] Frey-Wyssling, A (1978). "Definition of the organell concept" (in German). Gegenbaurs morphologisches Jahrbuch 124 (3): 455–7.
ISSN 0016-5840. PMID 689352.
[23] Albert Frey-Wyssling: Concerning the concept "Organelle". Experientia 34, 547 (1978). doi:10.1007/BF01935984
[24] Keeling, Pj; Archibald, Jm (April 2008). "Organelle evolution: what's in a name?" (http:/ / www. sciencedirect. com/
science?_ob=ArticleURL& _udi=B6VRT-4SB9SNV-K& _user=5731894& _rdoc=1& _fmt=& _orig=search& _sort=d& view=c&
_version=1& _urlVersion=0& _userid=5731894& md5=2f16ed5ee031ea9cdce4f7e2a934a8fa). Current biology : CB 18 (8): R345–7.
doi:10.1016/j.cub.2008.02.065. PMID 18430636. . Retrieved 2008-08-07.
[25] Imanian B, Carpenter KJ, Keeling PJ (March 2007). "Mitochondrial genome of a tertiary endosymbiont retains genes for electron transport
proteins" (http:/ / www3. interscience. wiley. com/ cgi-bin/ fulltext/ 118000427/ HTMLSTART). The Journal of eukaryotic microbiology 54
(2): 146–53. doi:10.1111/j.1550-7408.2007.00245.x. PMID 17403155. .
[26] Mullins, Christopher (2004). "Theory of Organelle Biogenesis: A Historical Perspective". The Biogenesis of Cellular Organelles. Springer
Science+Business Media, National Institutes of Health. ISBN 0-306-47990-7.
[27] C.Michael Hogan. 2010. Deoxyribonucleic acid. Encyclopedia of Earth. National Council for Science and the Environment. (http:/ / www.
eoearth. org/ articles/ view/ 158858/ ?topic=49496) eds. S.Draggan and C.Cleveland. Washington DC
[28] Campbell and Reece, Biology6th edition, Benjamin Cummings, 2002
[29] Cormack, Introduction to Histology, Lippincott, 1984
[30] Fahey RC, Newton GL, Arrack B, Overdank-Bogart T, Baley S (1984). "Entamoeba histolytica: a eukaryote without glutathione
metabolism". Science 224 (4644): 70–72. Bibcode 1984Sci...224...70F. doi:10.1126/science.6322306. PMID 6322306.
[31] Badano, Jose L.; Norimasa Mitsuma, Phil L. Beales, Nicholas Katsanis (September 2006). "The Ciliopathies : An Emerging Class of Human
Genetic Disorders" (http:/ / arjournals. annualreviews. org/ doi/ abs/ 10. 1146/ annurev. genom. 7. 080505. 115610). Annual Review of
Genomics and Human Genetics 7: 125–148. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. . Retrieved 2008-06-15.
[32] Tsai Y, Sawaya MR, Cannon GC, Cai F, Williams EB, Heinhorst S, Kerfeld CA, Yeates TO (Jun 2007). "Structural Analysis of CsoS1A
and the Protein Shell of the Halothiobacillus neapolitanus Carboxysome" (http:/ / biology. plosjournals. org/ perlserv/
?request=get-document& doi=10. 1371/ journal. pbio. 0050144). PLoS Biology 5 (6): e144. doi:10.1371/journal.pbio.0050144. PMC 1872035.
PMID 17518518. .
[33] Ryter A (1988). "Contribution of new cryomethods to a better knowledge of bacterial anatomy". Ann. Inst. Pasteur Microbiol. 139 (1):
33–44. doi:10.1016/0769-2609(88)90095-6. PMID 3289587.
[34] Komeili A, Li Z, Newman DK, Jensen GJ (2006). "Magnetosomes are cell membrane invaginations organized by the actin-like protein
MamK". Science 311 (5758): 242–5. Bibcode 2006Sci...311..242K. doi:10.1126/science.1123231. PMID 16373532.
[35] Scheffel A, Gruska M, Faivre D, Linaroudis A, Plitzko JM, Schüler D (2006). "An acidic protein aligns magnetosomes along a filamentous
structure in magnetotactic bacteria". Nature 440 (7080): 110–4. Bibcode 2006Natur.440..110S. doi:10.1038/nature04382. PMID 16299495.
[36] Fuerst JA (2005). "Intracellular compartmentation in planctomycetes". Annu. Rev. Microbiol. 59: 299–328.
doi:10.1146/annurev.micro.59.030804.121258. PMID 15910279.
[37] Cedano, J.; Aloy, P.; P'erez-Pons, J. A.; Querol, E. (1997). "Relation between amino acid composition and cellular location of proteins". J.
Mol. Biol. 266 (3): 594–600. doi:10.1006/jmbi.1996.0804. PMID 9067612.
[38] Chou, K. C.; Elrod, D. W. (1999). "Protein subcellular location prediction". Protein Engineering 12 (2): 107–118.
doi:10.1093/protein/12.2.107. PMID 10195282.
[39] Kuo-Chen Chou (2001) Prediction of protein cellular attributes using pseudo amino acid composition. PROTEINS: Structure, Function, and
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[40] Mundra, P.; Kumar, M.; Kumar, K. K.; Jayaraman, V. K.; Kulkarni, B. D. (2007). "Using pseudo amino acid composition to predict protein
subnuclear localization: Approached with PSSM". Pattern Recognition Letters 28 (13): 1610–1615. doi:10.1016/j.patrec.2007.04.001.
[41] Du, P.; Cao, S.; Li, Y. (2009). "SubChlo: predicting protein subchloroplast locations with pseudo-amino acid composition and the
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[42] Li, F. M.; Li, Q. Z. (2008). "Predicting protein subcellular location using Chou's pseudo amino acid composition and improved hybrid
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Organelle 309

External links
• Tree of Life Eukaryotes (http://tolweb.org/Eukaryotes/3)

Parasitology
Parasitology is the study of parasites, their hosts, and
the relationship between them. As a biological
discipline, the scope of parasitology is not determined
by the organism or environment in question, but by
their way of life. This means it forms a synthesis of
other disciplines, and draws on techniques from fields
such as cell biology, bioinformatics, biochemistry,
molecular biology, immunology, genetics, evolution
and ecology.

Fields
Adult black fly (Simulium yahense) with (Onchocerca volvulus)
The study of these diverse organisms means that the emerging from the insect's antenna. The parasite is responsible for
subject is often broken up into simpler, more focused the disease known as river blindness in Africa. Sample was
units, which use common techniques, even if they are chemically fixed and critical point dried, then observed using
conventional scanning electron microscopy. Magnified 100×.
not studying the same organisms or diseases. Much
research in parasitology falls somewhere between two
or more of these definitions. In general, the study of prokaryotes falls under the field of bacteriology rather than
parasitology.

Medical parasitology
One of the largest fields in parasitology, medical parasitology is the subject which deals with the parasites that infect
humans, the diseases caused by them, clinical picture and the response generated by humans against them. It is also
concerned with the various methods of their diagnosis, treatment and finally their prevention & control. A parasite is
an organism that live on or within another organism called the host . These include organisms such as:
• Plasmodium spp., the protozoan parasite which causes malaria. The four species of malaria parasites infective to
humans are Plasmodium falciparum,Plasmodium malariae, Plasmodium vivax & Plasmodium ovale.
• Leishmania donovani, the unicellular organism which causes leishmaniasis
• Entamoeba and Giardia, which cause intestinal infections (dysentery and diarrhoea)
• Multicellular organisms and worms such as Schistosoma spp., Wuchereria bancrofti, Necator americanus
(hookworm) and Taenia spp. (tapeworm)
• Ectoparasites such as ticks, scabies and lice
Medical parasitology can involve drug development, epidemiological studies and study of zoonoses.
Parasitology 310

Veterinary parasitology
The study of parasites that cause economic losses in agriculture or aquaculture operations, or which infect
companion animals. Examples of species studied are:
• Lucilia sericata, a blowfly, which lays eggs on the skins of farm animals. The maggots hatch and burrow into the
flesh, distressing the animal and causing economic loss to the farmer
• Otodectes cynotis, the cat ear mite, responsible for Canker.
• Gyrodactylus salaris, a monogenean parasite of salmon, which can wipe out populations which are not resistant.

Structural parasitology
This is the study of structures of proteins from parasites. Determination of parasitic protein structures may help to
better understand how these proteins function differently from homologous proteins in humans. In addition, protein
structures may inform the process of drug discovery.

Quantitative parasitology
Parasites exhibit an aggregated distribution among host individuals, thus the majority of parasites live in the minority
of hosts. This feature forces parasitologists to use advanced biostatistical methodologies.

Parasite ecology
Parasites can provide information about host population ecology. In fisheries biology, for example, parasite
communities can be used to distinguish distinct populations of the same fish species co-inhabiting a region.
Additionally, parasites possess a variety of specialized traits and life-history strategies that enable them to colonize
hosts. Understanding these aspects of parasite ecology, of interest in their own right, can illuminate
parasite-avoidance strategies employed by hosts

Conservation biology of parasites


Conservation biology is concerned with the protection and preservation of vulnerable species, including parasites. A
large proportion of parasite species are threatened by extinction, partly due to efforts to eradicate parasites which
infect humans or domestic animals, or damage human economy, but also caused by the decline or fragmentation of
host populations and the extinction of host species. to infect human

Taxonomy and phylogenetics


The huge diversity between parasitic organisms creates a challenge for biologists who wish to describe and catalogue
them. Recent developments in using DNA to identify separate species and to investigate the relationship between
groups at various taxonomic scales has been enormously useful to parasitologists, as many parasites are highly
degenerate, disguising relationships between species.
Parasitology 311

External links
• Online lectures in parasitology [1], University of South Carolina
• Companion Animal Parasite Council [2]
• American Society of Parasitologists [3]
• ARC-NHMRC Research Network for Parasitology [4]
• Australian Society for Parasitology [5]
• British Society for Parasitology [6]
• Chinese Society of Parasitology [7]
• Czech Society for Parasitology [8]
• European Scientific Counsel Companion Animal Parasites [9]
• Hungarian Society of Parasitologists [10]
• Indian Society of Parasitology [11]
• Israel Society for Parasitology, Protozoology and Tropical Diseases [12]
• Japanese Society of Parasitology [13]
• Korean Society for Parasitology [14]
• Nederlandse Vereniging voor Parasitologie [15]
• New Zealand Society for Parasitology [16]
• Scandinavian and Baltic Societies for Parasitology [17]
• Department of Parasitology, Cluj-Napoca, Romania [18]
• An Introduction to Parasitology [19]
• Parasites World [20]
• Institute of Parasitology [21], McGill University

References
[1] http:/ / media. med. sc. edu/ microbiology2007/
[2] http:/ / www. capcvet. org/
[3] http:/ / asp. unl. edu
[4] http:/ / www. parasite. org. au/ arcnet
[5] http:/ / www. parasite. org. au
[6] http:/ / www. bsp. uk. net/
[7] http:/ / www. ips. ioz. ac. cn/ Parasitologye. htm
[8] http:/ / www. parazitologie. cz
[9] http:/ / www. esccap. org/
[10] http:/ / www. parazitak. hu
[11] http:/ / www. parasitologyindia. org
[12] http:/ / parasitology-soc. md. huji. ac. il/
[13] http:/ / jsp. tm. nagasaki-u. ac. jp/ ~parasite/
[14] http:/ / www. parasitol. or. kr/ eng/
[15] http:/ / www. parasitologie. nl
[16] http:/ / nzsp. rsnz. govt. nz/
[17] http:/ / www. hi. is/ pub/ sbsp/
[18] http:/ / www. zooparaz. net
[19] http:/ / knol. google. com/ k/ klaus-rohde/ parasitism-an-introduction-to/ xk923bc3gp4/ 51#
[20] http:/ / parasites-world. com/
[21] http:/ / www. mcgill. ca/ parasitology/
Peptidoglycan 312

Peptidoglycan
Peptidoglycan, also known as murein, is a polymer consisting of sugars and amino acids that forms a mesh-like
layer outside the plasma membrane of bacteria (but not Archaea), forming the cell wall. The sugar component
consists of alternating residues of β-(1,4) linked N-acetylglucosamine and N-acetylmuramic acid. Attached to the
N-acetylmuramic acid is a peptide chain of three to five amino acids. The peptide chain can be cross-linked to the
peptide chain of another strand forming the 3D mesh-like layer.[1] Some Archaea have a similar layer of
pseudopeptidoglycan or pseudomurein, where the sugar residues are β-(1,3) linked N-acetylglucosamine and
N-acetyltalosaminuronic acid. That is why the cell wall of Archaea is insensitive to lysozyme.[2] Peptidoglycan
serves a structural role in the bacterial cell wall, giving structural strength, as well as counteracting the osmotic
pressure of the cytoplasm. A common misconception is that peptidoglycan gives the cell its shape; however, whereas
peptidoglycan helps maintain the structural strength of the cell, it is actually the MreB protein that facilitates cell
shape .[3][4] Peptidoglycan is also involved in binary fission during bacterial cell reproduction.
The peptidoglycan layer is substantially thicker in Gram-positive bacteria (20 to 80 nanometers) than in
Gram-negative bacteria (7 to 8 nanometers), with the attachment of the S-layer. Peptidoglycan forms around 90% of
the dry weight of Gram-positive bacteria but only 10% of Gram-negative strains. Thus, presence of high levels of
peptidoglycan is the primary determinant of the characterisation of bacteria as gram-positive.[5] In Gram-positive
strains, it is important in attachment roles and stereotyping purposes.[6] For both Gram-positive and Gram-negative
bacteria, particles of approximately 2 nm can pass through the peptidoglycan.[7]

Structure
The peptidoglycan layer in the bacterial cell wall is a crystal lattice
structure formed from linear chains of two alternating amino sugars,
namely N-acetylglucosamine (GlcNAc or NAG) and N-acetylmuramic
acid (MurNAc or NAM). The alternating sugars are connected by a
β-(1,4)-glycosidic bond. Each MurNAc is attached to a short (4- to
5-residue) amino acid chain, containing L-alanine, D-glutamic acid,
meso-diaminopimelic acid, and D-alanine in the case of Escherichia
coli (a Gram-negative bacteria) or L-alanine, D-glutamine, L-lysine, and
D-alanine with a 5-glycine interbridge between tetrapeptides in the case Peptidoglycan.
of Staphylococcus aureus (a Gram-positive bacteria). These amino
acids, except the L-amino acids, do not occur in proteins and are thought to help protect against attacks by most
peptidases.

Cross-linking between amino acids in different linear amino sugar chains occurs with the help of the enzyme
transpeptidase and results in a 3-dimensional structure that is strong and rigid. The specific amino acid sequence and
molecular structure vary with the bacterial species.[8]
Peptidoglycan 313

The structure of peptidoglycan. Gram-positive cell wall Penicillin binding protein


forming cross-links in
newly formed bacterial
cell wall.

Antibiotic inhibition
Some antibacterial drugs such as penicillin interfere with the production of peptidoglycan by binding to bacterial
enzymes known as penicillin-binding proteins or transpeptidases.[6] Penicillin-binding proteins form the bonds
between oligopeptide crosslinks in peptidoglycan. For a bacterial cell to reproduce through binary fission, more than
a million peptidoglycan subunits (NAM-NAG+oligopeptide) must be attached to existing subunits.[9] Mutations in
transpeptidases that lead to reduced interactions with an antibiotic are a significant source of emerging antibiotic
resistance.[10]
Considered the human body's own antibiotic, lysozymes found in tears work by breaking the β-(1,4)-glycosidic
bonds in peptidoglycan (see below) and thereby destroying many bacterial cells. Antibiotics such as penicillin
commonly target bacterial cell wall formation (of which peptidoglycan is an important component) because animal
cells do not have cell walls.

Biosynthesis
The peptidoglycan monomers are synthesized in the cytosol and are then attached to a membrane carrier bactoprenol.
Bactoprenol transports peptidoglycan monomers across the cell membrane where they are inserted into the existing
peptidoglycan.[11]
In the first step of peptidoglycan synthesis, the glutamine, which is an amino acid, donates an amino group to a
sugar, fructose 6-phosphate. This turns fructose 6-phosphate into glucosamine-6-phosphate. In step two, an acetyl
group is transferred from acetyl CoA to the amino group on the glucosamine-6-phosphate creating
N-acetyl-glucosamine-6-phosphate.[12] In step three of the synthesis process, the N-acetyl-glucosamine-6-phosphate
is isomerized, which will change N-acetyl-glucosamine-6-phosphate to N-acetyl-glucosamine-1-phosphate.[12]
In step four, the phosphate-N-acetyl-glucosamine-1-phosphate, which is now a mono phosphate, attacks UTP.
Uridine triphosphate, which is a pyrimidine nucleotide, has the ability to act as an energy source. When UDP is used
as an energy source, it gives off an inorganic phosphate. In this particular reaction after the monophosphate has
attacked the UTP, a phosphate is given off as pyrophosphate, an inorganic phosphate, and is replaced by the
monophosphate, creating UDP-Nacetylglucosamine (2,4. This initial stage, is used to create the precursor for the
NAG in peptidoglycan.
In step 5, some of the UDP-Nacetylglucosamine (UDP-GlcNAc) is converted to UDP-MurNAc (UDP-N
acetylmuramic acid) by the addition of a lactyl group to the glucosamine. Also in this reaction, C3 hydroxyl group
will remove a phosphate form the alpha carbon of phosphenol pyruvate. This creates what is called an enol
derivative that will be reduced to a “lactyl moiety” by NADPH in step six.[12]
Peptidoglycan 314

In step 7, the UDP–MurNAc is converted to UDP-MurNAC pentapeptide by the addition of five amino acids,
usually including the dipeptide D-alanyl-D-alanine.[12] Each of these reactions requires the energy source ATP.[12]
This is all referred to as Stage one.
Stage two is occurs in the cytoplasmic membrane. It is in the membrane where a lipid carrier called bactoprenol
carries peptidoglycan precursors through the cell membrane. Bactoprenol will attack the UDP-MurNAc penta,
creating a PP-MurNac penta, which is now a lipid. UDP-GlcNAc is then transported to MurNAc, creating
Lipid-PP-MurNAc penta-GlcNAc, a disaccharide, also a precursor to peptidoglycan.[12] How this molecule is
transported through the membrane is still not understood. However, once it is there, it is added to the growing glycan
chain.[12] The next reaction is known as tranglycosylation. In the reaction, the hydroxyl group of the GlcNAc will
attach to the MurNAc in the glycan, which will displace the lipid-PP from the glycan chain. The enzyme responsible
for this is transglycosylase.[12]

References
[1] Animation of Synthesis of Peptidoglycan Layer (http:/ / pharmaxchange. info/ press/ 2011/ 03/
animation-of-synthesis-of-peptidoglycan-layer/ )
[2] Madigan, M. T., J. M. Martinko, P. V. Dunlap, and D. P. Clark. Brock biology of microorganisms. 12th ed. San Francisco, CA:
Pearson/Benjamin Cummings, 2009.
[3] van den Ent F, Amos LA, Löwe J (2001). "Prokaryotic origin of the actin cytoskeleton." (http:/ / www. ncbi. nlm. nih. gov/ entrez/ eutils/
elink. fcgi?dbfrom=pubmed& tool=sumsearch. org/ cite& retmode=ref& cmd=prlinks& id=11544518). Nature 413 (6851): 39–44.
doi:10.1038/35092500. PMID 11544518. .
[4] van den Ent F, Johnson CM, Persons L, de Boer P, Löwe J (2010). "Bacterial actin MreB assembles in complex with cell shape protein
RodZ.". EMBO J 29 (6): 1081–90. doi:10.1038/emboj.2010.9. PMC 2845281. PMID 20168300.
[5] C.Michael Hogan. 2010. Bacteria. Encyclopedia of Earth. eds. Sidney Draggan and C.J.Cleveland, National Council for Science and the
Environment, Washington DC (http:/ / www. eoearth. org/ article/ Bacteria?topic=49480)
[6] Salton MRJ, Kim KS (1996). Structure. In: Baron's Medical Microbiology (Barron S et al., eds.) (http:/ / www. ncbi. nlm. nih. gov/ books/
bv. fcgi?rid=mmed. section. 289#297) (4th ed.). Univ of Texas Medical Branch. ISBN 0-9631172-1-1. .
[7] Demchick PH, Koch AL (1 February 1996). "The permeability of the wall fabric of Escherichia coli and Bacillus subtilis" (http:/ / jb. asm.
org/ cgi/ reprint/ 178/ 3/ 768). Journal of Bacteriology 178 (3): 768–73. PMC 177723. PMID 8550511. .
[8] Ryan KJ, Ray CG (editors) (2004). Sherris Medical Microbiology (4th ed.). McGraw Hill. ISBN 0-8385-8529-9.
[9] Bauman R (2007). 2nd. ed. Microbiology with Diseases by Taxonomy. Benjamin Cummings. ISBN 0-8053-7679-8.
[10] Spratt BG (April 1994). "Resistance to antibiotics mediated by target alterations" (http:/ / www. sciencemag. org/ cgi/
pmidlookup?view=long& pmid=8153626). Science (New York) 264 (5157): 388–93. doi:10.1126/science.8153626. PMID 8153626. .
[11] "II. THE PROKARYOTIC CELL: BACTERIA" (http:/ / student. ccbcmd. edu/ courses/ bio141/ lecguide/ unit1/ prostruct/ cw. html). .
Retrieved 1. MAY 2011.
[12] White, D. (2007). The physiology and biochemistry of prokaryates (3rd ed.). NY: Oxford University Press Inc..

External links
• Diagrammatic representation of peptidoglycan structures. (http://www.ncbi.nlm.nih.gov/books/bv.
fcgi?rid=mmed.figgrp.298)
Plant 315

Plant
Plants
Temporal range:
Early Cambrian to recent, but see text,

Scientific classification
Domain: Eukaryota
(unranked): Archaeplastida
Kingdom: Plantae
Haeckel, 1866[1]
Divisions
Green algae
• Chlorophyta
• Charophyta
Land plants (embryophytes)
• Non-vascular land plants (bryophytes)
• Marchantiophyta—liverworts
• Anthocerotophyta—hornworts
• Bryophyta—mosses
• †Horneophytopsida
• Vascular plants (tracheophytes)
• †Rhyniophyta—rhyniophytes
• †Zosterophyllophyta—zosterophylls
• Lycopodiophyta—clubmosses
• †Trimerophytophyta—trimerophytes
• Pteridophyta—ferns and horsetails
• †Progymnospermophyta
• Seed plants (spermatophytes)
• †Pteridospermatophyta—seed ferns
• Pinophyta—conifers
• Cycadophyta—cycads
• Ginkgophyta—ginkgo
• Gnetophyta—gnetae
• Magnoliophyta—flowering plants
†Nematophytes

Plants, also called green plants (Viridiplantae in Latin), are living organisms of the kingdom Plantae including
such multicellular groups as flowering plants, conifers, ferns and mosses, as well as, depending on definition, the
green algae, but not red or brown seaweeds like kelp, nor fungi or bacteria.
Plant 316

Green plants have cell walls with cellulose and characteristically obtain most of their energy from sunlight via
photosynthesis using chlorophyll contained in chloroplasts, which gives them their green color. Some plants are
parasitic and may not produce normal amounts of chlorophyll or photosynthesize. Plants are also characterized by
sexual reproduction, modular and indeterminate growth, and an alteration of generations, although asexual
reproduction is common, and some plants bloom only once while others bear only one bloom.
Precise numbers are difficult to determine, but as of 2010, there are thought to be 300–315 thousand species of
plants, of which the great majority, some 260–290 thousand, are seed plants (see the table below).[2] Green plants
provide most of the world's free oxygen and are the basis of most of the earth's ecologies, especially on land. Plants
described as grains, fruits and vegetables form mankind's basic foodstuffs, and have been domesticated for millennia.
Plants enrich our lives as flowers and ornaments. Until recently and in great variety they have served as the source of
most of our medicines and drugs. Their scientific study is known as botany.

Definition
Plants are one of the two groups into which all living things have been traditionally divided; the other is animals. The
division goes back at least as far as Aristotle (384 BC – 322 BC) who distinguished between plants which generally
do not move, and animals which often are mobile to catch their food. Much later, when Linnaeus (1707–1778)
created the basis of the modern system of scientific classification, these two groups became the kingdoms
Vegetabilia (later Metaphyta or Plantae) and Animalia (also called Metazoa). Since then, it has become clear that the
plant kingdom as originally defined included several unrelated groups, and the fungi and several groups of algae
were removed to new kingdoms. However, these organisms are still often considered plants, particularly in popular
contexts.
Outside of formal scientific contexts, the term "plant" implies an association with certain traits, such as being
multicellular, possessing cellulose, and having the ability to carry out photosynthesis.[3][4]

Current definitions of Plantae


When the name Plantae or plant is applied to a specific group of organisms or taxon, it usually refers to one of three
concepts. From least to most inclusive, these three groupings are:

Name(s) Scope Description

Land plants, also known as Plantae sensu This group includes the liverworts, hornworts, mosses, and vascular plants, as well as fossil plants
Embryophyta or Metaphyta. strictissimo similar to these surviving groups.

Green plants - also known Plantae sensu This group includes the land plants plus various groups of green algae, including stoneworts. The
as Viridiplantae, stricto names given to these groups vary considerably as of July 2011. Viridiplantae encompass a group of
Viridiphyta or organisms that possess chlorophyll a and b, have plastids that are bound by only two membranes, are
Chlorobionta capable of storing starch, and have cellulose in their cell walls. It is this clade which is mainly the
subject of this article.

Archaeplastida, Plastida or Plantae sensu This group comprises the green plants above plus Rhodophyta (red algae) and Glaucophyta
Primoplantae lato (glaucophyte algae). This clade includes the organisms that eons ago acquired their chloroplasts
directly by engulfing cyanobacteria.

Another way of looking at the relationships between the different groups which have been called "plants" is through
a cladogram, which shows their evolutionary relationships. The evolutionary history of plants is not yet completely
settled, but one accepted relationship between the three groups described above is shown below.[5] Those which have
been called "plants" are in bold.
Plant 317

Glaucophyta (glaucophyte algae)

Rhodophyta (red algae)

Chlorophyta (part of green algae)

streptophyte algae (part of green algae)


Archaeplastida

Viridiplantae Charales (stoneworts, often


Streptophyta included 
in green algae)

land plants or embryophytes

The way in which the groups of green algae are combined and named varies considerably between authors.
Many of the classification controversies involve organisms that are rarely encountered and are of minimal apparent
economic significance, but are crucial in developing an understanding of the evolution of modern flora.

Algae
Algae comprise several different groups of organisms which produce
energy through photosynthesis and for that reason have been included
in the plant kingdom in the past. Most conspicuous among the algae
are the seaweeds, multicellular algae that may roughly resemble land
plants, but are classified among the brown, red and green algae. Each
of these algal groups also includes various microscopic and
single-celled organisms. There is good evidence that some of these
algal groups arose independently from separate non-photosynthetic
ancestors, with the result that many groups of algae are no longer
classified within the plant kingdom as it is defined here.[6][7]

The Viridiplantae, the green plants – green algae and land plants –
form a clade, a group consisting of all the descendants of a common
ancestor. With a few exceptions among the green algae, all green
plants have many features in common, including cell walls containing
cellulose, chloroplasts containing chlorophylls a and b, and food stores
in the form of starch. They undergo closed mitosis without centrioles, Green algae from Ernst Haeckel's Kunstformen
and typically have mitochondria with flat cristae. The chloroplasts of der Natur, 1904.
green plants are surrounded by two membranes, suggesting they
originated directly from endosymbiotic cyanobacteria.

Two additional groups, the Rhodophyta (red algae) and Glaucophyta (glaucophyte algae), also have chloroplasts
which appear to be derived directly from endosymbiotic cyanobacteria, although they differ in the pigments which
are used in photosynthesis and so are different in colour. All three groups together are generally believed to have a
single common origin, and so are classified together in the taxon Archaeplastida, whose name implies that the
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chloroplasts or plastids of all the members of the taxon were derived from a single ancient endosymbiotic event. This
is the broadest modern definition of the plants.
In contrast, most other algae (e.g. heterokonts, haptophytes, dinoflagellates, and euglenids) not only have different
pigments but also have chloroplasts with three or four surrounding membranes. They are not close relatives of the
Archaeplastida, presumably having acquired chloroplasts separately from ingested or symbiotic green and red algae.
They are thus not included in even the broadest modern definition of the plant kingdom, although they were in the
past.
The green plants or Viridiplantae were traditionally divided into the green algae (including the stoneworts) and the
land plants. However, it is now known that the land plants evolved from within a group of green algae, so that the
green algae by themselves are a paraphyletic group, i.e. a group which excludes some of the descendants of a
common ancestor. Paraphyletic groups are generally avoided in modern classifications, so that in recent treatments
the Viridiplantae have been divided into two clades, the Chlorophyta and the Streptophyta (or Charophyta).[8][9]
The Chlorophyta (a name that has also been used for all green algae) are the sister group to the group from which the
land plants evolved. There are about 4,300 species[10] of mainly marine organisms, both unicellular and
multicellular. The latter include the sea lettuce, Ulva.
The other group within the Viridiplantae are the mainly freshwater or terrestrial Streptophyta (or Charophyta), which
consist of several groups of green algae plus the stoneworts and land plants. (The names have been used differently,
e.g. Streptophyta to mean the group which excludes the land plants and Charophyta for the stoneworts alone or the
stoneworts plus the land plants.) Streptophyte algae are either unicellular or form multicellular filaments, branched
or unbranched.[9] The genus Spirogyra is a filamentous streptophyte alga familiar to many, as it is often used in
teaching and is one of the organisms responsible for the algal "scum" which pond-owners so dislike. The freshwater
stoneworts strongly resemble land plants and are believed to be their closest relatives. Growing underwater, they
consist of a central stalk with whorls of branchlets, giving them a superficial resemblance to horsetails, species of the
genus Equisetum, which are true land plants.

Fungi
The classification of fungi has been controversial until quite recently in the history of biology. Linnaeus' original
classification placed the fungi within the Plantae, since they were unquestionably not animals or minerals and these
were the only other alternatives. With later developments in microbiology, in the 19th century Ernst Haeckel felt that
another kingdom was required to classify newly discovered micro-organisms. The introduction of the new kingdom
Protista in addition to Plantae and Animalia, led to uncertainty as to whether fungi truly were best placed in the
Plantae or whether they ought to be reclassified as protists. Haeckel himself found it difficult to decide and it was not
until 1969 that a solution was found whereby Robert Whittaker proposed the creation of the kingdom Fungi.
Molecular evidence has since shown that the last common ancestor (concestor) of the Fungi was probably more
similar to that of the Animalia than of any other kingdom, including the Plantae.
Whittaker's original reclassification was based on the fundamental difference in nutrition between the Fungi and the
Plantae. Unlike plants, which generally gain carbon through photosynthesis, and so are called autotrophic
phototrophs, fungi generally obtain carbon by breaking down and absorbing surrounding materials, and so are called
heterotrophic saprotrophs. In addition, the substructure of multicellular fungi is different from that of plants, taking
the form of many chitinous microscopic strands called hyphae, which may be further subdivided into cells or may
form a syncytium containing many eukaryotic nuclei. Fruiting bodies, of which mushrooms are most familiar
example, are the reproductive structures of fungi, and are unlike any structures produced by plants.
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Diversity
The table below shows some species count estimates of different green plant (Viridiplantae) divisions. It suggests
there are about 300,000 species of living Viridiplantae, of which 85-90% are flowering plants. (Note: as these are
from different sources and different dates, they are not necessarily comparable, and like all species counts, are
subject to a degree of uncertainty in some cases.)

Diversity of living green plant (Viridiplantae) divisions


Informal Division name Common name No. of living species Approximate No. in informal
group group

Green algae Chlorophyta green algae (chlorophytes) [11] [12] 8,500 (6,600 - 10,300)
3,800 – 4,300

Charophyta green algae (e.g. desmids & [13]


2,800; 4,000-6,000
stoneworts) [14]

Bryophytes Marchantiophyta liverworts [15] 19,000 (18,100 - 20,200)


6,000-8,000

Anthocerotophyta hornworts [16]


100-200

Bryophyta mosses [17]


12,000

Pteridophytes Lycopodiophyta club mosses [7] 12,000 (12,200)


1,200

Pteridophyta ferns, whisk ferns & horsetails [7]


11,000

Seed plants Cycadophyta cycads [18] 260,000 (259,511)


160

Ginkgophyta ginkgo [19]


1

Pinophyta conifers [7]


630

Gnetophyta gnetophytes [7]


70

Magnoliophyta flowering plants [20]


258,650

The naming of plants is governed by the International Code of Botanical Nomenclature and International Code of
Nomenclature for Cultivated Plants (see cultivated plant taxonomy).

Evolution
Further information: Evolutionary history of plants
The evolution of plants has resulted in increasing levels of complexity, from the earliest algal mats, through
bryophytes, lycopods, ferns to the complex gymnosperms and angiosperms of today. The groups which appeared
earlier continue to thrive, especially in the environments in which they evolved.
Evidence suggests that an algal scum formed on the land 1200 [21] million years ago, but it was not until the
Ordovician Period, around 450.0 [22] million years ago, that land plants appeared.[23] However, new evidence from
the study of carbon isotope ratios in Precambrian rocks has suggested that complex photosynthetic plants developed
on the earth over 1000 m.y.a.[24] These began to diversify in the late Silurian Period, around 420 [25] million years
ago, and the fruits of their diversification are displayed in remarkable detail in an early Devonian fossil assemblage
from the Rhynie chert. This chert preserved early plants in cellular detail, petrified in volcanic springs. By the middle
of the Devonian Period most of the features recognised in plants today are present, including roots, leaves and
secondary wood, and by late Devonian times seeds had evolved.[26] Late Devonian plants had thereby reached a
degree of sophistication that allowed them to form forests of tall trees. Evolutionary innovation continued after the
Devonian period. Most plant groups were relatively unscathed by the Permo-Triassic extinction event, although the
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structures of communities changed. This may have set the scene for the evolution of flowering plants in the Triassic
(~200 [27] million years ago), which exploded in the Cretaceous and Tertiary. The latest major group of plants to
evolve were the grasses, which became important in the mid Tertiary, from around 40 [28] million years ago. The
grasses, as well as many other groups, evolved new mechanisms of metabolism to survive the low CO2 <carbon
dioxide is really goood for health> and warm, dry conditions of the tropics over the last 10 [29] million years.
A proposed phylogenetic tree of Plantae, after Kenrick and Crane,[30] is as follows, with modification to the
Pteridophyta from Smith et al.[31] The Prasinophyceae may be a paraphyletic basal group to all green plants.

Prasinophyceae (micromonads)
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Spermatophytes (seed
Lignophytia plants)

Progymnospermophyta †

Pteridopsida (true ferns)


Euphyllophytina
Marattiopsida
Eutracheophytes Equisetopsida (horsetails)
Tracheophytes Pteridophyta
Psilotopsida (whisk ferns &
Polysporangiates
adders'-tongues)
Stomatophytes
Embryophytes Cladoxylopsida †
Streptobionta

Lycopodiophyta
Lycophytina
Zosterophyllophyta †

Rhyniophyta †

Aglaophyton †

Horneophytopsida †

Bryophyta (mosses)

Anthocerotophyta (hornworts)

Marchantiophyta (liverworts)

Charophyta
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Trebouxiophyceae
(Pleurastrophyceae)
Chlorophyta
Chlorophyceae

Ulvophyceae

Embryophytes
The plants that are likely most familiar to us are the multicellular land
plants, called embryophytes. They include the vascular plants, plants
with full systems of leaves, stems, and roots. They also include a few
of their close relatives, often called bryophytes, of which mosses and
liverworts are the most common.
All of these plants have eukaryotic cells with cell walls composed of
cellulose, and most obtain their energy through photosynthesis, using
light and carbon dioxide to synthesize food. About three hundred plant
species do not photosynthesize but are parasites on other species of
photosynthetic plants. Plants are distinguished from green algae, which
represent a mode of photosynthetic life similar to the kind modern
plants are believed to have evolved from, by having specialized
reproductive organs protected by non-reproductive tissues. Dicksonia antarctica, a species of tree fern

Bryophytes first appeared during the early Paleozoic. They can only
survive where moisture is available for significant periods, although some species are desiccation tolerant. Most
species of bryophyte remain small throughout their life-cycle. This involves an alternation between two generations:
a haploid stage, called the gametophyte, and a diploid stage, called the sporophyte. The sporophyte is short-lived and
remains dependent on its parent gametophyte.
Vascular plants first appeared during the Silurian period, and by the Devonian had diversified and spread into many
different land environments. They have a number of adaptations that allowed them to overcome the limitations of the
bryophytes. These include a cuticle resistant to desiccation, and vascular tissues which transport water throughout
the organism. In most the sporophyte acts as a separate individual, while the gametophyte remains small.
The first primitive seed plants, Pteridosperms (seed ferns) and Cordaites, both groups now extinct, appeared in the
late Devonian and diversified through the Carboniferous, with further evolution through the Permian and Triassic
periods. In these the gametophyte stage is completely reduced, and the sporophyte begins life inside an enclosure
called a seed, which develops while on the parent plant, and with fertilisation by means of pollen grains. Whereas
other vascular plants, such as ferns, reproduce by means of spores and so need moisture to develop, some seed plants
can survive and reproduce in extremely arid conditions.
Early seed plants are referred to as gymnosperms (naked seeds), as the seed embryo is not enclosed in a protective
structure at pollination, with the pollen landing directly on the embryo. Four surviving groups remain widespread
now, particularly the conifers, which are dominant trees in several biomes. The angiosperms, comprising the
flowering plants, were the last major group of plants to appear, emerging from within the gymnosperms during the
Jurassic and diversifying rapidly during the Cretaceous. These differ in that the seed embryo (angiosperm) is
enclosed, so the pollen has to grow a tube to penetrate the protective seed coat; they are the predominant group of
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flora in most biomes today.

Fossils
Plant fossils include roots, wood, leaves, seeds, fruit, pollen, spores,
phytoliths, and amber (the fossilized resin produced by some plants).
Fossil land plants are recorded in terrestrial, lacustrine, fluvial and
nearshore marine sediments. Pollen, spores and algae (dinoflagellates
and acritarchs) are used for dating sedimentary rock sequences. The
remains of fossil plants are not as common as fossil animals, although
plant fossils are locally abundant in many regions worldwide.

The earliest fossils clearly assignable to Kingdom Plantae are fossil


green algae from the Cambrian. These fossils resemble calcified
multicellular members of the Dasycladales. Earlier Precambrian fossils
are known which resemble single-cell green algae, but definitive
identity with that group of algae is uncertain.
The oldest known fossils of embryophytes date from the Ordovician,
though such fossils are fragmentary. By the Silurian, fossils of whole
plants are preserved, including the lycophyte Baragwanathia
longifolia. From the Devonian, detailed fossils of rhyniophytes have
been found. Early fossils of these ancient plants show the individual A petrified log in Petrified Forest National Park.
cells within the plant tissue. The Devonian period also saw the
evolution of what many believe to be the first modern tree, Archaeopteris. This fern-like tree combined a woody
trunk with the fronds of a fern, but produced no seeds.

The Coal measures are a major source of Paleozoic plant fossils, with many groups of plants in existence at this time.
The spoil heaps of coal mines are the best places to collect; coal itself is the remains of fossilised plants, though
structural detail of the plant fossils is rarely visible in coal. In the Fossil Forest at Victoria Park in Glasgow,
Scotland, the stumps of Lepidodendron trees are found in their original growth positions.
The fossilized remains of conifer and angiosperm roots, stems and branches may be locally abundant in lake and
inshore sedimentary rocks from the Mesozoic and Cenozoic eras. Sequoia and its allies, magnolia, oak, and palms
are often found.
Petrified wood is common in some parts of the world, and is most frequently found in arid or desert areas where it is
more readily exposed by erosion. Petrified wood is often heavily silicified (the organic material replaced by silicon
dioxide), and the impregnated tissue is often preserved in fine detail. Such specimens may be cut and polished using
lapidary equipment. Fossil forests of petrified wood have been found in all continents.
Fossils of seed ferns such as Glossopteris are widely distributed throughout several continents of the Southern
Hemisphere, a fact that gave support to Alfred Wegener's early ideas regarding Continental drift theory.

Structure, growth, and development


Most of the solid material in a plant is taken from the atmosphere. Through a process known as photosynthesis, most
plants use the energy in sunlight to convert carbon dioxide from the atmosphere, plus water, into simple sugars.
Parasitic plants, on the other hand, use the resources of its host to grow. These sugars are then used as building
blocks and form the main structural component of the plant. Chlorophyll, a green-colored, magnesium-containing
pigment is essential to this process; it is generally present in plant leaves, and often in other plant parts as well.
Plant 324

Plants usually rely on soil primarily for support and water (in quantitative terms), but also obtain compounds of
nitrogen, phosphorus, and other crucial elemental nutrients. Epiphytic and lithophytic plants often depend on
rainwater or other sources for nutrients and carnivorous plants supplement their nutrient requirements with insect
prey that they capture. For the majority of plants to grow successfully they also require oxygen in the atmosphere
and around their roots for respiration. However, some plants grow as submerged aquatics, using oxygen dissolved in
the surrounding water, and a few specialized vascular plants, such as mangroves, can grow with their roots in anoxic
conditions.

Factors affecting growth


The genotype of a plant affects its growth. For example, selected
varieties of wheat grow rapidly, maturing within 110 days, whereas
others, in the same environmental conditions, grow more slowly and
mature within 155 days.[32]
Growth is also determined by environmental factors, such as
temperature, available water, available light, and available nutrients in
the soil. Any change in the availability of these external conditions will
be reflected in the plants growth. The leaf is usually the primary site of
photosynthesis in plants.
Biotic factors are also capable of affecting plant growth. Plants
compete with other plants for space, water, light and nutrients. Plants
can be so crowded that no single individual produces normal growth,
causing etiolation and chlorosis. Optimal plant growth can be
hampered by grazing animals, suboptimal soil composition, lack of
mycorrhizal fungi, and attacks by insects or plant diseases, including
those caused by bacteria, fungi, viruses, and nematodes.[32]

Simple plants like algae may have short life spans as individuals, but
their populations are commonly seasonal. Other plants may be
organized according to their seasonal growth pattern: annual plants live
and reproduce within one growing season, biennial plants live for two
growing seasons and usually reproduce in second year, and perennial
plants live for many growing seasons and continue to reproduce once
There is no photosynthesis in deciduous leaves in
they are mature. These designations often depend on climate and other
autumn.
environmental factors; plants that are annual in alpine or temperate
regions can be biennial or perennial in warmer climates. Among the
vascular plants, perennials include both evergreens that keep their leaves the entire year, and deciduous plants which
lose their leaves for some part of it. In temperate and boreal climates, they generally lose their leaves during the
winter; many tropical plants lose their leaves during the dry season.

The growth rate of plants is extremely variable. Some mosses grow less than 0.001 millimeters per hour (mm/h),
while most trees grow 0.025-0.250 mm/h. Some climbing species, such as kudzu, which do not need to produce thick
supportive tissue, may grow up to 12.5 mm/h.
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Plants protect themselves from frost and dehydration stress with


antifreeze proteins, heat-shock proteins and sugars (sucrose is
common). LEA (Late Embryogenesis Abundant) protein expression is
induced by stresses and protects other proteins from aggregation as a
result of desiccation and freezing.[33]

Dried dead plants

Plant cell
Plant cells are typically distinguished by their large water-filled central
vacuole, chloroplasts, and rigid cell walls that are made up of cellulose,
hemicellulose, and pectin. Cell division is also characterized by the
development of a phragmoplast for the construction of a cell plate in
the late stages of cytokinesis. Just as in animals, plant cells
differentiate and develop into multiple cell types. Totipotent
meristematic cells can differentiate into vascular, storage, protective
(e.g. epidermal layer), or reproductive tissues, with more primitive
plants lacking some tissue types.[34]
Plant cell structure

Physiology

Photosynthesis
Plants are photosynthetic, which means that they manufacture their own food molecules using energy obtained from
light. The primary mechanism plants have for capturing light energy is the pigment chlorophyll. All green plants
contain two forms of chlorophyll, chlorophyll a and chlorophyll b. The latter of these pigments is not found in red or
brown algae.

Immune system
By means of cells that behave like nerves, plants receive and distribute within their systems information about
incident light intensity and quality. Incident light which stimulates a chemical reaction in one leaf, will cause a chain
reaction of signals to the entire plant via a type of cell termed a bundle sheath cell. Researchers from the Warsaw
University of Life Sciences in Poland, found that plants have a specific memory for varying light conditions which
prepares their immune systems against seasonal pathogens.[35] Plants use pattern-recognition receptors to recognize
conserved microbial signatures. This recognition triggers an immune response. The first plant receptors of conserved
microbial signatures were identified in rice (XA21, 1995)[36] and in Arabidopsis (FLS2, 2000).[37] Plants also carry
immune receptors that recognize highly variable pathogen effectors. These include the NBS-LRR class of proteins.
Plant 326

Internal distribution
Vascular plants differ from other plants in that they transport nutrients between different parts through specialized
structures, called xylem and phloem. They also have roots for taking up water and minerals. The xylem moves water
and minerals from the root to the rest of the plant, and the phloem provides the roots with sugars and other nutrient
produced by the leaves.[34]

Ecology
The photosynthesis conducted by land plants and algae is the ultimate source of energy and organic material in
nearly all ecosystems. Photosynthesis radically changed the composition of the early Earth's atmosphere, which as a
result is now 21% oxygen. Animals and most other organisms are aerobic, relying on oxygen; those that do not are
confined to relatively rare anaerobic environments. Plants are the primary producers in most terrestrial ecosystems
and form the basis of the food web in those ecosystems. Many animals rely on plants for shelter as well as oxygen
and food.
Land plants are key components of the water cycle and several other biogeochemical cycles. Some plants have
coevolved with nitrogen fixing bacteria, making plants an important part of the nitrogen cycle. Plant roots play an
essential role in soil development and prevention of soil erosion.

Distribution
Plants are distributed worldwide in varying numbers. While they inhabit a multitude of biomes and ecoregions, few
can be found beyond the tundras at the northernmost regions of continental shelves. At the southern extremes, plants
have adapted tenaciously to the prevailing conditions. (See Antarctic flora.)
Plants are often the dominant physical and structural component of habitats where they occur. Many of the Earth's
biomes are named for the type of vegetation because plants are the dominant organisms in those biomes, such as
grasslands and forests.

Ecological relationships
Numerous animals have coevolved with plants. Many animals pollinate
flowers in exchange for food in the form of pollen or nectar. Many
animals disperse seeds, often by eating fruit and passing the seeds in
their feces. Myrmecophytes are plants that have coevolved with ants.
The plant provides a home, and sometimes food, for the ants. In
exchange, the ants defend the plant from herbivores and sometimes
competing plants. Ant wastes provide organic fertilizer.

The majority of plant species have various kinds of fungi associated


with their root systems in a kind of mutualistic symbiosis known as
mycorrhiza. The fungi help the plants gain water and mineral nutrients
from the soil, while the plant gives the fungi carbohydrates
manufactured in photosynthesis. Some plants serve as homes for
endophytic fungi that protect the plant from herbivores by producing The Venus flytrap, a species of carnivorous plant.
toxins. The fungal endophyte, Neotyphodium coenophialum, in tall
fescue (Festuca arundinacea) does tremendous economic damage to the cattle industry in the U.S.

Various forms of parasitism are also fairly common among plants, from the semi-parasitic mistletoe that merely
takes some nutrients from its host, but still has photosynthetic leaves, to the fully parasitic broomrape and toothwort
that acquire all their nutrients through connections to the roots of other plants, and so have no chlorophyll. Some
Plant 327

plants, known as myco-heterotrophs, parasitize mycorrhizal fungi, and hence act as epiparasites on other plants.
Many plants are epiphytes, meaning they grow on other plants, usually trees, without parasitizing them. Epiphytes
may indirectly harm their host plant by intercepting mineral nutrients and light that the host would otherwise receive.
The weight of large numbers of epiphytes may break tree limbs. Hemiepiphytes like the strangler fig begin as
epiphytes but eventually set their own roots and overpower and kill their host. Many orchids, bromeliads, ferns and
mosses often grow as epiphytes. Bromeliad epiphytes accumulate water in leaf axils to form phytotelmata, complex
aquatic food webs.[38]
Approximately 630 plants are carnivorous, such as the Venus Flytrap (Dionaea muscipula) and sundew (Drosera
species). They trap small animals and digest them to obtain mineral nutrients, especially nitrogen and phosphorus.[39]

Importance
The study of plant uses by people is termed economic botany or
ethnobotany; some consider economic botany to focus on modern
cultivated plants, while ethnobotany focuses on indigenous plants
cultivated and used by native peoples. Human cultivation of plants is
part of agriculture, which is the basis of human civilization. Plant
agriculture is subdivided into agronomy, horticulture and forestry.

Food
Much of human nutrition depends on land plants, either directly or
indirectly.
Human nutrition depends to a large extent on cereals, especially maize
(or corn), wheat and rice. Other staple crops include potato, cassava,
and legumes. Human food also includes vegetables, spices, and certain Potato plant. Potatoes spread to the
fruits, nuts, herbs, and edible flowers. rest of the world after European
contact with the Americas in the late
Beverages produced from plants include coffee, tea, wine, beer and
15th and early 16th centuries and
alcohol. have since become an important field
Sugar is obtained mainly from sugar cane and sugar beet. crop.
Cooking oils and margarine come from maize, soybean, rapeseed,
safflower, sunflower, olive and others.
Food additives include gum arabic, guar gum, locust bean gum, starch
and pectin.
Livestock animals including cows, pigs, sheep, and goats are all
herbivores; and feed primarily or entirely on cereal plants, particularly
grasses.

Nonfood products
Wood is used for buildings, furniture, paper, cardboard, musical Timber in storage for later processing at a
instruments and sports equipment. Cloth is often made from cotton, sawmill.
flax or synthetic fibers derived from cellulose, such as rayon and
acetate. Renewable fuels from plants include firewood, peat and many other biofuels. Coal and petroleum are fossil
fuels derived from plants. Medicines derived from plants include aspirin, taxol, morphine,
Plant 328

quinine, reserpine, colchicine, digitalis and vincristine. There are


hundreds of herbal supplements such as ginkgo, Echinacea, feverfew,
and Saint John's wort. Pesticides derived from plants include nicotine,
rotenone, strychnine and pyrethrins. Drugs obtained from plants
include opium, cocaine and marijuana. Poisons from plants include
ricin, hemlock and curare. Plants are the source of many natural
products such as fibers, essential oils, natural dyes, pigments, waxes,
tannins, latex, gums, resins, alkaloids, amber and cork. Products
derived from plants include soaps, paints, shampoos, perfumes,
cosmetics, turpentine, rubber, varnish, lubricants, linoleum, plastics,
inks, chewing gum and hemp rope. Plants are also a primary source of
basic chemicals for the industrial synthesis of a vast array of organic
A section of a Yew branch showing 27 annual
chemicals. These chemicals are used in a vast variety of studies and growth rings, pale sapwood and dark heartwood,
experiments. and pith (centre dark spot). The dark radial lines
are longitudinal sections of small branches which
became included by growth of the tree.
Aesthetic uses
Thousands of plant species are cultivated for aesthetic purposes as well as to provide shade, modify temperatures,
reduce wind, abate noise, provide privacy, and prevent soil erosion. People use cut flowers, dried flowers and
houseplants indoors or in greenhouses. In outdoor gardens, lawn grasses, shade trees, ornamental trees, shrubs, vines,
herbaceous perennials and bedding plants are used. Images of plants are often used in art, architecture, humor,
language, and photography and on textiles, money, stamps, flags and coats of arms. Living plant art forms include
topiary, bonsai, ikebana and espalier. Ornamental plants have sometimes changed the course of history, as in
tulipomania. Plants are the basis of a multi-billion dollar per year tourism industry which includes travel to
arboretums, botanical gardens, historic gardens, national parks, tulip festivals, rainforests, forests with colorful
autumn leaves and the National Cherry Blossom Festival. Venus Flytrap, sensitive plant and resurrection plant are
examples of plants sold as novelties.

Scientific and cultural uses


Tree rings are an important method of dating in archeology and serve as a record of past climates. Basic biological
research has often been done with plants, such as the pea plants used to derive Gregor Mendel's laws of genetics.
Space stations or space colonies may one day rely on plants for life support. Plants are used as national and state
emblems, including state trees and state flowers. Ancient trees are revered and many are famous. Numerous world
records are held by plants. Plants are often used as memorials, gifts and to mark special occasions such as births,
deaths, weddings and holidays. Plants figure prominently in mythology, religion and literature. The field of
ethnobotany studies plant use by indigenous cultures which helps to conserve endangered species as well as discover
new medicinal plants. Gardening is the most popular leisure activity in the U.S. Working with plants or horticulture
therapy is beneficial for rehabilitating people with disabilities. Certain plants contain psychotropic chemicals which
are extracted and ingested, including tobacco, cannabis (marijuana), and opium.
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Negative effects
Weeds are plants that grow where people do not want them. People have spread plants beyond their native ranges
and some of these introduced plants become invasive, damaging existing ecosystems by displacing native species.
Invasive plants cause billions of dollars in crop losses annually by displacing crop plants, they increase the cost of
production and the use of chemical means to control them affects the environment.
Plants may cause harm to animals, including people. Plants that produce windblown pollen invoke allergic reactions
in people who suffer from hay fever. A wide variety of plants are poisonous. Toxalbumins are plant poisons fatal to
most mammals and act as a serious deterrent to consumption. Several plants cause skin irritations when touched,
such as poison ivy. Certain plants contain psychotropic chemicals, which are extracted and ingested or smoked,
including tobacco, cannabis (marijuana), cocaine and opium. Smoking causes damage to health or even death, while
some drugs may also be harmful or fatal to people.[40][41] Both illegal and legal drugs derived from plants may have
negative effects on the economy, affecting worker productivity and law enforcement costs.[42][43] Some plants cause
allergic reactions when ingested, while other plants cause food intolerances that negatively affect health.

References
[1] Haeckel G (1866). Generale Morphologie der Organismen. Berlin: Verlag von Georg Reimer. pp. vol.1: i–xxxii, 1–574, pls I–II; vol. 2:
i–clx, 1–462, pls I–VIII.
[2] http:/ / www. iucnredlist. org/ documents/ summarystatistics/ 2010_1RL_Stats_Table_1. pdf
[3] "plant[2 (http:/ / www. merriam-webster. com/ dictionary/ plant[2]) - Definition from the Merriam-Webster Online Dictionary"]. . Retrieved
2009-03-25.
[4] "plant (life form) -- Britannica Online Encyclopedia" (http:/ / www. britannica. com/ EBchecked/ topic/ 463192/ plant). . Retrieved
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[5] Based on Rogozin, I.B.; Basu, M.K.; Csürös, M. & Koonin, E.V. (2009), "Analysis of Rare Genomic Changes Does Not Support the
Unikont–Bikont Phylogeny and Suggests Cyanobacterial Symbiosis as the Point of Primary Radiation of Eukaryotes", Genome Biology and
Evolution 1: 99–113, doi:10.1093/gbe/evp011, PMC 2817406, PMID 20333181 and Becker, B. & Marin, B. (2009), "Streptophyte algae and
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slightly different cladogram in Lewis, Louise A. & McCourt, R.M. (2004), "Green algae and the origin of land plants", Am. J. Bot. 91 (10):
1535–1556, doi:10.3732/ajb.91.10.1535, PMID 21652308.
[6] Margulis, L. (1974). "Five-kingdom classification and the origin and evolution of cells". Evolutionary Biology 7: 45–78.
[7] Raven, Peter H., Ray F. Evert, & Susan E. Eichhorn, 2005. Biology of Plants, 7th edition. (New York: W. H. Freeman and Company). ISBN
0-7167-1007-2.
[8] Lewis, Louise A. & McCourt, R.M. (2004), "Green algae and the origin of land plants", Am. J. Bot. 91 (10): 1535–1556,
doi:10.3732/ajb.91.10.1535, PMID 21652308
[9] Becker, B. & Marin, B. (2009), "Streptophyte algae and the origin of embryophytes", Annals of Botany 103 (7): 999–1004,
doi:10.1093/aob/mcp044, PMC 2707909, PMID 19273476
[10] Guiry, M.D. & Guiry, G.M. (2007). "Phylum: Chlorophyta taxonomy browser" (http:/ / www. algaebase. org/ browse/ taxonomy/ ?id=4307).
AlgaeBase version 4.2 World-wide electronic publication, National University of Ireland, Galway. . Retrieved 2007-09-23.
[11] Van den Hoek, C., D. G. Mann, & H. M. Jahns, 1995. Algae: An Introduction to Phycology. pages 343, 350, 392, 413, 425, 439, & 448
(Cambridge: Cambridge University Press). ISBN 0-521-30419-9
[12] Guiry, M.D. & Guiry, G.M. (2011), AlgaeBase : Chlorophyta (http:/ / www. algaebase. org/ browse/ taxonomy/ ?searching=true&
gettaxon=Chlorophyta), World-wide electronic publication, National University of Ireland, Galway, , retrieved 2011-07-26
[13] Guiry, M.D. & Guiry, G.M. (2011), AlgaeBase : Charophyta (http:/ / www. algaebase. org/ browse/ taxonomy/ ?searching=true&
gettaxon=Charophyta), World-wide electronic publication, National University of Ireland, Galway, , retrieved 2011-07-26
[14] Van den Hoek, C., D. G. Mann, & H. M. Jahns, 1995. Algae: An Introduction to Phycology. pages 457, 463, & 476. (Cambridge: Cambridge
University Press). ISBN 0-521-30419-9
[15] Crandall-Stotler, Barbara. & Stotler, Raymond E., 2000. "Morphology and classification of the Marchantiophyta". page 21 in A. Jonathan
Shaw & Bernard Goffinet (Eds.), Bryophyte Biology. (Cambridge: Cambridge University Press). ISBN 0-521-66097-1
[16] Schuster, Rudolf M., The Hepaticae and Anthocerotae of North America, volume VI, pages 712-713. (Chicago: Field Museum of Natural
History, 1992). ISBN 0-914868-21-7.
[17] Goffinet, Bernard; William R. Buck (2004). "Systematics of the Bryophyta (Mosses): From molecules to a revised classification".
Monographs in Systematic Botany (Missouri Botanical Garden Press) 98: 205–239.
[18] Gifford, Ernest M. & Adriance S. Foster, 1988. Morphology and Evolution of Vascular Plants, 3rd edition, page 358. (New York: W. H.
Freeman and Company). ISBN 0-7167-1946-0.
Plant 330

[19] Taylor, Thomas N. & Edith L. Taylor, 1993. The Biology and Evolution of Fossil Plants, page 636. (New Jersey: Prentice-Hall). ISBN
0-13-651589-4.
[20] International Union for Conservation of Nature and Natural Resources, 2006. IUCN Red List of Threatened Species:Summary Statistics
(http:/ / www. iucnredlist. org/ )
[21] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=1200
[22] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=450
[23] "The oldest fossils reveal evolution of non-vascular plants by the middle to late Ordovician Period (~450-440 m.y.a.) on the basis of fossil
spores" Transition of plants to land (http:/ / www. clas. ufl. edu/ users/ pciesiel/ gly3150/ plant. html)
[24] "The apparent dominance of eukaryotes in non-marine settings by 1 Gyr ago indicates that eukaryotic evolution on land may have
commenced far earlier than previously thought." Earth’s earliest non-marine eukaryotes (http:/ / www. nature. com/ nature/ journal/ vaop/
ncurrent/ full/ nature09943. html)
[25] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=420
[26] Rothwell, G. W.; Scheckler, S. E.; Gillespie, W. H. (1989). "Elkinsia gen. nov., a Late Devonian gymnosperm with cupulate ovules".
Botanical Gazette 150 (2): 170–189. doi:10.1086/337763.
[27] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=200
[28] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=40
[29] http:/ / toolserver. org/ ~verisimilus/ Timeline/ Timeline. php?Ma=10
[30] Kenrick, Paul & Peter R. Crane. 1997. The Origin and Early Diversification of Land Plants: A Cladistic Study. (Washington, D.C.:
Smithsonian Institution Press). ISBN 1-56098-730-8.
[31] Smith Alan R., Pryer Kathleen M., Schuettpelz E., Korall P., Schneider H., Wolf Paul G. (2006). "A classification for extant ferns" (http:/ /
www. pryerlab. net/ publication/ fichier749. pdf) (PDF). Taxon 55 (3): 705–731. doi:10.2307/25065646. .
[32] Robbins, W.W., Weier, T.E., et al., Botany:Plant Science, 3rd edition , Wiley International, New York, 1965.
[33] Goyal, K., Walton, L. J., & Tunnacliffe, A. (2005). "LEA proteins prevent protein aggregation due to water stress" (http:/ / www.
webcitation. org/ 5il9QhYT0). Biochemical Journal 388 (Part 1): 151–157. doi:10.1042/BJ20041931. PMC 1186703. PMID 15631617.
Archived from the original (http:/ / www. biochemj. org/ bj/ 388/ 0151/ bj3880151. htm) on 2009-08-03. .
[34] Campbell, Reece, Biology, 7th edition, Pearson/Benjamin Cummings, 2005.
[35] BBC Report (http:/ / www. bbc. co. uk/ news/ 10598926)
[36] Song, W.Y. et al. (1995). "A receptor kinase-like protein encoded by the rice disease resistance gene, XA21". Science 270 (5243):
1804–1806. doi:10.1126/science.270.5243.1804. PMID 8525370.
[37] Gomez-Gomez, L. et al. (2000). "FLS2: an LRR receptor-like kinase involved in the perception of the bacterial elicitor flagellin in
Arabidopsis". Molecular Cell 5 (6): 1003–1011. doi:10.1016/S1097-2765(00)80265-8. PMID 10911994.
[38] Howard Frank, Bromeliad Phytotelmata (http:/ / entomology. ifas. ufl. edu/ frank/ bromeliadbiota/ bromfit. htm), October 2000
[39] Barthlott, W., S. Porembski, R. Seine, and I. Theisen. 2007. The Curious World of Carnivorous Plants: A Comprehensive Guide to Their
Biology and Cultivation. Timber Press: Portland, Oregon.
[40] "cocaine/crack" (http:/ / www. urban75. com/ Drugs/ drugcoke. html). .
[41] "Deaths related to cocaine" (http:/ / ar2005. emcdda. europa. eu/ en/ page050-en. html). .
[42] "Illegal drugs drain $160 billion a year from American economy" (http:/ / web. archive. org/ web/ 20080215071055/ http:/ / www.
whitehousedrugpolicy. gov/ NEWS/ press02/ 012302. html). Archived from the original (http:/ / www. whitehousedrugpolicy. gov/ NEWS/
press02/ 012302. html) on 2008-02-15. .
[43] "The social cost of illegal drug consumption in Spain" (http:/ / www. ingentaconnect. com/ content/ bsc/ add/ 2002/ 00000097/ 00000009/
art00012). .

Further reading
General
• Evans, L. T. (1998). Feeding the Ten Billion - Plants and Population Growth. Cambridge University Press.
Paperback, 247 pages. ISBN 0-521-64685-5.
• Kenrick, Paul & Crane, Peter R. (1997). The Origin and Early Diversification of Land Plants: A Cladistic Study.
Washington, D. C.: Smithsonian Institution Press. ISBN 1-56098-730-8.
• Raven, Peter H., Evert, Ray F., & Eichhorn, Susan E. (2005). Biology of Plants (7th ed.). New York: W. H.
Freeman and Company. ISBN 0-7167-1007-2.
• Taylor, Thomas N. & Taylor, Edith L. (1993). The Biology and Evolution of Fossil Plants. Englewood Cliffs, NJ:
Prentice Hall. ISBN 0-13-651589-4.
• Trewavas A (2003). "Aspects of Plant Intelligence" (http://aob.oxfordjournals.org/cgi/content/full/92/1/1).
Annals of Botany 92: 1–20.
Species estimates and counts
Plant 331

• International Union for Conservation of Nature and Natural Resources (IUCN) Species Survival Commission
(2004). IUCN Red List (http://www.iucnredlist.org/).
• Prance G. T. (2001). "Discovering the Plant World". Taxon 50: 345–359.

External links
• Jones, T. M., Reid, C. S., Urbatsch, L. E. Visual study of divisional Plantae (http://www.herbarium.lsu.edu/
keys/aca/). (requires Microsoft Silverlight)
• Plant (http://www.eol.org/pages/281) at the Encyclopedia of Life
• Chaw, S.-M. et al. (1997). "Molecular Phylogeny of Extant Gymnosperms and Seed Plant Evolution: Analysis of
Nuclear 18s rRNA Sequences" (http://mbe.library.arizona.edu/data/1997/1401/7chaw.pdf). Molec. Biol.
Evol. 14 (1): 56–68. PMID 9000754.
• Index Nominum Algarum (http://ucjeps.berkeley.edu/INA.html)
• Interactive Cronquist classification (http://florabase.calm.wa.gov.au/phylogeny/cronq88.html)
• Plant Photo Gallery of Japan (http://www.alpine-plants-jp.com/art/index_photo2b.htm) - Flavon's Wild herb
and Alpine plants
• Plant Picture Gallery (http://www.pflanzenliebe.de/)
• Plant Resources of Tropical Africa (http://www.prota.org/uk/About+Prota/)
• www.prota.org - PROTA’s mission (http://database.prota.org/search.htm)
• Tree of Life (http://tolweb.org/Green_plants)
Botanical and vegetation databases
• African Plants Initiative database (http://www.aluka.org/action/doBrowse?sa=1&sa_sel=)
• Australia (http://www.anbg.gov.au/cpbr/databases/)
• Chilean plants at Chilebosque (http://www.chilebosque.cl/)
• Dave's garden (http://davesgarden.com/pf/) plenty of information mostly about garden plants
• e-Floras (Flora of China, Flora of North America and others) (http://www.efloras.org/index.aspx)
• Flora Europaea (http://rbg-web2.rbge.org.uk/FE/fe.html)
• Flora of Central Europe (http://www.floraweb.de/) (German)
• Flora of North America (http://www.efloras.org/flora_page.aspx?flora_id=1)
• List of Japanese Wild Plants Online (http://www.alpine-plants-jp.com/botanical_name/
list_of_japanese_wild_plants_abelia_buxus.htm)
• Meet the Plants-National Tropical Botanical Garden (http://www.ntbg.org/plants/choose_a_plant.php)
• Lady Bird Johnson Wildflower Center - Native Plant Information Network at University of Texas, Austin (http://
www.wildflower.org/)
• The Plant List (http://www.theplantlist.org/)
• United States Department of Agriculture (http://plants.usda.gov/) not limited to continental US species
Polymer 332

Polymer
A polymer is a large molecule (macromolecule) composed of repeating
structural units. These sub-units are typically connected by covalent
chemical bonds. Although the term polymer is sometimes taken to refer
to plastics, it actually encompasses a large class of compounds
comprising both natural and synthetic materials with a wide variety of
properties.

Because of the extraordinary range of properties of polymeric


materials,[2] they play an essential and ubiquitous role in everyday
life.[3] This role ranges from familiar synthetic plastics and elastomers
to natural biopolymers such as nucleic acids and proteins that are
essential for life.
Appearance of real linear polymer chains as
Natural polymeric materials such as shellac, amber, and natural rubber recorded using an atomic force microscope on
have been used for centuries. A variety of other natural polymers exist, surface under liquid medium. Chain contour
such as cellulose, which is the main constituent of wood and paper. The length for this polymer is ~204 nm; thickness is
[1]
~0.4 nm.
list of synthetic polymers includes synthetic rubber, Bakelite, neoprene,
nylon, PVC, polystyrene, polyethylene, polypropylene,
polyacrylonitrile, PVB, silicone, and many more.

Most commonly, the continuously linked backbone of a polymer used for the preparation of plastics consists mainly
of carbon atoms. A simple example is polyethylene ('polythene' in British English), whose repeating unit is based on
ethylene monomer. However, other structures do exist; for example, elements such as silicon form familiar materials
such as silicones, examples being Silly Putty and waterproof plumbing sealant. Oxygen is also commonly present in
polymer backbones, such as those of polyethylene glycol, polysaccharides (in glycosidic bonds), and DNA (in
phosphodiester bonds).

Polymers are studied in the fields of polymer chemistry, polymer physics, and polymer science.

Etymology
The word polymer is derived from the Greek words πολύ- — poly- meaning "many"; and μέρος — meros meaning
"part". The term was coined in 1833 by Jöns Jacob Berzelius, although his definition of a polymer was quite
different from the modern definition.

Polymer synthesis
Polymerization is the process of combining many small molecules
known as monomers into a covalently bonded chain or network.
During the polymerization process, some chemical groups may be
lost from each monomer. This is the case, for example, in the
polymerization of PET polyester. The monomers are terephthalic
acid (HOOC-C6H4-COOH) and ethylene glycol
(HO-CH2-CH2-OH) but the repeating unit is
-OC-C6H4-COO-CH2-CH2-O-, which corresponds to the
combination of the two monomers with the loss of two water The repeating unit of the polymer polypropylene
molecules. The distinct piece of each monomer that is
incorporated into the polymer is known as a repeat unit or monomer residue.
Polymer 333

Laboratory synthesis
Laboratory synthetic methods are generally divided into two categories, step-growth polymerization and
chain-growth polymerization.[4] The essential difference between the two is that in chain growth polymerization,
monomers are added to the chain one at a time only,[5] whereas in step-growth polymerization chains of monomers
may combine with one another directly.[6] However, some newer methods such as plasma polymerization do not fit
neatly into either category. Synthetic polymerization reactions may be carried out with or without a catalyst.
Laboratory synthesis of biopolymers, especially of proteins, is an area of intensive research.

Biological synthesis
There are three main classes of biopolymers: polysaccharides,
polypeptides, and polynucleotides. In living cells, they may be
synthesized by enzyme-mediated processes, such as the formation
of DNA catalyzed by DNA polymerase. The synthesis of proteins
involves multiple enzyme-mediated processes to transcribe genetic
information from the DNA to RNA and subsequently translate that
information to synthesize the specified protein from amino acids.
The protein may be modified further following translation in order
to provide appropriate structure and functioning.

Modification of natural polymers


Many commercially important polymers are synthesized by
chemical modification of naturally occurring polymers. Prominent
examples include the reaction of nitric acid and cellulose to form
nitrocellulose and the formation of vulcanized rubber by heating
natural rubber in the presence of sulfur. Ways in which polymers
can be modified include oxidation, cross-linking and end-capping.

Polymer properties
Polymer properties are broadly divided into several classes based Microstructure of part of a DNA double helix
on the scale at which the property is defined as well as upon its biopolymer

physical basis.[7] The most basic property of a polymer is the


identity of its constituent monomers. A second set of properties, known as microstructure, essentially describe the
arrangement of these monomers within the polymer at the scale of a single chain. These basic structural properties
play a major role in determining bulk physical properties of the polymer, which describe how the polymer behaves
as a continuous macroscopic material. Chemical properties, at the nano-scale, describe how the chains interact
through various physical forces. At the macro-scale, they describe how the bulk polymer interacts with other
chemicals and solvents.

Monomers and repeat units


The identity of the monomer residues (repeat units) comprising a polymer is its first and most important attribute.
Polymer nomenclature is generally based upon the type of monomer residues comprising the polymer. Polymers that
contain only a single type of repeat unit are known as homopolymers, while polymers containing a mixture of repeat
units are known as copolymers. Poly(styrene), for example, is composed only of styrene monomer residues, and is
therefore classified as a homopolymer. Ethylene-vinyl acetate, on the other hand, contains more than one variety of
Polymer 334

repeat unit and is thus a copolymer. Some biological polymers are composed of a variety of different but structurally
related monomer residues; for example, polynucleotides such as DNA are composed of a variety of nucleotide
subunits.
A polymer molecule containing ionizable subunits is known as a polyelectrolyte or ionomer.

Microstructure
The microstructure of a polymer (sometimes called configuration) relates to the physical arrangement of monomer
residues along the backbone of the chain.[8] These are the elements of polymer structure that require the breaking of
a covalent bond in order to change. Structure has a strong influence on the other properties of a polymer. For
example, two samples of natural rubber may exhibit different durability, even though their molecules comprise the
same monomers.

Polymer architecture

An important microstructural feature of a polymer is its


architecture, which relates to the way branch points lead to a
deviation from a simple linear chain.[9] A branched polymer
molecule is composed of a main chain with one or more Branch point in a polymer
substituent side chains or branches. Types of branched polymers
include star polymers, comb polymers, brush polymers, dendronized polymers, ladders, and dendrimers.[9]

A polymer's architecture affects many of its physical properties including, but not limited to, solution viscosity, melt
viscosity, solubility in various solvents, glass transition temperature and the size of individual polymer coils in
solution.
A variety of techniques may be employed for the synthesis of a polymeric material with a range of architectures, for
example Living polymerization.

Chain length

The physical properties[10] of a


polymer are strongly dependent on the
size or length of the polymer chain.[11]
For example, as chain length is
increased, melting and boiling
temperatures increase quickly.[11]
Impact resistance also tends to increase
with chain length, as does the
viscosity, or resistance to flow, of the
polymer in its melt state.[12] Chain
length is related to melt viscosity
roughly as 1:103.2, so that a tenfold
increase in polymer chain length Various polymer architectures.
results in a viscosity increase of over
1000 times. Increasing chain length furthermore tends to decrease chain mobility, increase strength and toughness,
and increase the glass transition temperature (Tg). This is a result of the increase in chain interactions such as Van
der Waals attractions and entanglements that come with increased chain length. These interactions tend to fix the
individual chains more strongly in position and resist deformations and matrix breakup, both at higher stresses and
higher temperatures.
Polymer 335

A common means of expressing the length of a chain is the degree of polymerization, which quantifies the number
of monomers incorporated into the chain.[13][14] As with other molecules, a polymer's size may also be expressed in
terms of molecular weight. Since synthetic polymerization techniques typically yield a polymer product including a
range of molecular weights, the weight is often expressed statistically to describe the distribution of chain lengths
present in the same. Common examples are the number average molecular weight and weight average molecular
weight.[15][16] The ratio of these two values is the polydispersity index, commonly used to express the "width" of the
molecular weight distribution.[17] A final measurement is contour length, which can be understood as the length of
the chain backbone in its fully extended state.[18]
The flexibility of an unbranched chain polymer is characterized by its persistence length.

Monomer arrangement in copolymers

Monomers within a copolymer may be


organized along the backbone in a
variety of ways.
• Alternating copolymers possess
regularly alternating monomer
residues:[19] [AB...]n (2).
• Periodic copolymers have
monomer residue types arranged in
a repeating sequence: [AnBm...] m
being different from n .
• Statistical copolymers have
monomer residues arranged
according to a known statistical rule. A statistical copolymer in which the probability of finding a particular type
of monomer residue at a particular point in the chain is independent of the types of surrounding monomer residue
may be referred to as a truly random copolymer[20][21] (3).
• Block copolymers have two or more homopolymer subunits linked by covalent bonds[19] (4). Polymers with two
or three blocks of two distinct chemical species (e.g., A and B) are called diblock copolymers and triblock
copolymers, respectively. Polymers with three blocks, each of a different chemical species (e.g., A, B, and C) are
termed triblock terpolymers.
• Graft or grafted copolymers contain side chains that have a different composition or configuration than the
main chain.(5)

Tacticity
Tacticity describes the relative stereochemistry of chiral centers in neighboring structural units within a
macromolecule. There are three types: isotactic (all substituents on the same side), atactic (random placement of
substituents), and syndiotactic (alternating placement of substituents).

Polymer morphology
Polymer morphology generally describes the arrangement and microscale ordering of polymer chains in space.

Crystallinity
When applied to polymers, the term crystalline has a somewhat ambiguous usage. In some cases, the term crystalline
finds identical usage to that used in conventional crystallography. For example, the structure of a crystalline protein
or polynucleotide, such as a sample prepared for x-ray crystallography, may be defined in terms of a conventional
unit cell composed of one or more polymer molecules with cell dimensions of hundreds of angstroms or more.
Polymer 336

A synthetic polymer may be loosely described as crystalline if it contains regions of three-dimensional ordering on
atomic (rather than macromolecular) length scales, usually arising from intramolecular folding and/or stacking of
adjacent chains. Synthetic polymers may consist of both crystalline and amorphous regions; the degree of
crystallinity may be expressed in terms of a weight fraction or volume fraction of crystalline material. Few synthetic
polymers are entirely crystalline.[22]
The crystallinity of polymers is characterized by their degree of crystallinity, ranging from zero for a completely
non-crystalline polymer to one for a theoretical completely crystalline polymer. Polymers with microcrystalline
regions are generally tougher (can be bent more without breaking) and more impact-resistant than totally amorphous
polymers.[23]
Polymers with a degree of crystallinity approaching zero or one will tend to be transparent, while polymers with
intermediate degrees of crystallinity will tend to be opaque due to light scattering by crystalline or glassy regions.
Thus for many polymers, reduced crystallinity may also be associated with increased transparency.

Chain conformation
The space occupied by a polymer molecule is generally expressed in terms of radius of gyration, which is an average
distance from the center of mass of the chain to the chain itself. Alternatively, it may be expressed in terms of
pervaded volume, which is the volume of solution spanned by the polymer chain and scales with the cube of the
radius of gyration.[24]

Mechanical properties
The bulk properties of a polymer are those most often of end-use interest. These are the properties
that dictate how the polymer actually behaves on a macroscopic scale.

Tensile strength

The tensile strength of a material quantifies how much stress the material will endure before
suffering permanent deformation.[25][26] This is very important in applications that rely upon a
polymer's physical strength or durability. For example, a rubber band with a higher tensile strength
will hold a greater weight before snapping. In general, tensile strength increases with polymer chain
length and crosslinking of polymer chains.

Young's modulus of elasticity

Young's Modulus quantifies the elasticity of the polymer. It is defined, for small strains, as the ratio
A
of rate of change of stress to strain. Like tensile strength, this is highly relevant in polymer
polyethylene
applications involving the physical properties of polymers, such as rubber bands. The modulus is sample
strongly dependent on temperature. Viscoelasticity describes a complex time-dependent elastic necking
response, which will exhibit hysteresis in the stress-strain curve when the load is removed. Dynamic under
tension.
mechanical analysis or DMA measures this complex modulus by oscillating the load and measuring
the resulting strain as a function of time.
Polymer 337

Transport properties
Transport properties such as diffusivity relate to how rapidly molecules move through the polymer matrix. These are
very important in many applications of polymers for films and membranes.

Phase behavior

Melting point
The term melting point, when applied to polymers, suggests not a solid-liquid phase transition but a transition from a
crystalline or semi-crystalline phase to a solid amorphous phase. Though abbreviated as simply Tm, the property in
question is more properly called the crystalline melting temperature. Among synthetic polymers, crystalline melting
is only discussed with regards to thermoplastics, as thermosetting polymers will decompose at high temperatures
rather than melt.

Glass transition temperature


A parameter of particular interest in synthetic polymer manufacturing is the glass transition temperature (Tg), which
describes the temperature at which amorphous polymers undergo a transition from a rubbery, viscous amorphous
liquid, to a brittle, glassy amorphous solid. The glass transition temperature may be engineered by altering the degree
of branching or crosslinking in the polymer or by the addition of plasticizer.[27]

Mixing behavior

In general, polymeric mixtures are far


less miscible than mixtures of small
molecule materials. This effect results
from the fact that the driving force for
mixing is usually entropy, not
interaction energy. In other words,
miscible materials usually form a
solution not because their interaction
with each other is more favorable than
their self-interaction, but because of an
increase in entropy and hence free
energy associated with increasing the
amount of volume available to each
component. This increase in entropy
scales with the number of particles (or
moles) being mixed. Since polymeric
molecules are much larger and hence
generally have much higher specific
volumes than small molecules, the
number of molecules involved in a
polymeric mixture is far smaller than Phase diagram of the typical mixing behavior of weakly interacting polymer solutions.

the number in a small molecule


mixture of equal volume. The energetics of mixing, on the other hand, is comparable on a per volume basis for
polymeric and small molecule mixtures. This tends to increase the free energy of mixing for polymer solutions and
thus make solvation less favorable. Thus, concentrated solutions of polymers are far rarer than those of small
molecules.
Polymer 338

Furthermore, the phase behavior of polymer solutions and mixtures is more complex than that of small molecule
mixtures. Whereas most small molecule solutions exhibit only an upper critical solution temperature phase
transition, at which phase separation occurs with cooling, polymer mixtures commonly exhibit a lower critical
solution temperature phase transition, at which phase separation occurs with heating.
In dilute solution, the properties of the polymer are characterized by the interaction between the solvent and the
polymer. In a good solvent, the polymer appears swollen and occupies a large volume. In this scenario,
intermolecular forces between the solvent and monomer subunits dominate over intramolecular interactions. In a bad
solvent or poor solvent, intramolecular forces dominate and the chain contracts. In the theta solvent, or the state of
the polymer solution where the value of the second virial coefficient becomes 0, the intermolecular polymer-solvent
repulsion balances exactly the intramolecular monomer-monomer attraction. Under the theta condition (also called
the Flory condition), the polymer behaves like an ideal random coil. The transition between the states is known as a
coil-globule transition.

Inclusion of plasticizers
Inclusion of plasticizers tends to lower Tg and increase polymer flexibility. Plasticizers are generally small molecules
that are chemically similar to the polymer and create gaps between polymer chains for greater mobility and reduced
interchain interactions. A good example of the action of plasticizers is related to polyvinylchlorides or PVCs. A
uPVC, or unplasticized polyvinylchloride, is used for things such as pipes. A pipe has no plasticizers in it, because it
needs to remain strong and heat-resistant. Plasticized PVC is used for clothing for a flexible quality. Plasticizers are
also put in some types of cling film to make the polymer more flexible.

Chemical properties
The attractive forces between polymer chains play a large part in determining a polymer's properties. Because
polymer chains are so long, these interchain forces are amplified far beyond the attractions between conventional
molecules. Different side groups on the polymer can lend the polymer to ionic bonding or hydrogen bonding
between its own chains. These stronger forces typically result in higher tensile strength and higher crystalline
melting points.
The intermolecular forces in polymers can be affected by dipoles in the monomer units. Polymers containing amide
or carbonyl groups can form hydrogen bonds between adjacent chains; the partially positively charged hydrogen
atoms in N-H groups of one chain are strongly attracted to the partially negatively charged oxygen atoms in C=O
groups on another. These strong hydrogen bonds, for example, result in the high tensile strength and melting point of
polymers containing urethane or urea linkages. Polyesters have dipole-dipole bonding between the oxygen atoms in
C=O groups and the hydrogen atoms in H-C groups. Dipole bonding is not as strong as hydrogen bonding, so a
polyester's melting point and strength are lower than Kevlar's (Twaron), but polyesters have greater flexibility.
Ethene, however, has no permanent dipole. The attractive forces between polyethylene chains arise from weak van
der Waals forces. Molecules can be thought of as being surrounded by a cloud of negative electrons. As two polymer
chains approach, their electron clouds repel one another. This has the effect of lowering the electron density on one
side of a polymer chain, creating a slight positive dipole on this side. This charge is enough to attract the second
polymer chain. Van der Waals forces are quite weak, however, so polyethylene can have a lower melting
temperature compared to other polymers.
Polymer 339

Standardized polymer nomenclature


There are multiple conventions for naming polymer substances. Many commonly used polymers, such as those
found in consumer products, are referred to by a common or trivial name. The trivial name is assigned based on
historical precedent or popular usage rather than a standardized naming convention. Both the American Chemical
Society (ACS)[28] and IUPAC[29] have proposed standardized naming conventions; the ACS and IUPAC
conventions are similar but not identical.[30] Examples of the differences between the various naming conventions
are given in the table below:

Common name ACS name IUPAC name

Poly(ethylene oxide) or PEO Poly(oxyethylene) Poly(oxyethene)

Poly(ethylene terephthalate) or PET Poly(oxy-1,2-ethanediyloxycarbonyl-1,4-phenylenecarbonyl) Poly(oxyetheneoxyterephthaloyl)

Nylon 6 Poly[amino(1-oxo-1,6-hexanediyl)] Poly[amino(1-oxohexan-1,6-diyl)]

In both standardized conventions, the polymers' names are intended to reflect the monomer(s) from which they are
synthesized rather than the precise nature of the repeating subunit. For example, the polymer synthesized from the
simple alkene ethene is called polyethylene, retaining the -ene suffix even though the double bond is removed during
the polymerization process:

Polymer characterization
The characterization of a polymer requires several parameters which need to be specified. This is because a polymer
actually consists of a statistical distribution of chains of varying lengths, and each chain consists of monomer
residues which affect its properties.
A variety of lab techniques are used to determine the properties of polymers. Techniques such as wide angle X-ray
scattering, small angle X-ray scattering, and small angle neutron scattering are used to determine the crystalline
structure of polymers. Gel permeation chromatography is used to determine the number average molecular weight,
weight average molecular weight, and polydispersity. FTIR, Raman and NMR can be used to determine
composition. Thermal properties such as the glass transition temperature and melting point can be determined by
differential scanning calorimetry and dynamic mechanical analysis. Pyrolysis followed by analysis of the fragments
is one more technique for determining the possible structure of the polymer. Thermogravimetry is a useful technique
to evaluate the thermal stability of the polymer. Detailed analysis of TG curves also allow us to know a bit of the
phase segregation in polymers. Rheological properties are also commonly used to help determine molecular
architecture (molecular weight, molecular weight distribution and branching) as well as to understand how the
polymer will process, through measurements of the polymer in the melt phase. Another polymer characterization
technique is Automatic Continuous Online Monitoring of Polymerization Reactions (ACOMP) which provides
real-time characterization of polymerization reactions. It can be used as an analytical method in R&D, as a tool for
reaction optimization at the bench and pilot plant level and, eventually, for feedback control of full-scale reactors.
Polymer 340

ACOMP measures in a model-independent fashion the evolution of average molar mass and intrinsic viscosity,
monomer conversion kinetics and, in the case of copolymers, also the average composition drift and distribution. It is
applicable in the areas of free radical and controlled radical homo- and copolymerization, polyelectrolyte synthesis,
heterogeneous phase reactions, including emulsion polymerization, adaptation to batch and continuous reactors, and
modifications of polymers.[31][32][33]

Polymer degradation
Polymer degradation is a change in the
properties—tensile strength, color, shape, or molecular
weight—of a polymer or polymer-based product under
the influence of one or more environmental factors,
such as heat, light, chemicals and, in some cases,
galvanic action. It is often due to the scission of
polymer chain bonds via hydrolysis, leading to a
decrease in the molecular mass of the polymer.

Although such changes are frequently undesirable, in


some cases, such as biodegradation and recycling, they
may be intended to prevent environmental pollution.
Degradation can also be useful in biomedical settings.
A plastic item with thirty years of exposure to heat and cold, brake
For example, a copolymer of polylactic acid and fluid, and sunlight. Notice the discoloration, swollen dimensions, and
polyglycolic acid is employed in hydrolysable stitches crazing of the material
that slowly degrade after they are applied to a wound.

The susceptibility of a polymer to degradation depends on its structure. Epoxies and chains containing aromatic
functionalities are especially susceptible to UV degradation while polyesters are susceptible to degradation by
hydrolysis, while polymers containing an unsaturated backbone are especially susceptible to ozone cracking. Carbon
based polymers are more susceptible to thermal degradation than inorganic polymers such as polydimethylsiloxane
and are therefore not ideal for most high-temperature applications. High-temperature matrices such as bismaleimides
(BMI), condensation polyimides (with an O-C-N bond), triazines (with a nitrogen (N) containing ring), and blends
thereof are susceptible to polymer degradation in the form of galvanic corrosion when bare carbon fiber reinforced
polymer CFRP is in contact with an active metal such as aluminium in salt water environments.

The degradation of polymers to form smaller molecules may proceed by random scission or specific scission. The
degradation of polyethylene occurs by random scission—a random breakage of the bonds that hold the atoms of the
polymer together. When heated above 450 °C, polyethylene degrades to form a mixture of hydrocarbons. Other
polymers, such as poly(alpha-methylstyrene), undergo specific chain scission with breakage occurring only at the
ends. They literally unzip or depolymerize back to the constituent monomer.
The sorting of polymer waste for recycling purposes may be facilitated by the use of the Resin identification codes
developed by the Society of the Plastics Industry to identify the type of plastic.
Polymer 341

Product failure
In a finished product, such a change is to be prevented or delayed.
Failure of safety-critical polymer components can cause serious
accidents, such as fire in the case of cracked and degraded
polymer fuel lines. Chlorine-induced cracking of acetal resin
plumbing joints and polybutylene pipes has caused many serious
floods in domestic properties, especially in the USA in the 1990s.
Traces of chlorine in the water supply attacked vulnerable
polymers in the plastic plumbing, a problem which occurs faster if
any of the parts have been poorly extruded or injection molded.
Chlorine attack of acetal resin plumbing joint Attack of the acetal joint occurred because of faulty molding,
leading to cracking along the threads of the fitting which is a
serious stress concentration.

Polymer oxidation has caused accidents involving medical


devices. One of the oldest known failure modes is ozone cracking
caused by chain scission when ozone gas attacks susceptible
elastomers, such as natural rubber and nitrile rubber. They possess
double bonds in their repeat units which are cleaved during
ozonolysis. Cracks in fuel lines can penetrate the bore of the tube
and cause fuel leakage. If cracking occurs in the engine
compartment, electric sparks can ignite the gasoline and can cause Ozone-induced cracking in natural rubber tubing

a serious fire.

Fuel lines can also be attacked by another form of degradation: hydrolysis. Nylon 6,6 is susceptible to acid
hydrolysis, and in one accident, a fractured fuel line led to a spillage of diesel into the road. If diesel fuel leaks onto
the road, accidents to following cars can be caused by the slippery nature of the deposit, which is like black ice.

References
[1] Roiter, Y.; Minko, S. (2005). "AFM Single Molecule Experiments at the Solid-Liquid Interface: In Situ Conformation of Adsorbed Flexible
Polyelectrolyte Chains". Journal of the American Chemical Society 127 (45): 15688–15689. doi:10.1021/ja0558239. PMID 16277495.
[2] Painter, Paul C.; Coleman, Michael M. (1997). Fundamentals of polymer science : an introductory text. Lancaster, Pa.: Technomic Pub. Co..
p. 1. ISBN 1-56676-559-5.
[3] McCrum, N. G.; Buckley, C. P.; Bucknall, C. B. (1997). Principles of polymer engineering. Oxford ; New York: Oxford University Press.
p. 1. ISBN 0-19-856526-7.
[4] Sperling, L. H. (Leslie Howard) (2006). Introduction to physical polymer science. Hoboken, N.J.: Wiley. p. 10. ISBN 0-471-70606-X.
[5] Sperling, p. 11
[6] Sperling, p. 15
[7] S.A. Baeurle (2009). "Multiscale modeling of polymer materials using field-theoretic methodologies: a survey about recent developments".
Journal of Mathematical Chemistry 46 (2): 363–426. doi:10.1007/s10910-008-9467-3.
[8] Sperling, p. 30
[9] Rubinstein, Michael; Colby, Ralph H. (2003). Polymer physics. Oxford ; New York: Oxford University Press. p. 6. ISBN 0-19-852059-X.
[10] De Gennes, Pierre Gilles (1979). Scaling concepts in polymer physics. Ithaca, N.Y.: Cornell University Press. ISBN 0-8014-1203-X.
[11] Rubinstein, p. 5
[12] McCrum, p. 37
[13] McCrum, p. 30
[14] Rubinstein, p. 3
[15] McCrum, p. 33
[16] Rubinstein, pp. 23-24
[17] Painter, p. 22
[18] Rubinstein, p. 50
[19] Painter, p. 14
Polymer 342

[20] Painter, p. 15
[21] Sperling, p. 47
[22] "IUPAC Purple Book: Definition of terms relating to crystalline polymers (1988) See Sec.1.3 Degree of Crystallinity" (http:/ / www. iupac.
org/ publications/ books/ pbook/ PurpleBook-C4. pdf) (PDF). .
[23] Allcock, Harry R.; Lampe, Frederick W.; Mark, James E. (2003). Contemporary Polymer Chemistry (3 ed.). Pearson Education. p. 546.
ISBN 0-13-065056-0.
[24] Rubinstein, p. 13
[25] Ashby, Michael; Jones, David (1996). Engineering Materials (2 ed.). Butterworth-Heinermann. pp. 191–195. ISBN 0-7506-2766-2.
[26] Meyers, M. A.; Chawla, K. K. (1999). Mechanical Behavior of Materials (http:/ / www. toodoc. com/
Mechanical-Behavior-of-Materials-ebook. html). Cambridge University Press. p. 41. ISBN 978-0-521-86675-0. .
[27] Brandrup, J.; Immergut, E.H.; Grulke, E.A. (1999). Polymer Handbook (4 ed.). Wiley-Interscience. ISBN 0-471-47936-5.
[28] CAS: Index Guide, Appendix IV ((c) 1998)
[29] IUPAC (1976). "Nomenclature of Regular Single-Strand Organic Polymers". Pure Appl. Chem. 48 (3): 373–385.
doi:10.1351/pac197648030373.
[30] "Macromolecular Nomenclature Note No. 18" (http:/ / www. polyacs. org/ nomcl/ mnn18. html). .
[31] U.S. Patent 6052184 (http:/ / www. google. com/ patents?vid=6052184) and U.S. Patent 6653150 (http:/ / www. google. com/
patents?vid=6653150), other patents pending
[32] Florenzano, F. H.; Strelitzki, R.; Reed, W. F. (1998). "Absolute, Online Monitoring of Polymerization Reactions". Macromolecules 31 (21):
7226–7238. doi:10.1021/ma980876e.
[33] Alb, A. M.; Drenski, M. F.; Reed, W. F. (2008). "Implications to Industry: Perspective. Automatic continuous online monitoring of
polymerization reactions (ACOMP)". Polymer International 57 (3): 390–396. doi:10.1002/pi.2367.

Bibliography
• Cowie, J. M. G. (John McKenzie Grant) (1991). Polymers: chemistry and physics of modern material. Glasgow:
Blackie. ISBN 0-412-03121-3.
• Ezrin, Myer. (1996). Plastics failure guide : cause and preventio. Munich ; New York: Hanser Publishers :
Cincinnati. ISBN 1-56990-184-8.
• Lewis, P. R. (Peter Rhys); Reynolds, Ken.; Gagg, Colin. (2004). Forensic materials engineering : case studi.
Boca Raton: CRC Press. ISBN 0-8493-1182-9.
• Wright, David C. (2001). Environmental Stress Cracking of Plastics. RAPRA. ISBN 978-1-85957-064-7.
• Lewis, Peter Rhys (2010). Forensic polymer engineering : why polymer products fail in service. Cambridge
[etc.]: Woodhead Publishing. ISBN 1-84569-185-7.
• Workman, Jerome; Workman, Jerry (2001). Handbook of organic compounds: NIR, IR, Raman, and UV-Vis
spectra featuring polymers and surfactants. San Diego: Academic Press. ISBN 978-0-12-763560-6.

External links
• How To Identify the Polymer (http://fibreinfo.co.cc/?p=18)
• Polymer Chemistry Hypertext, Educational resource (http://www.polymerchemistryhypertext.com/)
• The Macrogalleria (http://www.pslc.ws/macrog/index.htm)
• Application notes on the characterization of polymers (http://www.campoly.com/application_notes.html)
• Distance learning course in polymers (http://openlearn.open.ac.uk/course/view.php?id=2937)
• Polymer Structures (http://openlearn.open.ac.uk/mod/resource/view.php?id=196631)
• Glossary of Polymer Abbreviations (http://www.theotherpages.org/abbrev.html)
• Sigma-Aldrich Polymer Glossary (http://www.sigmaaldrich.com/img/assets/3900/Glossary.pdf)
Polysaccharide 343

Polysaccharide
Polysaccharides are long carbohydrate molecules of
repeated monomer units joined together by glycosidic
bonds. They range in structure from linear to highly
branched. Polysaccharides are often quite
heterogeneous, containing slight modifications of the
repeating unit. Depending on the structure, these
macromolecules can have distinct properties from their 3D structure of cellulose, a beta-glucan polysaccharide.
monosaccharide building blocks. They may be
amorphous or even insoluble in water.[1][2]

When all the monosaccharides in a polysaccharide are the same type, the polysaccharide is called a
homopolysaccharide or homoglycan, but when more than one type of monosaccharide is present they are called
heteropolysaccharides or heteroglycans.[3][4]
Examples include storage polysaccharides such as starch and glycogen, and structural polysaccharides such as
cellulose and chitin.
Polysaccharides have a general formula of Cx(H2O)y where x is usually a large number between 200 and 2500.
Considering that the repeating units in the polymer backbone are often six-carbon monosaccharides, the general
formula can also be represented as (C6H10O5)n where 40≤n≤3000.

Structure
Natural saccharides are generally built of simple carbohydrates called monosaccharides with general formula
(CH2O)n where n is three or more. A typical monosaccharide has the structure H-(CHOH)x(C=O)-(CHOH)y-H, that
is, an aldehyde or ketone with many hydroxyl groups added, usually one on each carbon atom that is not part of the
aldehyde or ketone functional group. Examples of monosaccharides are glucose, fructose, and glyceraldehyde[5]
Polysaccharides are composed of long
chains of monosaccharide units bound
together by glycosidic bonds.
Polysaccharides contain more than ten
monosaccharide units. Definitions of
how large a carbohydrate must be to
fall into the categories polysaccharides
or oligosaccharides vary according to
personal opinion.

Polysaccharides is an important class


Amylose is a linear polymer of glucose mainly linked with α(1→4) bonds. It can be made
of biological polymers. Their function of several thousands of glucose units. It is one of the two components of starch, the other
in living organisms is usually either being amylopectin.
structure- or storage-related. Starch (a
polymer of glucose) is used as a storage polysaccharide in plants, being found in the form of both amylose and the
branched amylopectin. In animals, the structurally similar glucose polymer is the more densely branched glycogen,
sometimes called 'animal starch'. Glycogen's properties allow it to be metabolized more quickly, which suits the
active lives of moving animals.

Cellulose and chitin are examples of structural polysaccharides. Cellulose is used in the cell walls of plants and other
organisms, and is claimed to be the most abundant organic molecule on earth.[6] It has many uses such as a
Polysaccharide 344

significant role in the paper and textile industries, and is used as a feedstock for the production of rayon (via the
viscose process), cellulose acetate, celluloid, and nitrocellulose. Chitin has a similar structure, but has
nitrogen-containing side branches, increasing its strength. It is found in arthropod exoskeletons and in the cell walls
of some fungi. It also has multiple uses, including surgical threads.
Polysaccharides also include callose or laminarin, chrysolaminarin, xylan, arabinoxylan, mannan, fucoidan and
galactomannan.

Function

Nutrition
Polysaccharides are common sources of energy. Many organisms can easily break down starches into glucose,
however, most organisms cannot metabolize cellulose or other polysaccharides like chitin and arabinoxylans. These
carbohydrates types can be metabolized by some bacteria and protists. Ruminants and termites, for example, use
microorganisms to process cellulose.
Even though these complex carbohydrates are not very digestible, they may comprise important dietary elements for
humans. Called dietary fiber, these carbohydrates enhance digestion among other benefits. The main action of
dietary fiber is to change the nature of the contents of the gastrointestinal tract, and to change how other nutrients
and chemicals are absorbed.[7][8] Soluble fiber binds to bile acids in the small intestine, making them less likely to
enter the body; this in turn lowers cholesterol levels in the blood.[9] Soluble fiber also attenuates the absorption of
sugar, reduces sugar response after eating, normalizes blood lipid levels and, once fermented in the colon, produces
short-chain fatty acids as byproducts with wide-ranging physiological activities (discussion below). Although
insoluble fiber is associated with reduced diabetes risk, the mechanism by which this occurs is unknown.[10]
Not yet formally proposed as an essential macronutrient, dietary fiber is nevertheless regarded as important for the
diet, with regulatory authorities in many developed countries recommending increases in fiber intake.[7][8][11][12]

Storage polysaccharides

Starches
Starches are glucose polymers in which glucopyranose units are bonded by alpha-linkages. It is made up of a
mixture of amylose (15–20%) and amylopectin (80–85%). Amylose consists of a linear chain of several hundred
glucose molecules and Amylopectin is a branched molecule made of several thousand glucose units (every chain of
24–30 glucose units is one unit of Amylopectin). Starches are insoluble in water. They can be digested by
hydrolysis, catalyzed by enzymes called amylases, which can break the alpha-linkages (glycosidic bonds). Humans
and other animals have amylases, so they can digest starches. Potato, rice, wheat, and maize are major sources of
starch in the human diet. The formations of starches are the ways that plants store glucose.
Polysaccharide 345

Glycogen
Glycogen serves as the secondary long-term
energy storage in animal and fungal cells,
with the primary energy stores being held in
adipose tissue. Glycogen is made primarily
by the liver and the muscles, but can also be
made by glycogenesis within the brain and
stomach.[14]

Glycogen is the analogue of starch, a


glucose polymer in plants, and is sometimes
referred to as animal starch, having a
similar structure to amylopectin but more
extensively branched and compact than
starch. Glycogen is a polymer of α(1→4)
glycosidic bonds linked, with
α(1→6)-linked branches. Glycogen is found
in the form of granules in the
cytosol/cytoplasm in many cell types, and
plays an important role in the glucose cycle.
Glycogen forms an energy reserve that can Schematic 2-D cross-sectional view of glycogen. A core protein of glycogenin is
surrounded by branches of glucose units. The entire globular granule may contain
be quickly mobilized to meet a sudden need [13]
approximately 30,000 glucose units.
for glucose, but one that is less compact
than the energy reserves of triglycerides
(lipids).

In the liver hepatocytes, glycogen can


compose up to eight percent of the fresh
weight (100–120 g in an adult) soon after a
meal.[15] Only the glycogen stored in the
liver can be made accessible to other organs.
In the muscles, glycogen is found in a low
concentration (one to two percent of the
muscle mass). However, the amount of
glycogen stored in the body—especially
within the muscles, liver, and red blood
cells[16][17][18]—mostly depends on physical
training, basal metabolic rate, and eating
habits such as intermittent fasting. Small
amounts of glycogen are found in the
kidneys, and even smaller amounts in
certain glial cells in the brain and white
blood cells. The uterus also stores glycogen
during pregnancy to nourish the embryo.[15] A view of the atomic structure of a single branched strand of glucose units in a
glycogen molecule.
Glycogen is composed of a branched chain
of glucose residues. It is stored in liver and muscles.
• It is an energy reserve for animals.
Polysaccharide 346

• It is the chief form of carbohydrate stored in animal body.


• It is insoluble in water. It turns red when mixed with iodine.
• It also yields glucose on hydrolysis.

Structural polysaccharides

Arabinoxylans
Arabinoxylans are found in both the primary and secondary cell walls of plants and are the copolymers of two
pentose sugars: arabinose and xylose.

Cellulose
The structural component of plants are formed primarily from cellulose. Wood is largely cellulose and lignin, while
paper and cotton are nearly pure cellulose. Cellulose is a polymer made with repeated glucose units bonded together
by beta-linkages. Humans and many other animals lack an enzyme to break the beta-linkages, so they do not digest
cellulose. Certain animals such as termites can digest cellulose, because bacteria possessing the enzyme are present
in their gut. Cellulose is insoluble in water. It does not change color when mixed with iodine. On hydrolysis, it yields
glucose. It is the most abundant carbohydrate in nature.

Chitin
Chitin is one of many naturally occurring polymers. It forms a structural component of many animals, such as
exoskeletons. Over time it is bio-degradable in the natural environment. Its breakdown may be catalyzed by enzymes
called chitinases, secreted by microorganisms such as bacteria and fungi, and produced by some plants. Some of
these microorganisms have receptors to simple sugars from the decomposition of chitin. If chitin is detected, they
then produce enzymes to digest it by cleaving the glycosidic bonds in order to convert it to simple sugars and
ammonia.
Chemically, chitin is closely related to chitosan (a more water-soluble derivative of chitin). It is also closely related
to cellulose in that it is a long unbranched chain of glucose derivatives. Both materials contribute structure and
strength, protecting the organism.

Pectins
Pectins are a family of complex polysaccharides that contain 1,4-linked α-D-galactosyluronic acid residues. They are
present in most primary cell walls and in the non-woody parts of terrestrial plants.

Acidic polysaccharides
Acidic polysaccharides are polysaccharides that contain carboxyl groups, phosphate groups and/or sulfuric ester
groups.

Bacterial polysaccharides
Bacterial polysaccharides represent a diverse range of macromolecules that include peptidoglycan,
lipopolysaccharides, capsules and exopolysaccharides; compounds whose functions range from structural cell-wall
components (e.g., peptidoglycan), and important virulence factors (e.g., Poly-N-acetylglucosamine in S. aureus), to
permitting the bacterium to survive in harsh environments (e.g., Pseudomonas aeruginosa in the human lung).[19]
Polysaccharide biosynthesis is a tightly regulated, energy-intensive process and understanding the subtle interplay
between the regulation and energy conservation, polymer modification and synthesis, and the external ecological
functions is a huge area of research. The potential benefits are enormous and should enable for example the
Polysaccharide 347

development of novel antibacterial strategies (e.g., new antibiotics and vaccines) and the commercial exploitation to
develop novel applications.[20][21]

Bacterial capsular polysaccharides


Pathogenic bacteria commonly produce a thick, mucous-like, layer of polysaccharide. This "capsule" cloaks
antigenic proteins on the bacterial surface that would otherwise provoke an immune response and thereby lead to the
destruction of the bacteria. Capsular polysaccharides are water soluble, commonly acidic, and have molecular
weights on the order of 100-1000 kDa. They are linear and consist of regularly repeating subunits of one to six
monosaccharides. There is enormous structural diversity; nearly two hundred different polysaccharides are produced
by E. coli alone. Mixtures of capsular polysaccharides, either conjugated or native are used as vaccines.
Bacteria and many other microbes, including fungi and algae, often secrete polysaccharides as an evolutionary
adaptation to help them adhere to surfaces and to prevent them from drying out. Humans have developed some of
these polysaccharides into useful products, including xanthan gum, dextran, welan gum, gellan gum, diutan gum and
pullulan.
Most of these polysaccharides exhibit interesting and very useful visco-elastic properties when dissolved in water at
very low levels.[22] This gives many foods and various liquid consumer products, like lotions, cleaners and paints,
for example, a viscous appearance when stationary, but fluidity when the slightest shear is applied, such as when
wiped, poured or brushed. This property is referred to as pseudoplasticity, or shear thinning.

Viscosity of Welan gum [23]


Shear Rate (rpm) Viscosity (cP)

0.3 23330

0.5 16000

1 11000

2 5500

4 3250

5 2900

10 1700

20 900

50 520

100 310

Aqueous solutions of the polysaccharide alone have a curious behavior when stirred. After stopping, the swirl
continues due to momentum, then stops, and then reverses direction briefly. This recoil demonstrates the elastic
effect of the polysaccharide chains previously streched in solution, returning to their relaxed state.
Cell-surface polysaccharides play diverse roles in bacterial ecology and physiology. They serve as a barrier between
the cell wall and the environment, mediate host-pathogen interactions, and form structural components of biofilms.
These polysaccharides are synthesized from nucleotide-activated precursors (called nucleotide sugars) and, in most
cases, all the enzymes necessary for biosynthesis, assembly and transport of the completed polymer are encoded by
genes organized in dedicated clusters within the genome of the organism. Lipopolysaccharide is one of the most
important cell-surface polysaccharides, as it plays a key structural role in outer membrane integrity, as well as being
an important mediator of host-pathogen interactions.
The enzymes that make the A-band (homopolymeric) and B-band (heteropolymeric) O-antigens have been identified
and the metabolic pathways defined.[24] The exopolysaccharide alginate is a linear copolymer of β-1,4-linked
Polysaccharide 348

D-mannuronic acid and L-guluronic acid residues, and is responsible for the mucoid phenotype of late-stage cystic
fibrosis disease. The pel and psl loci are two recently discovered gene clusters that also encode exopolysaccharides
found to be important for biofilm formation. Rhamnolipid is a biosurfactant whose production is tightly regulated at
the transcriptional level, but the precise role that it plays in disease is not well understood at present. Protein
glycosylation, particularly of pilin and flagellin, is a recent focus of research by several groups and it has been shown
to be important for adhesion and invasion during bacterial infection.[25]

Chemical Identification tests for polysaccharides

Periodic acid-Schiff stain (PAS)


Polysaccharides with unprotected vicinal diols or amino sugars (i.e. some OH groups replaced with amine) give a
positive Periodic acid-Schiff stain (PAS). The list of polysaccharide that stains with PAS is long. Interesting, though
mucins of epithelial origins stain with PAS, mucins of connective tissue origin have so many acidic substitutions that
they don't have enough glycol or amino-alcohol groups left to react with PAS.

References
[1] Varki A, Cummings R, Esko J, Freeze H, Stanley P, Bertozzi C, Hart G, Etzler M (2008). Essentials of glycobiology (http:/ / www. ncbi. nlm.
nih. gov/ bookshelf/ br. fcgi?book=glyco2). Cold Spring Harbor Laboratory Press; 2nd edition. ISBN 0-87969-770-9. .
[2] Varki A, Cummings R, Esko J, Jessica Freeze, Hart G, Marth J (1999). Essentials of glycobiology (http:/ / www. ncbi. nlm. nih. gov/ books/
bv. fcgi?rid=glyco. TOC& depth=2). Cold Spring Harbor Laboratory Press. ISBN 0-87969-560-9. .
[3] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "homopolysaccharide (homoglycan)" (http:/ / goldbook. iupac. org/ H02856. html). IUPAC
Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.{{{file}}}. ISBN 0-9678550-9-8. .
[4] Nic, M.; Jirat, J.; Kosata, B., eds. (2006–). "heteropolysaccharide (heteroglycan)" (http:/ / goldbook. iupac. org/ H02812. html). IUPAC
Compendium of Chemical Terminology (Online ed.). doi:10.1351/goldbook.{{{file}}}. ISBN 0-9678550-9-8. .
[5] Matthews, C. E.; K. E. Van Holde; K. G. Ahern (1999) Biochemistry. 3rd edition. Benjamin Cummings. ISBN 0-8053-3066-6
[6] N.A.Campbell (1996) Biology (4th edition). Benjamin Cummings NY. p.23 ISBN 0-8053-1957-3
[7] "Dietary Reference Intakes for Energy, Carbohydrate, fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients) (2005),
Chapter 7: Dietary, Functional and Total fiber." (http:/ / www. nal. usda. gov/ fnic/ DRI/ / DRI_Energy/ 339-421. pdf). US Department of
Agriculture, National Agricultural Library and National Academy of Sciences, Institute of Medicine, Food and Nutrition Board. .
[8] Eastwood M, Kritchevsky D (2005). "Dietary fiber: how did we get where we are?". Annu Rev Nutr 25: 1–8.
doi:10.1146/annurev.nutr.25.121304.131658. PMID 16011456.
[9] Anderson JW, Baird P, Davis RH et al. (2009). "Health benefits of dietary fiber". Nutr Rev 67 (4): 188–205.
doi:10.1111/j.1753-4887.2009.00189.x. PMID 19335713.
[10] Weickert MO, Pfeiffer AF (2008). "Metabolic effects of dietary fiber consumption and prevention of diabetes". J Nutr 138 (3): 439–42.
PMID 18287346.
[11] "Dietary reference values for carbohydrates and dietary fiber" (http:/ / www. efsa. europa. eu/ EFSA/ DocumentSet/
nda_op_drv_carbohydrates_draft_en_released for consultation,0. pdf?ssbinary=true). European Food Safety Authority. .
[12] Jones PJ, Varady KA (2008). "Are functional foods redefining nutritional requirements?" (http:/ / article. pubs. nrc-cnrc. gc. ca/ ppv/
RPViewDoc?issn=1715-5312& volume=33& issue=1& startPage=118) (PDF). Appl Physiol Nutr Metab 33 (1): 118–23.
doi:10.1139/H07-134. PMID 18347661. .
[13] Page 12 in: (http:/ / books. google. dk/ books?id=SRptlOx7yj4C& printsec=frontcover& hl=en) Exercise physiology: energy, nutrition, and
human performance By William D. McArdle, Frank I. Katch, Victor L. Katch Edition: 6, illustrated Published by Lippincott Williams &
Wilkins, 2006 ISBN 0-7817-4990-5, ISBN 978-0-7817-4990-9, 1068 pages
[14] Anatomy and Physiology. Saladin, Kenneth S. McGraw-Hill, 2007.
[15] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http:/ / www. phschool. com/ el_marketing. html).
Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. .
[16] Moses SW, Bashan N, Gutman A (December 1972). "Glycogen metabolism in the normal red blood cell" (http:/ / www. bloodjournal. org/
cgi/ pmidlookup?view=long& pmid=5083874). Blood 40 (6): 836–43. PMID 5083874. .
[17] http:/ / jeb. biologists. org/ cgi/ reprint/ 129/ 1/ 141. pdf
[18] Miwa I, Suzuki S (November 2002). "An improved quantitative assay of glycogen in erythrocytes". Annals of Clinical Biochemistry 39 (Pt
6): 612–3. doi:10.1258/000456302760413432. PMID 12564847.
[19] Sutherland, I. W. (2002). Vandamme, E. J., Ed.. ed. Polysaccharides from Microorganisms, Plants and Animals, in: Biopolymers, Volume
5, Polysaccharides I: Polysaccharides from Prokaryotes. Weiheim Wiley VCH. pp. 1–19. ISBN 978-3-527-30226-0.
Polysaccharide 349

[20] Ullrich M (editor) (2009). Bacterial Polysaccharides: Current Innovations and Future Trends. Caister Academic Press.
ISBN 978-1-904455-45-5.
[21] Rehm BHA (editor). (2009). Microbial Production of Biopolymers and Polymer Precursors: Applications and Perspectives. Caister
Academic Press. ISBN 978-1-904455-36-3.
[22] Viscosity of Welan Gum vs. Concentration in Water. http:/ / www. xydatasource. com/ xy-showdatasetpage. php?datasetcode=345115&
dsid=80
[23] http:/ / www. xydatasource. com/ xy-showdatasetpage. php?datasetcode=45615& dsid=76& searchtext=polysaccharide
[24] Guo H, Yi W, Song JK, Wang PG (2008). "Current understanding on biosynthesis of microbial polysaccharides". Curr Top Med Chem 8
(2): 141–51. doi:10.2174/156802608783378873. PMID 18289083.
[25] Cornelis P (editor). (2008). Pseudomonas: Genomics and Molecular Biology (http:/ / www. horizonpress. com/ pseudo) (1st ed.). Caister
Academic Press. ISBN 978-1-904455-19-6. . .

External links
• Polysaccharide Structure (http://employees.csbsju.edu/hjakubowski/classes/ch331/cho/complexoligosacch.
htm)
• Applications and commercial sources of polysaccharides (http://www.polysaccharidecenter.com)
• European Polysaccharide Network of Excellence (http://www.epnoe.eu)
Prion 350

Prion
Prion Diseases (TSEs)
Classification and external resources

Microscopic "holes" are characteristic in prion-affected tissue sections, causing the tissue to develop a "spongy" architecture.

ICD-10 [1]
A81

ICD-9 [2]
046

A prion i/ˈpriːɒn/[3] is an infectious agent composed of protein in a misfolded form.[4] This is in contrast to all
other known infectious agents (virus/bacteria/fungus/parasite) which must contain nucleic acids (either DNA, RNA,
or both). The word prion, coined in 1982 by Stanley B. Prusiner, is derived from the words protein and infection.[5]
Prions are responsible for the transmissible spongiform encephalopathies in a variety of mammals, including bovine
spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle and Creutzfeldt–Jakob disease (CJD)
in humans. All known prion diseases affect the structure of the brain or other neural tissue and all are currently
untreatable and universally fatal.[6]
Prions propagate by transmitting a misfolded protein state. When a prion enters a healthy organism, it induces
existing, properly folded proteins to convert into the disease-associated, prion form; the prion acts as a template to
guide the misfolding of more protein into prion form. These newly formed prions can then go on to convert more
proteins themselves; this triggers a chain reaction that produces large amounts of the prion form.[7] All known prions
induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly
packed beta sheets. Amyloid aggregates are fibrils, growing at their ends, and replicating when breakage causes two
growing ends to become four growing ends. The incubation period of prion diseases is determined by the
exponential growth rate associated with prion replication, which is a balance between the linear growth and the
breakage of aggregates.[8] (Note that the propagation of the prion depends on the presence of normally folded protein
in which the prion can induce misfolding; animals which do not express the normal form of the prion protein cannot
develop or transmit the disease.)
This altered structure is extremely stable and accumulates in infected tissue, causing tissue damage and cell death.[9]
This structural stability means that prions are resistant to denaturation by chemical and physical agents, making
disposal and containment of these particles difficult. Prions come in different strains, each with a slightly different
structure, and most of the time, strains breed true. Prion replication is nevertheless subject to occasional epimutation
and then natural selection just like other forms of replication.[10] However, the number of possible distinct prion
strains is likely far smaller than the number of possible DNA sequences, so evolution takes place within a limited
space.
Prion 351

All known mammalian prion diseases are caused by the so-called prion protein, PrP. The endogenous, properly
folded, form is denoted PrPC (for Common or Cellular) while the disease-linked, misfolded form is denoted PrPSc
(for Scrapie, after one of the diseases first linked to prions and neurodegeneration.)[11][12] The precise structure of
the prion is not known, though they can be formed by combining PrPC, polyadenylic acid, and lipids in a Protein
Misfolding Cyclic Amplification (PMCA) reaction.[13]
Proteins showing prion-type behavior are also found in some fungi, which has been useful in helping to understand
mammalian prions. Interestingly, fungal prions do not appear to cause disease in their hosts.[14]

Discovery
Radiation biologist Tikvah Alper and mathematician John Stanley Griffith developed the hypothesis during the
1960s that some transmissible spongiform encephalopathies are caused by an infectious agent consisting solely of
proteins.[15][16] Their theory was developed to explain the discovery that the mysterious infectious agent causing the
diseases scrapie and Creutzfeldt–Jakob disease resisted ionizing radiation. A single ionizing "hit" normally destroys
an entire infectious particle, and the dose needed to hit half the particles depends on the size of the particles. The data
suggested that the infectious agent was too small to be a virus.
Francis Crick recognized the potential importance of the Griffith protein-only hypothesis for scrapie propagation in
the second edition of his "Central dogma of molecular biology": while asserting that the flow of sequence
information from protein to protein, or from protein to RNA and DNA was "precluded", he noted that Griffith's
hypothesis was a potential contradiction (although it was not so promoted by Griffith).[17] The revised hypothesis
was later formulated, in part, to accommodate discovery of reverse transcription by Howard Temin and David
Baltimore.
Stanley B. Prusiner of the University of California, San Francisco announced in 1982 that his team had purified the
hypothetical infectious prion, and that the infectious agent consisted mainly of a specific protein – though they did
not manage to isolate the protein until two years after Prusiner's announcement.[18] While the infectious agent was
named a prion, the specific protein that the prion was composed of is also known as the Prion Protein (PrP), though
this protein may occur both in infectious and non-infectious forms. Prusiner was awarded the Nobel Prize in
Physiology or Medicine in 1997 for his research into prions.[19]

Structure

Isoforms
The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals.
However, PrP found in infectious material has a different structure and is resistant to proteases, the enzymes in the
body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious
form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease
occurring in sheep.[20] While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a
relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their
relationship to the form(s) that are pathogenic in vivo is not yet clear.

PrPC
PrPC is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), one disulfide bond, a
molecular mass of 35-36 kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface
form anchored via glycolipid and two transmembrane forms.[21] The normal protein is not sedimentable; meaning it
cannot be separated by centrifuging techniques.[11] Its function is a complex issue that continues to be investigated.
PrPC binds copper (II) ions with high affinity.[22] The significance of this finding is not clear, but it presumably
relates to PrP structure or function. PrPC is readily digested by proteinase K and can be liberated from the cell
Prion 352

surface in vitro by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the
glycophosphatidylinositol (GPI) glycolipid anchor.[23] PrP has been reported to play important roles in cell-cell
adhesion and intracellular signaling in vivo, and may therefore be involved in cell-cell communication in the
brain.[24]

PrPSc
The infectious isoform of PrP, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by
changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. Although the exact 3D
structure of PrPSc is not known, it has a higher proportion of β-sheet structure in place of the normal α-helix
structure.[25] Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to
form plaques. It is unclear if these aggregates are the cause of cell damage or are simply a side effect of the
underlying disease process.[26] The end of each fiber acts as a template onto which free protein molecules may
attach, allowing the fiber to grow. Under most circumstances, only PrP molecules with an identical amino acid
sequence to the infectious PrPSc are incorporated into the growing fiber.[11] However, rare cross-species transmission
is also possible. In a different prion, sup35p was shown to be able to be incorporated into existing aggregations even
when three of the five oligopeptide repeats normally present were deleted.[27]

Prion replication mechanism


The first hypothesis that tried to explain how prions replicate in a
protein-only manner was the heterodimer model.[28] This model
assumed that a single PrPSc molecule binds to a single PrPC molecule
and catalyzes its conversion into PrPSc. The two PrPSc molecules then
come apart and can go on to convert more PrPC. However, a model of
prion replication must explain both how prions propagate, and why
their spontaneous appearance is so rare. Manfred Eigen showed that
the heterodimer model requires PrPSc to be an extraordinarily effective
catalyst, increasing the rate of the conversion reaction by a factor of
around 1015.[29] This problem does not arise if PrPSc exists only in
Heterodimer model of prion propagation aggregated forms such as amyloid, where cooperativity may act as a
barrier to spontaneous conversion. What is more, despite considerable
effort, infectious monomeric PrPSc has never been isolated.

An alternative model assumes that PrPSc exists only as fibrils, and that
fibril ends bind PrPC and convert it into PrPSc. If this were all, then the
quantity of prions would increase linearly, forming ever longer fibrils.
But exponential growth of both PrPSc and of the quantity of infectious
particles is observed during prion disease.[30][31][32] This can be
explained by taking into account fibril breakage.[33] A mathematical
solution for the exponential growth rate resulting from the combination
Fibril model of prion propagation.
of fibril growth and fibril breakage has been found.[8] The exponential
growth rate depends largely on the square root of the PrPC
concentration.[8] The incubation period is determined by the exponential growth rate, and in vivo data on prion
diseases in transgenic mice match this prediction.[8] The same square root dependence is also seen in vitro in
experiments with a variety of different amyloid proteins.[34]

The mechanism of prion replication has implications for designing drugs. Since the incubation period of prion
diseases is so long, an effective drug does not need to eliminate all prions, but simply needs to slow down the rate of
exponential growth. Models predict that the most effective way to achieve this, using a drug with the lowest possible
Prion 353

dose, is to find a drug that binds to fibril ends and blocks them from growing any further.[35]

PrP function
It has been proposed that neurodegeneration caused by prions may be related to abnormal function of PrP. However,
the physiological function of the prion protein remains a controversial matter. While data from in vitro experiments
suggest many dissimilar roles, studies on PrP knockout mice have provided only limited information because these
animals exhibit only minor abnormalities. In recent research done in mice, it was found that the cleavage of PrP
proteins in peripheral nerves causes the activation of myelin repair in Schwann Cells and that the lack of PrP proteins
caused demyelination in those cells.[36]

PrP and long-term memory


A review of evidence in 2005 suggested that PrP may have a normal function in maintenance of long-term
memory.[37] As well, a 2004 study found that mice lacking genes for normal cellular PrP protein show altered
hippocampal long-term potentiation.[38]

PrP and stem cell renewal


A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is
necessary for an organism's self-renewal of bone marrow. The study showed that all long-term hematopoietic stem
cells expressed PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibited
increased sensitivity to cell depletion.[39]

Prion disease

Diseases caused by prions

Affected animal(s) Disease

sheep, goat [40]


Scrapie

cattle [40]
Bovine spongiform encephalopathy (BSE), mad cow disease
[40] Transmissible mink encephalopathy (TME)
mink
[40] Chronic wasting disease (CWD)
white-tailed deer, elk, mule deer, moose
[40] Feline spongiform encephalopathy (FSE)
cat
[40] Exotic ungulate encephalopathy (EUE)
nyala, oryx, greater kudu
[41] Spongiform encephalopathy
ostrich
(Not been shown to be transmissible.)
Prion 354

human [40]
Creutzfeldt–Jakob disease (CJD)

Iatrogenic Creutzfeldt–Jakob disease (iCJD)

Variant Creutzfeldt–Jakob disease (vCJD)


Familial Creutzfeldt–Jakob disease (fCJD)

Sporadic Creutzfeldt–Jakob disease (sCJD)


[40]
Gerstmann–Sträussler–Scheinker syndrome (GSS)
[42]
Fatal familial insomnia (FFI)
[40]
Kuru

Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form
plaques known as amyloid, which disrupt the normal tissue structure. This disruption is characterized by "holes" in
the tissue with resultant spongy architecture due to the vacuole formation in the neurons.[43] Other histological
changes include astrogliosis and the absence of an inflammatory reaction.[44] While the incubation period for prion
diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and
death.[45] Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination
dysfunction), and behavioural or personality changes.
All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and
fatal.[46] A vaccine has been developed in mice, however, that may provide insight into providing a vaccine in
humans to resist prion infections.[47] Additionally, in 2006 scientists announced that they had genetically engineered
cattle lacking a necessary gene for prion production – thus theoretically making them immune to BSE,[48] building
on research indicating that mice lacking normally occurring prion protein are resistant to infection by scrapie prion
protein.[49]
Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all
mammals.[50] Due to small differences in PrP between different species it is unusual for a prion disease to be
transmitted from one species to another. The human prion disease variant Creutzfeldt-Jakob disease, however, is
believed to be caused by a prion which typically infects cattle, causing Bovine spongiform encephalopathy and is
transmitted through infected meat.[51]

Transmission
It has been recognized that prion diseases can arise in three different ways: acquired, familial, or sporadic.[52] It is
often assumed that the diseased form directly interacts with the normal form to make it rearrange its structure. One
idea, the "Protein X" hypothesis, is that an as-yet unidentified cellular protein (Protein X) enables the conversion of
PrPC to PrPSc by bringing a molecule of each of the two together into a complex.[53]
Current research suggests that the primary method of infection in animals is through ingestion. It is thought that
prions may be deposited in the environment through the remains of dead animals and via urine, saliva, and other
body fluids. They may then linger in the soil by binding to clay and other minerals.[54]
A University of California research team, led by Nobel Prize winner Stanley Prusiner, has proven that infection can
occur from prions in manure.[55] And since manure is present in many areas surrounding water reservoirs, as well as
used on many crop fields, it raises the possibility of widespread transmission. It was reported in January 2011 that
researchers had discovered prions spreading through airborne transmission on aerosol particles, in an animal testing
experiment focusing on scrapie infection in laboratory mice.[56] Preliminary evidence supporting the notion that
prions can be transmitted through use of urine-derived human menopausal gonadotropin, administered for the
treatment of infertility, was published in 2011.[57]
Prion 355

Sterilization
Infectious particles possessing nucleic acid are dependent upon it to direct their continued replication. Prions,
however, are infectious by their effect on normal versions of the protein. Sterilizing prions therefore involves the
denaturation of the protein to a state where the molecule is no longer able to induce the abnormal folding of normal
proteins. Prions are generally quite resistant to proteases, heat, radiation, and formalin treatments,[58] although their
infectivity can be reduced by such treatments. Effective prion decontamination relies upon protein hydrolysis or
reduction or destruction of protein tertiary structure. Examples include bleach, caustic soda, and strongly acidic
detergents such as LpH.[59] 134°C (274°F) for 18 minutes in a pressurized steam autoclave may not be enough to
deactivate the agent of disease.[60][61] Ozone sterilization is currently being studied as a potential method for prion
denature and deactivation.[62] Renaturation of a completely denatured prion to infectious status has not yet been
achieved; however, partially denatured prions can be renatured to an infective status under certain artificial
conditions.[63]
The World Health Organization recommends any of the following three procedures for the sterilization of all
heat-resistant surgical instruments to ensure that they are not contaminated with prions:
1. Immerse in a pan containing 1N NaOH and heat in a gravity-displacement autoclave at 121°C for 30 minutes;
clean; rinse in water; and then perform routine sterilization processes.
2. Immerse in 1N NaOH or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; transfer
instruments to water; heat in a gravity-displacement autoclave at 121°C for 1 hour; clean; and then perform
routine sterilization processes.
3. Immerse in 1N NaOH or sodium hypochlorite (20,000 parts per million available chlorine) for 1 hour; remove
and rinse in water, then transfer to an open pan and heat in a gravity-displacement (121°C) or in a porous-load
(134°C) autoclave for 1 hour; clean; and then perform routine sterilization processes.[64]

Debate
Whether prions are the agent which causes disease or merely a symptom caused by a different agent is still debated
by a minority of researchers. The following sections describe several hypotheses: some pertain to the composition of
the infectious agent (protein-only, protein with other components, virus, or other), while others pertain to its
mechanism of reproduction.

Protein-only hypothesis
Prior to the discovery of prions, it was thought that all pathogens used nucleic acids to direct their replication. The
"protein-only hypothesis" states that a protein structure can replicate without the use of nucleic acid. This was
initially controversial as it contradicts the so-called "central dogma of molecular biology", which describes nucleic
acid as the central form of replicative information.
Evidence in favor of a protein-only hypothesis includes:[65]
• No virus particles, bacteria, or fungi have been conclusively associated with prion diseases, although
Saccharomyces cerevisiae has been known to be associated with infectious, yet non-lethal prions, such as Sup35p.
• No nucleic acid has been conclusively associated with infectivity; agent is resistant to ultraviolet radiation.
• No immune response to infection.
• PrPSc experimentally transmitted between one species and another results in PrPSc with the amino-acid sequence
of the recipient species, suggesting that replication of the donor agent does not occur.
• Familial prion disease occurs in families with a mutation in the PrP gene, and mice with PrP mutations develop
prion disease despite controlled conditions where transmission is prevented.
• Animals lacking PrPC do not contract prion disease.
• Infectious prions can be formed de novo from purified non-infectious components, in the absence of gene-coding
nucleic acids.[13]
Prion 356

Genetic factors
A gene for the normal protein has been identified: the PRNP gene.[66] In all inherited cases of prion disease, there is
a mutation in the PRNP gene. Many different PRNP mutations have been identified and these proteins are more
likely to fold into abnormal prion.[67] Although this discovery puts a hole in the general prion hypothesis, that prions
can only aggregate proteins of identical amino acid make up. These mutations can occur throughout the gene. Some
mutations involve expansion of the octapeptide repeat region at the N-terminal of PrP. Other mutations that have
been identified as a cause of inherited prion disease occur at positions 102, 117 & 198 (GSS), 178, 200, 210 & 232
(CJD) and 178 (Fatal Familial Insomnia, FFI). The cause of prion disease can be sporadic, genetic, and infectious, or
a combination of these factors.[68] For example, in order to have scrapie, both an infectious agent and a susceptible
genotype need to be present.[67]

Multi-component hypothesis
In 2007, biochemist Surachai Supattapone and his colleagues at Dartmouth College produced purified infectious
prions de novo from defined components (PrPC, co-purified lipids, and a synthetic polyanionic molecule).[13] These
researchers also showed that the polyanionic molecule required for prion formation was selectively incorporated into
high-affinity complexes with PrP molecules, leading them to hypothesize that infectious prions may be composed of
multiple host components, including PrP, lipid, and polyanionic molecules, rather than PrPSc alone.[69]
In 2010, Jiyan Ma and colleagues at The Ohio State University produced infectious prions from a recipe of
bacterially expressed recombinant PrP, POPG phospholipid, and RNA, further supporting the multi-component
hypothesis.[70] This finding is in contrast to studies that found minimal infectious prions produced from recombinant
PrP alone.[71][72]

Heavy metal poisoning hypothesis


Recent reports suggest that imbalance of brain metal homeostasis is a significant cause of PrPSc-associated
neurotoxicity, though the underlying mechanisms are difficult to explain based on existing information. Proposed
hypotheses include a functional role for PrPC in metal metabolism, and loss of this function due to aggregation to the
disease associated PrPSc form as the cause of brain metal imbalance. Other views suggest gain of toxic function by
PrPSc due to sequestration of PrPC-associated metals within the aggregates, resulting in the generation of
redox-active PrPSc complexes. The physiological implications of some PrPC-metal interactions are known, while
others are still unclear. The pathological implications of PrPC-metal interaction include metal-induced oxidative
damage, and in some instances conversion of PrPC to a PrPSc-like form.[73]

Viral hypothesis
The protein-only hypothesis has been criticised by those who feel that the simplest explanation of the evidence to
date is viral.[74] For more than a decade, Yale University neuropathologist Laura Manuelidis has been proposing that
prion diseases are caused instead by an unidentified slow virus. In January 2007, she and her colleagues published an
article reporting to have found a virus in 10%, or less, of their scrapie-infected cells in culture.[75][76]
The virion hypothesis states that TSEs are caused by a replicable informational molecule (which is likely to be a
nucleic acid) bound to PrP. Many TSEs, including scrapie and BSE, show strains with specific and distinct
biological properties, a feature which supporters of the virion hypothesis feel is not explained by prions.
Evidence in favor of a viral hypothesis includes:[65]
• Strain variation: differences in prion infectivity, incubation, symptomology and progression among species
resembles that seen between viruses, especially RNA viruses
• The long incubation and rapid onset of symptoms resembles lentiviruses, such as HIV-induced AIDS
• Viral-like particles that do not appear to be composed of PrP have been found in some of the cells of scrapie- or
CJD-infected cell lines.[76]
Prion 357

Recent studies propagating TSE infectivity in cell-free reactions[77] and in purified component chemical reactions[13]
strongly suggest against TSE viral nature. More recently, using a similar defined recipe of multiple components (PrP,
POPG lipid, RNA), Jiyan Ma and colleagues generated infectious prions from recombinant PrP expressed from E.
coli,[70] casting further doubt on the viral hypothesis.

Fungi
Fungal proteins exhibiting templated conformational change were discovered in the yeast Saccharomyces cerevisiae
by Reed Wickner in the early 1990s. For their mechanistic similarity to mammalian prions, they were termed yeast
prions. Subsequently, a prion has also been found in the fungus Podospora anserina. These prions behave similarly
to PrP, but are generally nontoxic to their hosts. Susan Lindquist's group at the Whitehead Institute has argued some
of the fungal prions are not associated with any disease state, but may have a useful role; however, researchers at the
NIH have also provided arguments suggesting fungal prions could be considered a diseased state.[78] Thus, the issue
of whether fungal proteins are diseases, or have evolved for some specific functions, still remains unresolved.[79]
As of 2012, there are eight known prion proteins in fungi, seven in Saccharomyces cerevisiae (Sup35, Rnq1, Ure2,
Swi1, Mot3, Cyc8 and Mod5) and one in Podospora anserina (HET-s). The article that reported the discovery of a
prion form the Mca1 protein has recently been retracted due to the fact that the data could not be reproduced[80] .
Notably, most of the fungal prions are based on glutamine/asparagine-rich sequences, with the exception of HET-s
and Mod5.
Research into fungal prions has given strong support to the protein-only concept, since purified protein extracted
from cells with a prion state has been demonstrated to convert the normal form of the protein into a misfolded form
in vitro, and in the process, preserve the information corresponding to different strains of the prion state. It has also
shed some light on prion domains, which are regions in a protein that promote the conversion into a prion. Fungal
prions have helped to suggest mechanisms of conversion that may apply to all prions, though fungal prions appear
distinct from infectious mammalian prions in the lack of cofactor required for propagation. The characteristic prion
domains may vary between species—e.g. characteristic fungal prion domains are not found in mammalian prions.

Fungal Prions

Protein Natural host Normal function Prion state Prion phenotype Year
identified

Ure2p Saccharomyces Nitrogen catabolite repressor [URE3] Growth on poor nitrogen sources 1994
cerevisiae

Sup35p S. cerevisiae Translation termination factor [PSI+] Increased levels of nonsense suppression 1994

HET-S Podospora anserina Regulates heterokaryon [Het-s] Heterokaryon formation between


incompatibility incompatible strains

Rnq1p S. cerevisiae Protein template factor [RNQ+],[PIN+] Promotes aggregation of other prions

Mca1 S. cerevisiae Putative yeast caspase [MCA+] Unknown 2008

Swi1 S. cerevisiae Chromatin remodeling [SWI+] Poor growth on some carbon sources 2008

Cyc8 S. cerevisiae Transcriptional repressor [OCT+] Transcriptional derepression of multiple 2009


genes

Mot3 S. cerevisiae Nuclear transcription factor [MOT3+] Transcriptional derepression of anaerobic 2009
genes

Sfp1 S. cerevisiae Putative transcription factor [ISP+] Antisuppression [81]


2010
Prion 358

Potential treatments and diagnosis


Advancements in computer modeling have allowed for scientists to identify compounds which can serve as a
treatment for prion-caused diseases, such as one compound found to bind a cavity in the PrPC and stabilize the
conformation, reducing the amount of harmful PrPSc.[82]
Recently, antiprion antibodies capable of crossing the blood-brain-barrier and targeting cytosolic prion protein (an
otherwise major obstacle in prion therapeutics) have been described.[83]
In the last decade, some progress has been reported dealing with ultra-high-pressure inactivation of prion infectivity
in processed meat.[84]
In 2011 it was discovered that prions could be degraded by lichens.[85][86]
There continues to be a very practical problem with diagnosis of prion diseases, including BSE and CJD. They have
an incubation period of months to decades during which there are no symptoms, even though the pathway of
converting the normal brain PrP protein into the toxic, disease-related PrP Sc form has started. At present, there is
virtually no way to detect PrPSc reliably except by examining the brain using neuropathological and
immunohistochemical methods after death. Accumulation of the abnormally folded PrPSc form of the PrP protein is a
characteristic of the disease, but it is present at very low levels in easily accessible body fluids like blood or urine.
Researchers have tried to develop methods to measure PrPSc, but there are still no fully accepted methods for use in
materials such as blood.
In 2010, a team from New York described detection of PrPSc even when initially present at only one part in a
hundred thousand million (10−11) in brain tissue. The method combines amplification with a novel technology called
Surround Optical Fiber Immunoassay (SOFIA) and some specific antibodies against PrPSc. After amplifying and
then concentrating any PrPSc, the samples are labelled with a fluorescent dye using an antibody for specificity and
then finally loaded into a micro-capillary tube. This tube is placed in a specially constructed apparatus so that it is
totally surrounded by optical fibres to capture all light emitted once the dye is excited using a laser. The technique
allowed detection of PrPSc after many fewer cycles of conversion than others have achieved, substantially reducing
the possibility of artefacts, as well as speeding up the assay. The researchers also tested their method on blood
samples from apparently healthy sheep that went on to develop scrapie. The animals’ brains were analysed once any
symptoms became apparent. The researchers could therefore compare results from brain tissue and blood taken once
the animals exhibited symptoms of the diseases, with blood obtained earlier in the animals’ lives, and from
uninfected animals. The results showed very clearly that PrPSc could be detected in the blood of animals long before
the symptoms appeared.[87][88]

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[79] Halfmann R, Alberti S, Lindquist S (2010). "Prions, protein homeostasis, and phenotypic diversity". Trends in Cell Biology 20 (3): 125–33.
doi:10.1016/j.tcb.2009.12.003. PMC 2846750. PMID 20071174.
[80] Nemecek, J; Nakayashiki, T, Wickner, RB (2011 Jun 14). "Retraction for Nemecek et al.: A prion of yeast metacaspase homolog (Mca1p)
detected by a genetic screen.". Proceedings of the National Academy of Sciences of the United States of America 108 (24): 10022.
PMID 21628591.
[81] Rogoza, T. et al. (24 May 2010). "Non-Mendelian determinant ISP+ in yeast is a nuclear-residing prion form of the global transcriptional
regulator Sfp" (http:/ / www. pnas. org/ content/ early/ 2010/ 05/ 17/ 1005949107. abstract). Proceedings of the National Academy of Sciences
of the United States of America (PNAS) 107 (23): 10573–7. doi:10.1073/pnas.1005949107. PMC 2890785. PMID 20498075. . Retrieved 26
April 2012.
[82] Kuwata K, Nishida N, Matsumoto T, et al. (July 2007). "Hot spots in prion protein for pathogenic conversion" (http:/ / www. pnas. org/ cgi/
pmidlookup?view=long& pmid=17616582). Proceedings of the National Academy of Sciences of the United States of America 104 (29):
11921–6. doi:10.1073/pnas.0702671104. PMC 1924567. PMID 17616582. . Retrieved 2010-02-28.
[83] http:/ / www. plosone. org/ article/ info%3Adoi%2F10. 1371%2Fjournal. pone. 0009804
[84] http:/ / www. pnas. org/ content/ 100/ 10/ 6093. full. pdf Ultra-high-pressure inactivation of prion infectivity in processed meat : A practical
method to prevent human infection
[85] Johnson, Christopher; Bennett; Biro; Duque-Velasquez; Rodriguez; Bessen; Rocke; Bartz; James P. Bennett, Steven M. Biro, Juan Camilo
Duque-Velasquez, Cynthia M. Rodriguez, Richard A. Bessen, Tonie E. Rocke (17th). Bartz, Jason C. ed. "Degradation of the
Disease-Associated Prion Protein by a Serine Protease from Lichens" (http:/ / www. plosone. org/ article/ info:doi/ 10. 1371/ journal. pone.
0019836). PLoS ONE 6 (5): 9836. Bibcode 2011PLoSO...6E9836J. doi:10.1371/journal.pone.0019836. . Retrieved 20 May 2011.
[86] Yam, Philip. "Natural Born Prion Killers: Lichens Degrade "Mad Cow" Related Brain Pathogen" (http:/ / www. scientificamerican. com/
blog/ post. cfm?id=natural-born-prion-killers-lichens-2011-05-19). Scientific American. . Retrieved 20 May 2011.
[87] "Detecting Prions in Blood" (https:/ / www. sgm. ac. uk/ pubs/ micro_today/ pdf/ 081010. pdf). Microbiology Today.: 195. August 2010. .
Retrieved 2011-08-21.
[88] "SOFIA: An Assay Platform for Ultrasensitive Detection of PrPSc in Brain and Blood" (http:/ / www. bionosis. com/ news/ Bionosis PrioNet
Poster. pdf). SUNY Downstate Medical Center. . Retrieved 2011-08-19.

Further reading
• Deadly Feasts: The "Prion" Controversy and the Public's Health, Richard Rhodes, 1998, Touchstone, ISBN
0-684-84425-7
• The Pathological Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases, Phillip Yam, 2003,
Springer, ISBN 0-387-95508-9
• The Family That Couldn't Sleep by D. T. Max provides a history of prion diseases.
• The Prion Protein (http://www.horizonpress.com/cimb/prionprotein.html) a special issue of the open-access
journal Current Issues in Molecular Biology
• The Prion's Elusive Reason for Being (http://arjournals.annualreviews.org/doi/abs/10.1146/annurev.neuro.
31.060407.125620) Note: Behind a paywall.

External links

General
• CDC (http://www.cdc.gov/ncidod/dvrd/prions/) – USA Centers for Disease Control and Prevention –
information on prion diseases
• World Health Organisation (http://www.who.int/zoonoses/diseases/prion_diseases/en/) – WHO information
on prion diseases
• Prion Animation (http://www.1lec.com/Microbiology/Prion/index.html) (Flash required)
Prion 363

Reports and committees


• The UK BSE Inquiry (http://collections.europarchive.org/tna/20090505194948/http://bseinquiry.gov.uk) –
Report of the UK public inquiry into BSE and variant CJD
• UK Spongiform Encephalopathy Advisory Committee (SEAC) (http://www.seac.gov.uk/)

Genetics
• Mammalian prion classification (http://www.ncbi.nlm.nih.gov/ICTVdb/ICTVdB/90.001.0.01.htm)
International Committee on Taxonomy of Viruses – ICTVdb
• Online Mendelian Inheritance in Man: Prion protein (http://www.ncbi.nlm.nih.gov/entrez/dispomim.
cgi?id=176640) – PrP, inherited prion disease and transgenic animal models.
• The Surprising World of Prion Biology--A New Mechanism of Inheritance (http://www.ibioseminars.org/
index.php?option=com_content&view=article&id=164&Itemid=153) on-line lecture by Susan Lindquist

Research
• Institute for Neurodegenerative Diseases (http://ind.universityofcalifornia.edu/) – labs studying prion diseases,
run by Stanley B. Prusiner, MD
• Prion Disease Database (PDDB) (http://prion.systemsbiology.net/cgi-bin/dispatcher.cgi/Welcome/display) -
Comprehensive transcriptome resource for systems biology research in prion diseases.
• iBioSeminars (http://www.ibioseminars.org/index.php?option=com_content&view=article&id=406&
Itemid=372) - Susan Lindquist's iBioSeminars on I. Protein Folding and Prions and II. Prions and Evolution.
• http://www.prion.ucl.ac.uk/MRC Prion Unit run by Professor John Collinge. Study of all forms of prion
disease and development of therapies.

Other
• UCSF Memory and Aging Center (http://memory.ucsf.edu/cjd/) – medical center for diagnosis and care of
people with prion disease and research into origin and treatment of prion diseases. ( YouTube channel (http://
www.youtube.com/ucsfmemoryandaging))
Protein 364

Protein
Proteins (  /ˈproʊˌtiːnz/ or /ˈproʊti.ɪnz/) are biochemical compounds
consisting of one or more polypeptides typically folded into a globular
or fibrous form, facilitating a biological function.
A polypeptide is a single linear polymer chain of amino acids bonded
together by peptide bonds between the carboxyl and amino groups of
adjacent amino acid residues. The sequence of amino acids in a protein
is defined by the sequence of a gene, which is encoded in the genetic
code. In general, the genetic code specifies 20 standard amino acids;
however, in certain organisms the genetic code can include
selenocysteine and—in certain archaea—pyrrolysine. Shortly after or
even during synthesis, the residues in a protein are often chemically
modified by posttranslational modification, which alters the physical
and chemical properties, folding, stability, activity, and ultimately, the A representation of the 3D structure of the protein
function of the proteins. Sometimes proteins have non-peptide groups myoglobin showing colored alpha helices. This
attached, which can be called prosthetic groups or cofactors. Proteins protein was the first to have its structure solved
by X-ray crystallography. Towards the
can also work together to achieve a particular function, and they often
right-center among the coils, a prosthetic group
associate to form stable protein complexes. called a heme group is shown colored largely in
green.
Like other biological macromolecules such as polysaccharides and
nucleic acids, proteins are essential parts of organisms and participate
in virtually every process within cells. Many proteins are enzymes that catalyze biochemical reactions and are vital
to metabolism. Proteins also have structural or mechanical functions, such as actin and myosin in muscle and the
proteins in the cytoskeleton, which form a system of scaffolding that maintains cell shape. Other proteins are
important in cell signaling, immune responses, cell adhesion, and the cell cycle. Proteins are also necessary in
animals' diets, since animals cannot synthesize all the amino acids they need and must obtain essential amino acids
from food. Through the process of digestion, animals break down ingested protein into free amino acids that are then
used in metabolism.

Proteins may be purified from other cellular components using a variety of techniques such as ultracentrifugation,
precipitation, electrophoresis, and chromatography; the advent of genetic engineering has made possible a number of
methods to facilitate purification. Methods commonly used to study protein structure and function include
immunohistochemistry, site-directed mutagenesis, nuclear magnetic resonance and mass spectrometry.
Protein 365

Biochemistry
Most proteins consist of linear polymers
built from series of up to 20 different
L-α-amino acids. All proteinogenic amino
acids possess common structural features,
including an α-carbon to which an amino
group, a carboxyl group, and a variable side
chain are bonded. Only proline differs from
this basic structure as it contains an unusual
ring to the N-end amine group, which forces
the CO–NH amide moiety into a fixed
conformation.[1] The side chains of the
standard amino acids, detailed in the list of
standard amino acids, have a great variety of
chemical structures and properties; it is the
combined effect of all of the amino acid side Chemical structure of the peptide bond (bottom) and the three-dimensional
chains in a protein that ultimately structure of a peptide bond between an alanine and an adjacent amino acid
determines its three-dimensional structure (top/inset)

and its chemical reactivity.[2] The amino


acids in a polypeptide chain are linked by
peptide bonds. Once linked in the protein
chain, an individual amino acid is called a
residue, and the linked series of carbon,
nitrogen, and oxygen atoms are known as
the main chain or protein backbone.[3] Resonance structures of the peptide bond that links individual amino acids to form
a protein polymer

The peptide bond has two resonance forms


that contribute some double-bond character and inhibit rotation around its axis, so that the alpha carbons are roughly
coplanar. The other two dihedral angles in the peptide bond determine the local shape assumed by the protein
backbone.[4] The end of the protein with a free carboxyl group is known as the C-terminus or carboxy terminus,
whereas the end with a free amino group is known as the N-terminus or amino terminus. The words protein,
polypeptide, and peptide are a little ambiguous and can overlap in meaning. Protein is generally used to refer to the
complete biological molecule in a stable conformation, whereas peptide is generally reserved for a short amino acid
oligomers often lacking a stable three-dimensional structure. However, the boundary between the two is not well
defined and usually lies near 20–30 residues.[5] Polypeptide can refer to any single linear chain of amino acids,
usually regardless of length, but often implies an absence of a defined conformation.
Protein 366

Synthesis
Proteins are assembled from amino acids using information encoded in
genes. Each protein has its own unique amino acid sequence that is
specified by the nucleotide sequence of the gene encoding this protein.
The genetic code is a set of three-nucleotide sets called codons and
each three-nucleotide combination designates an amino acid, for
example AUG (adenine-uracil-guanine) is the code for methionine.
Because DNA contains four nucleotides, the total number of possible
codons is 64; hence, there is some redundancy in the genetic code, with
some amino acids specified by more than one codon.[6] Genes encoded A ribosome produces a protein using mRNA as
in DNA are first transcribed into pre-messenger RNA (mRNA) by template.
proteins such as RNA polymerase. Most organisms then process the
pre-mRNA (also known as a primary transcript) using various forms
of Post-transcriptional modification to form the mature mRNA, which
is then used as a template for protein synthesis by the ribosome. In
prokaryotes the mRNA may either be used as soon as it is produced, or
be bound by a ribosome after having moved away from the nucleoid.
In contrast, eukaryotes make mRNA in the cell nucleus and then The DNA sequence of a gene encodes the amino
translocate it across the nuclear membrane into the cytoplasm, where acid sequence of a protein.

protein synthesis then takes place. The rate of protein synthesis is


higher in prokaryotes than eukaryotes and can reach up to 20 amino acids per second.[7]

The process of synthesizing a protein from an mRNA template is known as translation. The mRNA is loaded onto
the ribosome and is read three nucleotides at a time by matching each codon to its base pairing anticodon located on
a transfer RNA molecule, which carries the amino acid corresponding to the codon it recognizes. The enzyme
aminoacyl tRNA synthetase "charges" the tRNA molecules with the correct amino acids. The growing polypeptide is
often termed the nascent chain. Proteins are always biosynthesized from N-terminus to C-terminus.[6]
The size of a synthesized protein can be measured by the number of amino acids it contains and by its total
molecular mass, which is normally reported in units of daltons (synonymous with atomic mass units), or the
derivative unit kilodalton (kDa). Yeast proteins are on average 466 amino acids long and 53 kDa in mass.[5] The
largest known proteins are the titins, a component of the muscle sarcomere, with a molecular mass of almost 3,000
kDa and a total length of almost 27,000 amino acids.[8]

Chemical synthesis
Short proteins can also be synthesized chemically by a family of methods known as peptide synthesis, which rely on
organic synthesis techniques such as chemical ligation to produce peptides in high yield.[9] Chemical synthesis
allows for the introduction of non-natural amino acids into polypeptide chains, such as attachment of fluorescent
probes to amino acid side chains.[10] These methods are useful in laboratory biochemistry and cell biology, though
generally not for commercial applications. Chemical synthesis is inefficient for polypeptides longer than about 300
amino acids, and the synthesized proteins may not readily assume their native tertiary structure. Most chemical
synthesis methods proceed from C-terminus to N-terminus, opposite the biological reaction.[11]
Protein 367

Structure
Most proteins fold into unique
3-dimensional structures. The shape into
which a protein naturally folds is known as
its native conformation.[12] Although many
proteins can fold unassisted, simply through
the chemical properties of their amino acids,
others require the aid of molecular
chaperones to fold into their native
states.[13] Biochemists often refer to four The crystal structure of the chaperonin. Chaperonins assist protein folding.
distinct aspects of a protein's structure:[14]

• Primary structure: the amino acid


sequence.
• Secondary structure: regularly repeating
local structures stabilized by hydrogen
bonds. The most common examples are
the alpha helix, beta sheet and turns.
Because secondary structures are local,
many regions of different secondary
structure can be present in the same Three possible representations of the three-dimensional structure of the protein
protein molecule. triose phosphate isomerase. Left: all-atom representation colored by atom type.
Middle: Simplified representation illustrating the backbone conformation, colored
• Tertiary structure: the overall shape of a by secondary structure. Right: Solvent-accessible surface representation colored by
single protein molecule; the spatial residue type (acidic residues red, basic residues blue, polar residues green,
relationship of the secondary structures to nonpolar residues white)

one another. Tertiary structure is


generally stabilized by nonlocal interactions, most commonly the formation of a hydrophobic core, but also
through salt bridges, hydrogen bonds, disulfide bonds, and even posttranslational modifications. The term
"tertiary structure" is often used as synonymous with the term fold. The tertiary structure is what controls the
basic function of the protein.
• Quaternary structure: the structure formed by several protein molecules (polypeptide chains), usually called
protein subunits in this context, which function as a single protein complex.
Proteins are not entirely rigid molecules. In addition to these levels of structure, proteins may shift between several
related structures while they perform their functions. In the context of these functional rearrangements, these tertiary
or quaternary structures are usually referred to as "conformations", and transitions between them are called
conformational changes. Such changes are often induced by the binding of a substrate molecule to an enzyme's
active site, or the physical region of the protein that participates in chemical catalysis. In solution proteins also
undergo variation in structure through thermal vibration and the collision with other molecules.[15]
Protein 368

Proteins can be informally divided into three


main classes, which correlate with typical
tertiary structures: globular proteins, fibrous
proteins, and membrane proteins. Almost all
globular proteins are soluble and many are
enzymes. Fibrous proteins are often
structural, such as collagen, the major Molecular surface of several proteins showing their comparative sizes. From left to
right are: immunoglobulin G (IgG, an antibody), hemoglobin, insulin (a hormone),
component of connective tissue, or keratin,
adenylate kinase (an enzyme), and glutamine synthetase (an enzyme).
the protein component of hair and nails.
Membrane proteins often serve as receptors
or provide channels for polar or charged molecules to pass through the cell membrane.[16]

A special case of intramolecular hydrogen bonds within proteins, poorly shielded from water attack and hence
promoting their own dehydration, are called dehydrons.[17]

Structure determination
Discovering the tertiary structure of a protein, or the quaternary structure of its complexes, can provide important
clues about how the protein performs its function. Common experimental methods of structure determination include
X-ray crystallography and NMR spectroscopy, both of which can produce information at atomic resolution.
However, NMR experiments are able to provide information from which a subset of distances between pairs of
atoms can be estimated, and the final possible conformations for a protein are determined by solving a distance
geometry problem. Dual polarisation interferometry is a quantitative analytical method for measuring the overall
protein conformation and conformational changes due to interactions or other stimulus. Circular dichroism is another
laboratory technique for determining internal beta sheet/ helical composition of proteins. Cryoelectron microscopy is
used to produce lower-resolution structural information about very large protein complexes, including assembled
viruses;[18] a variant known as electron crystallography can also produce high-resolution information in some cases,
especially for two-dimensional crystals of membrane proteins.[19] Solved structures are usually deposited in the
Protein Data Bank (PDB), a freely available resource from which structural data about thousands of proteins can be
obtained in the form of Cartesian coordinates for each atom in the protein.[20]

Many more gene sequences are known than protein structures. Further, the set of solved structures is biased toward
proteins that can be easily subjected to the conditions required in X-ray crystallography, one of the major structure
determination methods. In particular, globular proteins are comparatively easy to crystallize in preparation for X-ray
crystallography. Membrane proteins, by contrast, are difficult to crystallize and are underrepresented in the PDB.[21]
Structural genomics initiatives have attempted to remedy these deficiencies by systematically solving representative
structures of major fold classes. Protein structure prediction methods attempt to provide a means of generating a
plausible structure for proteins whose structures have not been experimentally determined.

Cellular functions
Proteins are the chief actors within the cell, said to be carrying out the duties specified by the information encoded in
genes.[5] With the exception of certain types of RNA, most other biological molecules are relatively inert elements
upon which proteins act. Proteins make up half the dry weight of an Escherichia coli cell, whereas other
macromolecules such as DNA and RNA make up only 3% and 20%, respectively.[22] The set of proteins expressed
in a particular cell or cell type is known as its proteome.
Protein 369

The chief characteristic of proteins that also allows their diverse set of
functions is their ability to bind other molecules specifically and
tightly. The region of the protein responsible for binding another
molecule is known as the binding site and is often a depression or
"pocket" on the molecular surface. This binding ability is mediated by
the tertiary structure of the protein, which defines the binding site
pocket, and by the chemical properties of the surrounding amino acids'
side chains. Protein binding can be extraordinarily tight and specific;
for example, the ribonuclease inhibitor protein binds to human The enzyme hexokinase is shown as a
angiogenin with a sub-femtomolar dissociation constant (<10−15 M) conventional ball-and-stick molecular model. To
but does not bind at all to its amphibian homolog onconase (>1 M). scale in the top right-hand corner are two of its
substrates, ATP and glucose.
Extremely minor chemical changes such as the addition of a single
methyl group to a binding partner can sometimes suffice to nearly
eliminate binding; for example, the aminoacyl tRNA synthetase specific to the amino acid valine discriminates
against the very similar side chain of the amino acid isoleucine.[23]

Proteins can bind to other proteins as well as to small-molecule substrates. When proteins bind specifically to other
copies of the same molecule, they can oligomerize to form fibrils; this process occurs often in structural proteins that
consist of globular monomers that self-associate to form rigid fibers. Protein–protein interactions also regulate
enzymatic activity, control progression through the cell cycle, and allow the assembly of large protein complexes
that carry out many closely related reactions with a common biological function. Proteins can also bind to, or even
be integrated into, cell membranes. The ability of binding partners to induce conformational changes in proteins
allows the construction of enormously complex signaling networks.[24] Importantly, as interactions between proteins
are reversible, and depend heavily on the availability of different groups of partner proteins to form aggregates that
are capable to carry out discrete sets of function, study of the interactions between specific proteins is a key to
understand important aspects of cellular function, and ultimately the properties that distinguish particular cell
types.[25][26]

Enzymes
The best-known role of proteins in the cell is as enzymes, which catalyze chemical reactions. Enzymes are usually
highly specific and accelerate only one or a few chemical reactions. Enzymes carry out most of the reactions
involved in metabolism, as well as manipulating DNA in processes such as DNA replication, DNA repair, and
transcription. Some enzymes act on other proteins to add or remove chemical groups in a process known as
posttranslational modification. About 4,000 reactions are known to be catalyzed by enzymes.[27] The rate
acceleration conferred by enzymatic catalysis is often enormous—as much as 1017-fold increase in rate over the
uncatalyzed reaction in the case of orotate decarboxylase (78 million years without the enzyme, 18 milliseconds with
the enzyme).[28]
The molecules bound and acted upon by enzymes are called substrates. Although enzymes can consist of hundreds
of amino acids, it is usually only a small fraction of the residues that come in contact with the substrate, and an even
smaller fraction—three to four residues on average—that are directly involved in catalysis.[29] The region of the
enzyme that binds the substrate and contains the catalytic residues is known as the active site.
Dirigent proteins are members of a class of proteins which dictate the stereochemistry of a compound synthesized by
other enzymes.
Protein 370

Cell signaling and ligand binding


Many proteins are involved in the process of cell signaling and signal
transduction. Some proteins, such as insulin, are extracellular proteins that
transmit a signal from the cell in which they were synthesized to other cells in
distant tissues. Others are membrane proteins that act as receptors whose main
function is to bind a signaling molecule and induce a biochemical response in the
cell. Many receptors have a binding site exposed on the cell surface and an
effector domain within the cell, which may have enzymatic activity or may
undergo a conformational change detected by other proteins within the cell.[30]

Antibodies are protein components of an adaptive immune system whose main


function is to bind antigens, or foreign substances in the body, and target them
for destruction. Antibodies can be secreted into the extracellular environment or
anchored in the membranes of specialized B cells known as plasma cells.
Whereas enzymes are limited in their binding affinity for their substrates by the Ribbon diagram of a mouse antibody
necessity of conducting their reaction, antibodies have no such constraints. An against cholera that binds a
antibody's binding affinity to its target is extraordinarily high.[31] carbohydrate antigen

Many ligand transport proteins bind particular small biomolecules and transport
them to other locations in the body of a multicellular organism. These proteins must have a high binding affinity
when their ligand is present in high concentrations, but must also release the ligand when it is present at low
concentrations in the target tissues. The canonical example of a ligand-binding protein is haemoglobin, which
transports oxygen from the lungs to other organs and tissues in all vertebrates and has close homologs in every
biological kingdom.[32] Lectins are sugar-binding proteins which are highly specific for their sugar moieties. Lectins
typically play a role in biological recognition phenomena involving cells and proteins.[33] Receptors and hormones
are highly specific binding proteins.

Transmembrane proteins can also serve as ligand transport proteins that alter the permeability of the cell membrane
to small molecules and ions. The membrane alone has a hydrophobic core through which polar or charged molecules
cannot diffuse. Membrane proteins contain internal channels that allow such molecules to enter and exit the cell.
Many ion channel proteins are specialized to select for only a particular ion; for example, potassium and sodium
channels often discriminate for only one of the two ions.[34]

Structural proteins
Structural proteins confer stiffness and rigidity to otherwise-fluid biological components. Most structural proteins are
fibrous proteins; for example, actin and tubulin are globular and soluble as monomers, but polymerize to form long,
stiff fibers that make up the cytoskeleton, which allows the cell to maintain its shape and size. Collagen and elastin
are critical components of connective tissue such as cartilage, and keratin is found in hard or filamentous structures
such as hair, nails, feathers, hooves, and some animal shells.[35]
Other proteins that serve structural functions are motor proteins such as myosin, kinesin, and dynein, which are
capable of generating mechanical forces. These proteins are crucial for cellular motility of single celled organisms
and the sperm of many multicellular organisms which reproduce sexually. They also generate the forces exerted by
contracting muscles.[36]
Protein 371

Methods of study
As some of the most commonly studied biological molecules, the activities and structures of proteins are examined
both in vitro and in vivo. In vitro studies of purified proteins in controlled environments are useful for learning how a
protein carries out its function: for example, enzyme kinetics studies explore the chemical mechanism of an enzyme's
catalytic activity and its relative affinity for various possible substrate molecules. By contrast, in vivo experiments on
proteins' activities within cells or even within whole organisms can provide complementary information about where
a protein functions and how it is regulated.

Protein purification
In order to perform in vitro analysis, a protein must be purified away from other cellular components. This process
usually begins with cell lysis, in which a cell's membrane is disrupted and its internal contents released into a
solution known as a crude lysate. The resulting mixture can be purified using ultracentrifugation, which fractionates
the various cellular components into fractions containing soluble proteins; membrane lipids and proteins; cellular
organelles, and nucleic acids. Precipitation by a method known as salting out can concentrate the proteins from this
lysate. Various types of chromatography are then used to isolate the protein or proteins of interest based on
properties such as molecular weight, net charge and binding affinity.[37] The level of purification can be monitored
using various types of gel electrophoresis if the desired protein's molecular weight and isoelectric point are known,
by spectroscopy if the protein has distinguishable spectroscopic features, or by enzyme assays if the protein has
enzymatic activity. Additionally, proteins can be isolated according their charge using electrofocusing.[38]
For natural proteins, a series of purification steps may be necessary to obtain protein sufficiently pure for laboratory
applications. To simplify this process, genetic engineering is often used to add chemical features to proteins that
make them easier to purify without affecting their structure or activity. Here, a "tag" consisting of a specific amino
acid sequence, often a series of histidine residues (a "His-tag"), is attached to one terminus of the protein. As a result,
when the lysate is passed over a chromatography column containing nickel, the histidine residues ligate the nickel
and attach to the column while the untagged components of the lysate pass unimpeded. A number of different tags
have been developed to help researchers purify specific proteins from complex mixtures.[39]
Protein 372

Cellular localization
The study of proteins in vivo is often concerned
with the synthesis and localization of the protein
within the cell. Although many intracellular
proteins are synthesized in the cytoplasm and
membrane-bound or secreted proteins in the
endoplasmic reticulum, the specifics of how
proteins are targeted to specific organelles or
cellular structures is often unclear. A useful
technique for assessing cellular localization uses
genetic engineering to express in a cell a fusion
protein or chimera consisting of the natural
protein of interest linked to a "reporter" such as
green fluorescent protein (GFP).[40] The fused
protein's position within the cell can be cleanly
and efficiently visualized using microscopy,[41]
as shown in the figure opposite.

Other methods for elucidating the cellular


location of proteins requires the use of known
compartmental markers for regions such as the
ER, the Golgi, lysosomes/vacuoles,
mitochondria, chloroplasts, plasma membrane,
etc. With the use of fluorescently tagged versions
of these markers or of antibodies to known Proteins in different cellular compartments and structures tagged with green
fluorescent protein (here, white)
markers, it becomes much simpler to identify the
localization of a protein of interest. For example,
indirect immunofluorescence will allow for fluorescence colocalization and demonstration of location. Fluorescent
dyes are used to label cellular compartments for a similar purpose.[42]

Other possibilities exist, as well. For example, immunohistochemistry usually utilizes an antibody to one or more
proteins of interest that are conjugated to enzymes yielding either luminescent or chromogenic signals that can be
compared between samples, allowing for localization information. Another applicable technique is cofractionation in
sucrose (or other material) gradients using isopycnic centrifugation.[43] While this technique does not prove
colocalization of a compartment of known density and the protein of interest, it does increase the likelihood, and is
more amenable to large-scale studies.

Finally, the gold-standard method of cellular localization is immunoelectron microscopy. This technique also uses an
antibody to the protein of interest, along with classical electron microscopy techniques. The sample is prepared for
normal electron microscopic examination, and then treated with an antibody to the protein of interest that is
conjugated to an extremely electro-dense material, usually gold. This allows for the localization of both
ultrastructural details as well as the protein of interest.[44]
Through another genetic engineering application known as site-directed mutagenesis, researchers can alter the
protein sequence and hence its structure, cellular localization, and susceptibility to regulation. This technique even
allows the incorporation of unnatural amino acids into proteins, using modified tRNAs,[45] and may allow the
rational design of new proteins with novel properties.[46]
Protein 373

Proteomics and bioinformatics


The total complement of proteins present at a time in a cell or cell type is known as its proteome, and the study of
such large-scale data sets defines the field of proteomics, named by analogy to the related field of genomics. Key
experimental techniques in proteomics include 2D electrophoresis,[47] which allows the separation of a large number
of proteins, mass spectrometry,[48] which allows rapid high-throughput identification of proteins and sequencing of
peptides (most often after in-gel digestion), protein microarrays,[49] which allow the detection of the relative levels
of a large number of proteins present in a cell, and two-hybrid screening, which allows the systematic exploration of
protein–protein interactions.[50] The total complement of biologically possible such interactions is known as the
interactome.[51] A systematic attempt to determine the structures of proteins representing every possible fold is
known as structural genomics.[52]
The large amount of genomic and proteomic data available for a variety of organisms, including the human genome,
allows researchers to efficiently identify homologous proteins in distantly related organisms by sequence alignment.
Sequence profiling tools can perform more specific sequence manipulations such as restriction enzyme maps, open
reading frame analyses for nucleotide sequences, and secondary structure prediction. From this data phylogenetic
trees can be constructed and evolutionary hypotheses developed using special software like ClustalW regarding the
ancestry of modern organisms and the genes they express. The field of bioinformatics seeks to assemble, annotate,
and analyze genomic and proteomic data, applying computational techniques to biological problems such as gene
finding and cladistics.

Structure prediction and simulation


Complementary to the field of structural genomics, protein structure prediction seeks to develop efficient ways to
provide plausible models for proteins whose structures have not yet been determined experimentally.[53] The most
successful type of structure prediction, known as homology modeling, relies on the existence of a "template"
structure with sequence similarity to the protein being modeled; structural genomics' goal is to provide sufficient
representation in solved structures to model most of those that remain.[54] Although producing accurate models
remains a challenge when only distantly related template structures are available, it has been suggested that sequence
alignment is the bottleneck in this process, as quite accurate models can be produced if a "perfect" sequence
alignment is known.[55] Many structure prediction methods have served to inform the emerging field of protein
engineering, in which novel protein folds have already been designed.[56] A more complex computational problem is
the prediction of intermolecular interactions, such as in molecular docking and protein–protein interaction
prediction.[57]
The processes of protein folding and binding can be simulated using such technique as molecular mechanics, in
particular, molecular dynamics and Monte Carlo, which increasingly take advantage of parallel and distributed
computing (Folding@home project;[58] molecular modeling on GPU). The folding of small alpha-helical protein
domains such as the villin headpiece[59] and the HIV accessory protein[60] have been successfully simulated in silico,
and hybrid methods that combine standard molecular dynamics with quantum mechanics calculations have allowed
exploration of the electronic states of rhodopsins.[61]

Nutrition
Most microorganisms and plants can biosynthesize all 20 standard amino acids, while animals (including humans)
must obtain some of the amino acids from the diet.[22] The amino acids that an organism cannot synthesize on its
own are referred to as essential amino acids. Key enzymes that synthesize certain amino acids are not present in
animals — such as aspartokinase, which catalyzes the first step in the synthesis of lysine, methionine, and threonine
from aspartate. If amino acids are present in the environment, microorganisms can conserve energy by taking up the
amino acids from their surroundings and downregulating their biosynthetic pathways.
Protein 374

In animals, amino acids are obtained through the consumption of foods containing protein. Ingested proteins are then
broken down into amino acids through digestion, which typically involves denaturation of the protein through
exposure to acid and hydrolysis by enzymes called proteases. Some ingested amino acids are used for protein
biosynthesis, while others are converted to glucose through gluconeogenesis, or fed into the citric acid cycle. This
use of protein as a fuel is particularly important under starvation conditions as it allows the body's own proteins to be
used to support life, particularly those found in muscle.[62] Amino acids are also an important dietary source of
nitrogen.

History and etymology


Proteins were recognized as a distinct class of biological molecules in the eighteenth century by Antoine Fourcroy
and others, distinguished by the molecules' ability to coagulate or flocculate under treatments with heat or acid.
Noted examples at the time included albumin from egg whites, blood serum albumin, fibrin, and wheat gluten.
Proteins were first described by the Dutch chemist Gerardus Johannes Mulder and named by the Swedish chemist
Jöns Jacob Berzelius in 1838. Mulder carried out elemental analysis of common proteins and found that nearly all
proteins had the same empirical formula, C400H620N100O120P1S1.[63] He came to the erroneous conclusion that they
might be composed of a single type of (very large) molecule. The term "protein" to describe these molecules was
proposed by Mulder's associate Berzelius; protein is derived from the Greek word πρωτεῖος (proteios), meaning
"primary",[64] "in the lead", or "standing in front".[65] Mulder went on to identify the products of protein degradation
such as the amino acid leucine for which he found a (nearly correct) molecular weight of 131 Da.[63]
Early nutritional scientists such as the German Carl von Voit believed that protein was the most important nutrient
for maintaining the structure of the body, because it was generally believed that "flesh makes flesh."[66] The central
role of proteins as enzymes in living organisms was not fully appreciated until 1926, when James B. Sumner showed
that the enzyme urease was in fact a protein.[67]
The difficulty in purifying proteins in large quantities made them very difficult for early protein biochemists to
study. Hence, early studies focused on proteins that could be purified in large quantities, e.g., those of blood, egg
white, various toxins, and digestive/metabolic enzymes obtained from slaughterhouses. In the 1950s, the Armour
Hot Dog Co. purified 1 kg of pure bovine pancreatic ribonuclease A and made it freely available to scientists; this
gesture helped ribonuclease A become a major target for biochemical study for the following decades.[63]
Linus Pauling is credited with the successful prediction of regular
protein secondary structures based on hydrogen bonding, an idea first
put forth by William Astbury in 1933.[68] Later work by Walter
Kauzmann on denaturation,[69][70] based partly on previous studies by
Kaj Linderstrøm-Lang,[71] contributed an understanding of protein
folding and structure mediated by hydrophobic interactions.

The first protein to be sequenced was insulin, by Frederick Sanger, in


1949. Sanger correctly determined the amino acid sequence of insulin,
John Kendrew with model of myoglobin in
thus conclusively demonstrating that proteins consisted of linear progress.
polymers of amino acids rather than branched chains, colloids, or
cyclols.[72] He won the Nobel Prize for this achievement in 1958.
The first protein structures to be solved were hemoglobin and myoglobin, by Max Perutz and Sir John Cowdery
Kendrew, respectively, in 1958.[73][74] The first atomic-resolution structures of proteins were solved by X-ray
diffraction analysis in the 1960s (Perutz and Kendrew shared the 1962 Nobel Prize in Chemistry for these
discoveries) and by NMR in the 1980s. As of 2009, the Protein Data Bank has over 55,000 atomic-resolution
structures of proteins.[75] In more recent times, cryo-electron microscopy of large macromolecular assemblies[76] and
computational protein structure prediction of small protein domains[77] are two methods approaching atomic
Protein 375

resolution.

Footnotes
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[4] Murray et al., p. 31.
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[14] Murray et al., pp. 30–34.
[15] van Holde and Mathews, pp. 368–75.
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References
• Branden C, Tooze J (1999). Introduction to Protein Structure. New York: Garland Pub. ISBN 0-8153-2305-0.
• Murray RF, Harper HW, Granner DK, Mayes PA, Rodwell VW (2006). Harper's Illustrated Biochemistry. New
York: Lange Medical Books/McGraw-Hill. ISBN 0-07-146197-3.
• Van Holde KE, Mathews CK (1996). Biochemistry. Menlo Park, California: Benjamin/Cummings Pub. Co., Inc.
ISBN 0-8053-3931-0.

External links

Databases and projects


• The Protein Naming Utility (http://www.jcvi.org/pn-utility)
• Human Protein Atlas (http://www.proteinatlas.org/)
• NCBI Entrez Protein database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=protein)
• NCBI Protein Structure database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=structure)
• Human Protein Reference Database (http://www.hprd.org/)
• Human Proteinpedia (http://www.humanproteinpedia.org/)
• Folding@Home (Stanford University) (http://folding.stanford.edu/)
• Comparative Toxicogenomics Database (http://ctd.mdibl.org/) curates protein–chemical interactions, as well
as gene/protein–disease relationships and chemical-disease relationships.
• Bioinformatic Harvester (http://harvester.fzk.de/) A Meta search engine (29 databases) for gene and protein
information.
• Protein Databank in Europe (http://www.pdbe.org/) (see also PDBeQuips (http://www.pdbe.org/quips),
short articles and tutorials on interesting PDB structures)
• Research Collaboratory for Structural Bioinformatics (http://www.rcsb.org/) (see also Molecule of the Month
(http://www.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html),
Protein 378

presenting short accounts on selected proteins from the PDB)


• Proteopedia – Life in 3D (http://www.proteopedia.org/): rotatable, zoomable 3D model with wiki annotations
for every known protein molecular structure.
• UniProt the Universal Protein Resource (http://www.expasy.uniprot.org/)
• neXtProt – Exploring the universe of human proteins (http://www.nextprot.org/): human-centric protein
knowledge resource

Tutorials and educational websites


• "An Introduction to Proteins" (http://hopes.stanford.edu/basics/proteins/p0.html) from HOPES (Huntington's
Disease Outreach Project for Education at Stanford)
• Proteins: Biogenesis to Degradation – The Virtual Library of Biochemistry and Cell Biology (http://www.
biochemweb.org/proteins.shtml)

Proteoglycan
Not to be confused with bacterial peptidoglycan.
Proteoglycans are proteins[1] that are heavily
glycosylated. The basic proteoglycan unit consists of a
"core protein" with one or more covalently attached
glycosaminoglycan (GAG) chain(s).[2] The point of
attachment is a Ser residue to which the
glycosaminoglycan is joined through a tetrasaccharide
bridge (For example: chondroitin
sulfate-GlcA-Gal-Gal-Xyl-PROTEIN). The Ser residue
is generally in the sequence -Ser-Gly-X-Gly- (where X
can be any amino acid residue), although not every
protein with this sequence has an attached
glycosaminoglycan. The chains are long, linear
carbohydrate polymers that are negatively charged
under physiological conditions, due to the occurrence
of sulfate and uronic acid groups. Proteoglycans occur
in the connective tissue.
Aggrecan, the major proteoglycan in cartilage, has 2316 amino acids

Types
Proteoglycans can be categorised depending upon the nature of their glycosaminoglycan chains. Proteoglycans can
also be categorised by size (kDa).
Types include:
Proteoglycan 379

Glycosaminoglycans Small proteoglycans Large proteoglycans

chondroitin sulfate/dermatan sulfate decorin, kDa=36 versican, kDa=260-370, present in many adult tissues including blood vessels and skin
biglycan, kDa=38

heparan sulfate/chondroitin sulfate testican, kDa=44 perlecan, kDa=400-470

chondroitin sulfate neurocan, kDa=136


aggrecan, kDa=220, the major proteoglycan in cartilage

keratan sulfate fibromodulin,


kDa=42
lumican, kDa=38

Certain members are considered members of the "small leucine-rich proteoglycan family" (SLRP).[3] These include
decorin, biglycan, fibromodulin and lumican.

Function
Proteoglycans are a major component of the animal extracellular matrix, the "filler" substance existing between cells
in an organism. Here they form large complexes, both to other proteoglycans, to hyaluronan and to fibrous matrix
proteins (such as collagen). They are also involved in binding cations (such as sodium, potassium and calcium) and
water, and also regulating the movement of molecules through the matrix. Evidence also shows they can affect the
activity and stability of proteins and signalling molecules within the matrix. Individual functions of proteoglycans
can be attributed to either the protein core or the attached GAG chain and serve as lubricants.

Synthesis
The protein component of proteoglycans is synthesized by ribosomes and translocated into the lumen of the rough
endoplasmic reticulum. Glycosylation of the proteoglycan occurs in the Golgi apparatus in multiple enzymatic steps.
First a special link tetrasaccharide is attached to a serine side chain on the core protein to serve as a primer for
polysaccharide growth. Then sugars are added one at a time by glycosyl transferase. The completed proteoglycan is
then exported in secretory vesicles to the extracellular matrix of the cell.

Proteoglycans and disease


An inability to break down proteoglycans is characteristic of a group of genetic disorders, called
mucopolysaccharidoses. The inactivity of specific lysosomal enzymes that normally degrade glycosaminoglycans
leads to the accumulation of proteoglycans within cells. This leads to a variety of disease symptoms, depending upon
the type of proteoglycan that is not degraded.

References
[1] Proteoglycans (http:/ / www. nlm. nih. gov/ cgi/ mesh/ 2011/ MB_cgi?mode=& term=Proteoglycans) at the US National Library of Medicine
Medical Subject Headings (MeSH)
[2] Gerhard Meisenberg; William H. Simmons (2006). Principles of medical biochemistry (http:/ / books. google. com/
books?id=y2A0h64iNlcC& pg=PA243). Elsevier Health Sciences. pp. 243–. ISBN 978-0-323-02942-1. . Retrieved 6 February 2011.
[3] Hans-Joachim Gabius; Sigrun Gabius (February 2002). Glycosciences: Status and Perspectives (http:/ / books. google. com/
books?id=G0DiximLj5YC& pg=PA209). John Wiley and Sons. pp. 209–. ISBN 978-3-527-30888-0. . Retrieved 6 February 2011.
Proteoglycan 380

External links
• Diagram at nd.edu (http://www.nd.edu/~aseriann/proteogly.html)
• Diagram at usip.edu (http://tonga.usip.edu/gmoyna/biochem341/lecture35.html)

Red blood cell


Red blood cells, or erythrocytes, are the most common type of blood cell
and the vertebrate organism's principal means of delivering oxygen (O2) to
the body tissues via the blood flow through the circulatory system.[1] They
take up oxygen in the lungs or gills and release it while squeezing through
the body's capillaries.
These cells' cytoplasm is rich in haemoglobin, an iron-containing
biomolecule that can bind oxygen and is responsible for the blood's red
color.
In humans, mature red blood cells are oval and flexible biconcave disks.
They lack a cell nucleus and most organelles to accommodate maximum
space for haemoglobin. 2.4 million new erythrocytes are produced per
Human red blood cells (6–8μm)
second.[2] The cells develop in the bone marrow and circulate for about
100–120 days in the body before their components are recycled by
macrophages. Each circulation takes about 20 seconds. Approximately a quarter of the cells in the human body are
red blood cells.[3][4]

Red blood cells are also known as RBCs, red cells,[5] red blood corpuscles (an archaic term), haematids,
erythroid cells or erythrocytes (from Greek erythros for "red" and kytos for "hollow", with cyte translated as "cell"
in modern usage).

History
The oldest intact red blood cells ever discovered were found in Ötzi the Iceman, a natural mummy of a man who
died around 3255 BCE. These cells were discovered in May 2012.[6]
The first person to describe red blood cells was the young Dutch biologist Jan Swammerdam, who had used an early
microscope in 1658 to study the blood of a frog.[7] Unaware of this work, Anton van Leeuwenhoek provided another
microscopic description in 1674, this time providing a more precise description of red blood cells, even
approximating their size, "25,000 times smaller than a fine grain of sand".
In 1901, Karl Landsteiner published his discovery of the three main blood groups—A, B, and C (which he later
renamed to O). Landsteiner described the regular patterns in which reactions occurred when serum was mixed with
red blood cells, thus identifying compatible and conflicting combinations between these blood groups. A year later
Alfred von Decastello and Adriano Sturli, two colleagues of Landsteiner, identified a fourth blood group—AB.
In 1959, by use of X-ray crystallography, Dr. Max Perutz was able to unravel the structure of hemoglobin, the red
blood cell protein that carries oxygen.[8]
Red blood cell 381

Vertebrate erythrocytes
Erythrocytes consist mainly of hemoglobin, a complex
metalloprotein containing heme groups whose iron atoms
temporarily bind to oxygen molecules (O2) in the lungs or gills
and release them throughout the body. Oxygen can easily diffuse
through the red blood cell's cell membrane. Hemoglobin in the
erythrocytes also carries some of the waste product carbon dioxide
back from the tissues; most waste carbon dioxide, however, is
transported back to the pulmonary capillaries of the lungs as
bicarbonate (HCO3-) dissolved in the blood plasma. Myoglobin, a
compound related to hemoglobin, acts to store oxygen in muscle
cells.[10]

The color of erythrocytes is due to the heme group of hemoglobin.


The blood plasma alone is straw-colored, but the red blood cells
change color depending on the state of the hemoglobin: when
combined with oxygen the resulting oxyhemoglobin is scarlet, and
when oxygen has been released the resulting deoxyhemoglobin is
of a dark red burgundy color, appearing bluish through the vessel
wall and skin. Pulse oximetry takes advantage of this color change
to directly measure the arterial blood oxygen saturation using
colorimetric techniques.

The sequestration of oxygen carrying proteins inside specialized


There is an immense size variation in vertebrate
cells (rather than having them dissolved in body fluid) was an
erythrocytes, as well as a correlation between cell and
important step in the evolution of vertebrates as it allows for less nucleus size. Mammalian erythrocytes, which do not
viscous blood, higher concentrations of oxygen, and better contain nuclei, are considerably smaller than those of
[9]
diffusion of oxygen from the blood to the tissues. The size of most other vertebrates.

erythrocytes varies widely among vertebrate species; erythrocyte


width is on average about 25% larger than capillary diameter and it has been hypothesized that this improves the
oxygen transfer from erythrocytes to tissues.[11]

The only known vertebrates without erythrocytes are the crocodile icefishes (family Channichthyidae); they live in
very oxygen rich cold water and transport oxygen freely dissolved in their blood.[12] While they do not use
hemoglobin any more, remnants of hemoglobin genes can be found in their genome.[13]

Nucleus
Erythrocytes in mammals are anucleate when mature, meaning that they lack a cell nucleus. In comparison, the
erythrocytes of other vertebrates have nuclei; the only known exceptions are salamanders of the Batrachoseps genus
and fish of the Maurolicus genus with closely related species.[14][15]

Secondary functions
When erythrocytes undergo shear stress in constricted vessels, they release ATP which causes the vessel walls to
relax and dilate so as to promote normal blood flow.[16]
When their hemoglobin molecules are deoxygenated, erythrocytes release S-nitrosothiols which also acts to dilate
vessels,[17] thus directing more blood to areas of the body depleted of oxygen.
Red blood cell 382

It has been recently demonstrated that erythrocytes can also synthesize nitric oxide enzymatically, using L-arginine
as substrate, just like endothelial cells.[18] Exposure of erythrocytes to physiological levels of shear stress activates
nitric oxide synthase and export of nitric oxide,[19] which may contribute to the regulation of vascular tonus.
Erythrocytes can also produce hydrogen sulfide, a signalling gas that acts to relax vessel walls. It is believed that the
cardioprotective effects of garlic are due to erythrocytes converting its sulfur compounds into hydrogen sulfide.[20]
Erythrocytes also play a part in the body's immune response: when lysed by pathogens such as bacteria, their
hemoglobin releases free radicals which break down the pathogen's cell wall and membrane, killing it.[21][22]

Mammalian erythrocytes
Mammalian erythrocytes are unique among
the vertebrates as they are non-nucleated
cells in their mature form. These cells have
nuclei during early phases of erythropoiesis,
but extrude them during development as
they mature in order to provide more space
for hemoglobin. In mammals, erythrocytes
also lose all other cellular organelles such as
their mitochondria, Golgi apparatus and
endoplasmic reticulum.

As a result of not containing mitochondria,


these cells use none of the oxygen they
transport; instead they produce the energy Typical mammalian erythrocytes: (a) seen from surface; (b) in profile, forming
rouleaux; (c) rendered spherical by water; (d) rendered crenate by salt. (c) and (d)
carrier ATP by the glycolysis of glucose and
do not normally occur in the body.
lactic acid fermentation on the resulting
pyruvate.

Because of the lack of nuclei and organelles, mature red blood cells do not contain DNA and cannot synthesize any
RNA, and consequently cannot divide and have limited repair capabilities.[23] This also entails that no virus can
evolve to target mammalian red cells.
Mammalian erythrocytes are typically shaped as biconcave disks: flattened and depressed in the center, with a
dumbbell-shaped cross section, and a torus-shaped rim on the edge of the disk. This distinctive biconcave shape
optimises the flow properties of blood in the large vessels, such as maximization of laminar flow and minimization
of platelet scatter, which suppresses their atherogenic activity in those large vessels.[24] However, there are some
exceptions concerning shape in the artiodactyl order (even-toed ungulates including cattle, deer, and their relatives),
which displays a wide variety of bizarre erythrocyte morphologies: small and highly ovaloid cells in llamas and
camels (family Camelidae), tiny spherical cells in mouse deer (family Tragulidae), and cells which assume fusiform,
lanceolate, crescentic, and irregularly polygonal and other angular forms in red deer and wapiti (family Cervidae).
Members of this order have clearly evolved a mode of red blood cell development substantially different from the
mammalian norm.[9][25] Overall, mammalian erythrocytes are remarkably flexible and deformable so as to squeeze
through tiny capillaries, as well as to maximize their apposing surface by assuming a cigar shape, where they
efficiently release their oxygen load.[26]
In large blood vessels, red blood cells sometimes occur as a stack, flat side next to flat side. This is known as
rouleaux formation, and it occurs more often if the levels of certain serum proteins are elevated, as for instance
during inflammation.
The spleen acts as a reservoir of red blood cells, but this effect is somewhat limited in humans. In some other
mammals such as dogs and horses, the spleen sequesters large numbers of red blood cells which are dumped into the
Red blood cell 383

blood during times of exertion stress, yielding a higher oxygen transport capacity.

Scanning electron micrograph of blood cells. From left


to right: human erythrocyte, thrombocyte (platelet),
leukocyte.

Human erythrocytes
A typical human erythrocyte has a disk diameter of 6–8 µm and a
thickness of 2 µm, being much smaller than most other human
cells. These cells have an average volume of about 90 fL[27] with a
surface of about 136 μm2, and can swell up to a sphere shape
containing 150 fL, without membrane distension.
Adult humans have roughly 2–3 × 1013 (20-30 trillion) red blood
cells at any given time, comprising approximately one quarter of Two drops of blood are shown with a bright red
the total human body cell number (women have about 4 to 5 oxygenated drop on the left and a deoxygenated drop
million erythrocytes per microliter (cubic millimeter) of blood and on the right.

men about 5 to 6 million; people living at high altitudes with low


oxygen tension will have more). Red blood cells are thus much
more common than the other blood particles: there are about
4,000–11,000 white blood cells and about 150,000–400,000
platelets in each microliter of human blood.

Human red blood cells take on average 20 seconds to complete


one cycle of circulation.[3][4][28]
As red blood cells contain no nucleus, protein biosynthesis is
currently assumed to be absent in these cells, although a recent
study indicates the presence of all the necessary biomachinery in
the cells to do so.[23] An animation of a typical human red blood cell cycle
in the circulatory system. This animation occurs at real
The blood's red color is due to the spectral properties of the hemic
time (20 seconds of cycle) and shows the red blood cell
iron ions in hemoglobin. Each human red blood cell contains deform as it enters capillaries, as well as changing
approximately 270 million of these hemoglobin biomolecules, color as it alternates in states of oxygenation along the
each carrying four heme groups; hemoglobin comprises about a circulatory system.

third of the total cell volume. This protein is responsible for the
transport of more than 98% of the oxygen (the remaining oxygen is carried dissolved in the blood plasma). The red
blood cells of an average adult human male store collectively about 2.5 grams of iron, representing about 65% of the
total iron contained in the body.[29][30] (See Human iron metabolism.)
Red blood cell 384

Life cycle
Human erythrocytes are produced through a process named erythropoiesis, developing from committed stem cells to
mature erythrocytes in about 7 days. When matured, these cells live in blood circulation for about 100 to 120 days.
At the end of their lifespan, they become senescent, and are removed from circulation.

Erythropoiesis
Erythropoiesis is the development process by which new erythrocytes are produced; it lasts about 7 days. Through
this process erythrocytes are continuously produced in the red bone marrow of large bones, at a rate of about 2
million per second in a healthy adult. (In the embryo, the liver is the main site of red blood cell production.) The
production can be stimulated by the hormone erythropoietin (EPO), synthesised by the kidney. Just before and after
leaving the bone marrow, the developing cells are known as reticulocytes; these comprise about 1% of circulating
red blood cells.

Functional lifetime
The functional lifetime of an erythrocyte is about 100–120 days, during which time the erythrocytes are continually
moved by the blood flow push (in arteries), pull (in veins) and a combination of the two as they squeeze through
microvessels such as capillaries.

Senescence
The aging erythrocyte undergoes changes in its plasma membrane, making it susceptible to selective recognition by
macrophages and subsequent phagocytosis in the reticuloendothelial system (spleen, liver and bone marrow), thus
removing old and defective cells and continually purging the blood. This process is termed eryptosis, erythrocyte
programmed cell death. This process normally occurs at the same rate of production by erythropoiesis, balancing the
total circulating red blood cell count. Eryptosis is increased in a wide variety of diseases including sepsis, haemolytic
uremic syndrome, malaria, sickle cell anemia, beta-thalassemia, glucose-6-phosphate dehydrogenase deficiency,
phosphate depletion, iron deficiency and Wilson's disease. Eryptosis can be elicited by osmotic shock, oxidative
stress, energy depletion as well as a wide variety of endogenous mediators and xenobiotics. Excessive eryptosis is
observed in erythrocytes lacking the cGMP-dependent protein kinase type I or the AMP-activated protein kinase
AMPK. Inhibitors of eryptosis include erythropoietin, nitric oxide, catecholamines and high concentrations of urea.
Much of the resulting breakdown products are recirculated in the body. The heme constituent of hemoglobin are
broken down into Fe3+ and biliverdin. The biliverdin is reduced to bilirubin, which is released into the plasma and
recirculated to the liver bound to albumin. The iron is released into the plasma to be recirculated by a carrier protein
called transferrin. Almost all erythrocytes are removed in this manner from the circulation before they are old
enough to hemolyze. Hemolyzed hemoglobin is bound to a protein in plasma called haptoglobin which is not
excreted by the kidney.[31]

Membrane composition
The membrane of the red blood cell plays many roles that aid in regulating their surface deformability, flexibility,
adhesion to other cells and immune recognition. These functions are highly dependent on its composition, which
defines its properties. The red blood cell membrane is composed of 3 layers: the glycocalyx on the exterior, which is
rich in carbohydrates; the lipid bilayer which contains many transmembrane proteins, besides its lipidic main
constituents; and the membrane skeleton, a structural network of proteins located on the inner surface of the lipid
bilayer. Half of the membrane mass in human and most mammalian erythrocytes are proteins. The other half are
lipids, namely phospholipids and cholesterol.[32]
Red blood cell 385

Membrane lipids

The erythrocyte cell membrane comprises a typical


lipid bilayer, similar to what can be found in virtually
all human cells. Simply put, this lipid bilayer is
composed of cholesterol and phospholipids in equal
proportions by weight. The lipid composition is
important as it defines many physical properties such as
membrane permeability and fluidity. Additionally, the
activity of many membrane proteins is regulated by
interactions with lipids in the bilayer.

Unlike cholesterol which is evenly distributed between


the inner and outer leaflets, the 5 major phospholipids
are asymmetrically disposed, as shown below:
Outer monolayer
• Phosphatidylcholine (PC);
• Sphingomyelin (SM).
Inner monolayer
• Phosphatidylethanolamine (PE);
• Phosphoinositol (PI) (small amounts).
• Phosphatidylserine (PS);
This asymmetric phospholipid distribution among the
bilayer is the result of the function of several The most common erythrocyte cell membrane lipids, schematically
disposed as they are distributed on the bilayer. Relative abundances
energy-dependent and energy-independent
are not at scale.
phospholipid transport proteins. Proteins called
“Flippases” move phospholipids from the outer to the
inner monolayer while others called “floppases” do the opposite operation, against a concentration gradient in an
energy dependent manner. Additionally, there are also “scramblase” proteins that move phospholipids in both
directions at the same time, down their concentration gradients in an energy independent manner. There is still
considerable debate ongoing regarding the identity of these membrane maintenance proteins in the red cell
membrane.

The maintenance of an asymmetric phospholipid distribution in the bilayer (such as an exclusive localization of PS
and PIs in the inner monolayer) is critical for the cell integrity and function due to several reasons:
• Macrophages recognize and phagocytose red cells that expose PS at their outer surface. Thus the confinement of
PS in the inner monolayer is essential if the cell is to survive its frequent encounters with macrophages of the
reticuloendothelial system, especially in the spleen.
• Premature destruction of thallassemic and sickle red cells has been linked to disruptions of lipid asymmetry
leading to exposure of PS on the outer monolayer.
• An exposure of PS can potentiate adhesion of red cells to vascular endothelial cells, effectively preventing normal
transit through the microvasculature. Thus it is important that PS is maintained only in the inner leaflet of the
bilayer to ensure normal blood flow in microcirculation.
• Both PS and phosphatidylinositol-4,5-bisphosphate (PIP2) can regulate membrane mechanical function, due to
their interactions with skeletal proteins such as spectrin and protein 4.1R. Recent studies have shown that binding
of spectrin to PS promotes membrane mechanical stability. PIP2 enhances the binding of protein band 4.1R to
glycophorin C but decreases its interaction with protein band 3, and thereby may modulate the linkage of the
Red blood cell 386

bilayer to the membrane skeleton.


The presence of specialized structures named "lipid rafts" in the erythrocyte membrane have been described by
recent studies. These are structures enriched in cholesterol and sphingolipids associated with specific membrane
proteins, namely flotillins, stomatins (band 7), G-proteins, and β-adrenergic receptors. Lipid rafts that have been
implicated in cell signaling events in nonerythroid cells have been shown in erythroid cells to mediate β2-adregenic
receptor signaling and increase cAMP levels, and thus regulating entry of malarial parasites into normal red
cells.[33][34]

Membrane proteins

The proteins of the membrane skeleton are responsible for the


deformability, flexibility and durability of the red blood cell, enabling
it to squeeze through capillaries less than half the diameter of the
erythrocyte (7-8 μm) and recovering the discoid shape as soon as these
cells stop receiving compressive forces, in a similar fashion to an
object made of rubber.
There are currently more than 50 known membrane proteins, which
can exist in a few hundred up to a million copies per erythrocyte.
Approximately 25 of these membrane proteins carry the various blood
group antigens, such as the A, B and Rh antigens, among many others.
These membrane proteins can perform a wide diversity of functions,
such as transporting ions and molecules across the red cell membrane,
adhesion and interaction with other cells such as endothelial cells, as
signaling receptors, as well as other currently unknown functions. The Red blood cell membrane proteins separated by
[35]
SDS-Page and silverstained
blood types of humans are due to variations in surface glycoproteins of
erythrocytes. Disorders of the proteins in these membranes are
associated with many disorders, such as hereditary spherocytosis, hereditary elliptocytosis, hereditary
stomatocytosis, and paroxysmal nocturnal hemoglobinuria.[32][33]

The red blood cell membrane proteins organized according to their function:
Transport
• Band 3 - Anion transporter, also an important structural component
of the erythrocyte cell membrane, makes up to 25% of the cell
membrane surface, each red cell contains approximately one million
copies. Defines the Diego Blood Group;[36]
• Aquaporin 1 - water transporter, defines the Colton Blood Group;
• Glut1 - glucose and L-dehydroascorbic acid transporter;
• Kidd antigen protein - urea transporter; Red Blood Cell membrane major proteins
• RhAG - gas transporter, probably of carbon dioxide, defines Rh
Blood Group and the associated unusual blood group phenotype Rhnull;
• Na+/K+ - ATPase;
• Ca2+ - ATPase;
• Na+ K+ 2Cl- - cotransporter;
• Na+-Cl- - cotransporter;
• Na-H exchanger;
• K-Cl - cotransporter;
• Gardos Channel.
Red blood cell 387

Cell adhesion
• ICAM-4 - interacts with integrins;
• BCAM - a glycoprotein that defines the Lutheran blood group and also known as Lu or laminin-binding protein.
Structural role - The following membrane proteins establish linkages with skeletal proteins and may play an
important role in regulating cohesion between the lipid bilayer and membrane skeleton, likely enabling the red cell to
maintain its favorable membrane surface area by preventing the membrane from collapsing (vesiculating).
• Ankyrin-based macromolecular complex - proteins linking the bilayer to the membrane skeleton through the
interaction of their cytoplasmic domains with Ankyrin.
• Band 3 - also assembles various glycolytic enzymes, the presumptive CO2 transporter, and carbonic anhydrase
into a macromolecular complex termed a “metabolon,” which may play a key role in regulating red cell
metabolism and ion and gas transport function);
• RhAG - also involved in transport, defines associated unusual blood group phenotype Rhmod.
• Protein 4.1R-based macromolecular complex - proteins interacting with Protein 4.1R.
• Protein 4.1R - weak expression of Gerbich antigens;
• Glycophorin C and D - glycoprotein, defines Gerbich Blood Group;
• XK - defines the Kell Blood Group and the Mcleod unusual phenotype (lack of Kx antigen and greatly reduced
expression of Kell antigens);
• RhD/RhCE - defines Rh Blood Group and the associated unusual blood group phenotype Rhnull;
• Duffy protein - has been proposed to be associated with chemokine clearance;[37]
• Adducin - interaction with band 3;
• Dematin- interaction with the Glut1 glucose transporter.
[32][33]

Surface electrostatic potential


The zeta potential is an electrochemical property of cell surfaces that is determined by the net electrical charge of
molecules exposed at the surface of cell membranes of the cell. The normal zeta potential of the erythrocyte is -15.7
millivolts (mV).[38] Much of this potential appears to be contributed by the exposed sialic acid residues in the
membrane: their removal results in zeta potential of -6.06 mV.

Clinical notes

Separation and blood doping


Red blood cells can be obtained from whole blood by centrifugation, which separates the cells from the blood plasma
in a process known as blood fractionation. Packed red blood cells, which are made in this way from whole blood
with the plasma removed, are used in transfusion medicine.[39] During plasma donation, the red blood cells are
pumped back into the body right away and only the plasma is collected.
Some athletes have tried to improve their performance by blood doping: first about 1 litre of their blood is extracted,
then the red blood cells are isolated, frozen and stored, to be reinjected shortly before the competition. (Red blood
cells can be conserved for 5 weeks at −79 °C.) This practice is hard to detect but may endanger the human
cardiovascular system which is not equipped to deal with blood of the resulting higher viscosity. Another method of
blood doping involves injection with erythropoietin in order to stimulate production of red blood cells.
Red blood cell 388

Artificially grown red blood cells


In 2008 it was reported that human embryonic stem cells had been successfully coaxed into becoming erythrocytes
in the lab. The difficult step was to induce the cells to eject their nucleus; this was achieved by growing the cells on
stromal cells from the bone marrow. It is hoped that these artificial erythrocytes can eventually be used for blood
transfusions.[40]

Diseases and diagnostic tools


Blood diseases involving the red blood cells include:
• Anemias (or anaemias) are diseases characterized by low oxygen
transport capacity of the blood, because of low red cell count or some
abnormality of the red blood cells or the hemoglobin.
• Iron deficiency anemia is the most common anemia; it occurs when
the dietary intake or absorption of iron is insufficient, and hemoglobin,
which contains iron, cannot be formed
• Sickle-cell disease is a genetic disease that results in abnormal
hemoglobin molecules. When these release their oxygen load in the
tissues, they become insoluble, leading to mis-shaped red blood cells.
These sickle shaped red cells are less deformable and viscoelastic
Affected by Sickle-cell disease, red blood
meaning that they have become rigid and can cause blood vessel
cells alter shape and threaten to damage
blockage, pain, strokes, and other tissue damage. internal organs.

• Thalassemia is a genetic disease that results in the production of an


abnormal ratio of hemoglobin subunits.
• Spherocytosis is a genetic disease that causes a defect in the red blood cell's cytoskeleton, causing the red
blood cells to be small, sphere-shaped, and fragile instead of donut-shaped and flexible.
• Pernicious anemia is an autoimmune disease wherein the body lacks intrinsic factor, required to absorb vitamin
B12 from food. Vitamin B12 is needed for the production of hemoglobin.
• Aplastic anemia is caused by the inability of the bone marrow to produce blood cells.
• Pure red cell aplasia is caused by the inability of the bone marrow to produce only red blood cells.
• Hemolysis is the general term for excessive breakdown of red blood
cells. It can have several causes and can result in hemolytic anemia.
• The malaria parasite spends part of its life-cycle in red blood
cells, feeds on their hemoglobin and then breaks them apart,
causing fever. Both sickle-cell disease and thalassemia are more
common in malaria areas, because these mutations convey some
protection against the parasite. Effect of osmotic pressure on blood cells

• Polycythemias (or erythrocytoses) are diseases characterized by a


surplus of red blood cells. The increased viscosity of the blood can cause a number of symptoms.
• In polycythemia vera the increased number of red blood cells results from an abnormality in the bone marrow.
Red blood cell 389

• Several microangiopathic diseases, including disseminated


intravascular coagulation and thrombotic microangiopathies, present
with pathognomonic (diagnostic) red blood cell fragments called
schistocytes. These pathologies generate fibrin strands that sever red
blood cells as they try to move past a thrombus.

Micrographs of the effects of osmotic pressure

• Inherited hemolytic anemias caused by abnormalities of the erythrocyte membrane comprise an important group
of inherited disorders. These disorders are characterized by clinical and biochemical heterogeneity and also
genetic heterogeneity, as evidenced by recent molecular studies.
• The Hereditary spherocytosis (HS) syndromes are a group of inherited disorders characterized by the presence
of spherical-shaped erythrocytes on the peripheral blood smear. HS is found worldwide. It is the most common
inherited anemia in individuals of northern European descent, affecting approximately 1 in 1000-2500
individuals depending on the diagnostic criteria. The primary defect in hereditary spherocytosis is a deficiency
of membrane surface area. Decreased surface area may produced by two different mechanisms: 1) Defects of
spectrin, ankyrin, or protein 4.2 lead to reduced density of the membrane skeleton, destabilizing the overlying
lipid bilayer and releasing band 3-containing microvesicles. 2) Defects of band 3 lead to band 3 deficiency and
loss of its lipid-stabilizing effect. This results in the loss of band 3-free microvesicles. Both pathways result in
membrane loss, decreased surface area, and formation of spherocytes with decreased deformability. These
deformed erythrocytes become trapped in the hostile environment of the spleen where splenic conditioning
inflicts further membrane damage, amplifying the cycle of membrane injury.
• Hereditary elliptocytosis
• Hereditary pyropoikilocytosis
• Hereditary stomatocytosis[41]
• Hemolytic transfusion reaction is the destruction of donated red blood cells after a transfusion, mediated by host
antibodies, often as a result of a blood type mismatch.
Several blood tests involve red blood cells, including the RBC count (the number of red blood cells per volume of
blood), the hematocrit (percentage of blood volume occupied by red blood cells), and the erythrocyte sedimentation
rate. The blood type needs to be determined to prepare for a blood transfusion or an organ transplantation.

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[16] Wan J, Ristenpart WD, Stone HA (October 2008). "Dynamics of shear-induced ATP release from red blood cells". Proceedings of the
National Academy of Sciences of the United States of America 105 (43): 16432–7. Bibcode 2008PNAS..10516432W.
doi:10.1073/pnas.0805779105. PMC 2575437. PMID 18922780.
[17] Diesen DL, Hess DT, Stamler JS (August 2008). "Hypoxic vasodilation by red blood cells: evidence for an s-nitrosothiol-based signal".
Circulation Research 103 (5): 545–53. doi:10.1161/CIRCRESAHA.108.176867. PMC 2763414. PMID 18658051.
[18] Kleinbongard P, Schutz R, Rassaf T et al. (2006). "Red blood cells express a functional endothelial nitric oxide synthase". Blood 107 (7):
2943–51. doi:10.1182/blood-2005-10-3992. PMID 16368881.
[19] Ulker P, Sati L, Celik-Ozenci C, Meiselman HJ, Baskurt OK (2009). "Mechanical stimulation of nitric oxide synthesizing mechanisms in
erythrocytes". Biorheology 46 (2): 121–32. doi:10.3233/BIR-2009-0532. PMID 19458415.
[20] Benavides, Gloria A; Giuseppe L Squadrito, Robert W Mills, Hetal D Patel, T Scott Isbell, Rakesh P Patel, Victor M Darley-Usmar,
Jeannette E Doeller, David W Kraus (2007-11-13). "Hydrogen sulfide mediates the vasoactivity of garlic" (http:/ / www. pnas. org/ content/
104/ 46/ 17977. full). Proceedings of the National Academy of Sciences of the United States of America 104 (46): 17977–17982.
Bibcode 2007PNAS..10417977B. doi:10.1073/pnas.0705710104. PMC 2084282. PMID 17951430. . Retrieved 2010-03-03.
[21] Red blood cells do more than just carry oxygen. New findings by NUS team show they aggressively attack bacteria too. (http:/ / www. dbs.
nus. edu. sg/ eventlist/ happenings/ details/ 2007/ dingSTsep07. pdf), The Straits Times, 1 September 2007
[22] Jiang N, Tan NS, Ho B, Ding JL (October 2007). "Respiratory protein-generated reactive oxygen species as an antimicrobial strategy".
Nature Immunology 8 (10): 1114–22. doi:10.1038/ni1501. PMID 17721536.
[23] Kabanova S, Kleinbongard P, Volkmer J, Andrée B, Kelm M, Jax TW (2009). "Gene expression analysis of human red blood cells" (http:/ /
www. medsci. org/ v06p0156. htm). International Journal of Medical Sciences 6 (4): 156–9. PMC 2677714. PMID 19421340. .
[24] Uzoigwe C (2006). "The human erythrocyte has developed the biconcave disc shape to optimise the flow properties of the blood in the large
vessels". Medical Hypotheses 67 (5): 1159–63. doi:10.1016/j.mehy.2004.11.047. PMID 16797867.
[25] Gregory TR (2001). "The bigger the C-value, the larger the cell: genome size and red blood cell size in vertebrates". Blood Cells, Molecules
& Diseases 27 (5): 830–43. doi:10.1006/bcmd.2001.0457. PMID 11783946.
[26] Goodman SR, Kurdia A, Ammann L, Kakhniashvili D, Daescu O (December 2007). "The human red blood cell proteome and interactome".
Experimental Biology and Medicine 232 (11): 1391–408. doi:10.3181/0706-MR-156. PMID 18040063.
[27] McLaren CE, Brittenham GM, Hasselblad V (April 1987). "Statistical and graphical evaluation of erythrocyte volume distributions". Am. J.
Physiol. 252 (4 Pt 2): H857–66. PMID 3565597.
[28] Hillman, Robert S.; Ault, Kenneth A.; Rinder, Henry M. (2005). Hematology in Clinical Practice: A Guide to Diagnosis and Management
(4 ed.). McGraw-Hill Professional. p. 1. ISBN 0-07-144035-6.
[29] Iron Metabolism (http:/ / www. med-ed. virginia. edu/ courses/ path/ innes/ nh/ iron. cfm), University of Virginia Pathology. Accessed 22
September 2007.
[30] Iron Transport and Cellular Uptake (http:/ / sickle. bwh. harvard. edu/ iron_transport. html) by Kenneth R. Bridges, Information Center for
Sickle Cell and Thalassemic Disorders. Accessed 22 September 2007.
[31] Föller M, Huber SM, Lang F (October 2008). "Erythrocyte programmed cell death". IUBMB Life 60 (10): 661–8. doi:10.1002/iub.106.
PMID 18720418.
[32] Yazdanbakhsh K, Lomas-Francis C, Reid ME (October 2000). "Blood groups and diseases associated with inherited abnormalities of the red
blood cell membrane". Transfusion Medicine Reviews 14 (4): 364–74. doi:10.1053/tmrv.2000.16232. PMID 11055079.
[33] Mohandas N, Gallagher PG (November 2008). "Red cell membrane: past, present, and future". Blood 112 (10): 3939–48.
doi:10.1182/blood-2008-07-161166. PMC 2582001. PMID 18988878.
[34] Rodi PM, Trucco VM, Gennaro AM (June 2008). "Factors determining detergent resistance of erythrocyte membranes". Biophysical
Chemistry 135 (1–3): 14–8. doi:10.1016/j.bpc.2008.02.015. PMID 18394774.
[35] Hempelmann E, Götze O (1984). "Characterization of membrane proteins by polychromatic silver staining". Hoppe Seyler's Z Physiol Chem
365: 241–242.
[36] Iolascon A, Perrotta S, Stewart GW (March 2003). "Red blood cell membrane defects". Reviews in Clinical and Experimental Hematology 7
(1): 22–56. PMID 14692233.
[37] Denomme GA (July 2004). "The structure and function of the molecules that carry human red blood cell and platelet antigens". Transfusion
Medicine Reviews 18 (3): 203–31. doi:10.1016/j.tmrv.2004.03.006. PMID 15248170.
[38] Tokumasu F, Ostera GR, Amaratunga C, Fairhurst RM (2012) Modifications in erythrocyte membrane zeta potential by Plasmodium
falciparum infection. Exp Parasitol
Red blood cell 391

[39] "Circular of Information for Blood and Blood Products" (http:/ / www. aabb. org/ resources/ bct/ Documents/ coi0809r. pdf) (pdf). American
Association of Blood Banks, American Red Cross, America's Blood Centers. . Retrieved 2010-11-01.
[40] First red blood cells grown in the lab (http:/ / www. newscientist. com/ article/ dn14565-first-red-blood-cells-grown-in-the-lab. html), New
Scientist News, 19 August 2008
[41] An X, Mohandas N (May 2008). "Disorders of red cell membrane". British Journal of Haematology 141 (3): 367–75.
doi:10.1111/j.1365-2141.2008.07091.x. PMID 18341630.

External links
• Blood Groups and Red Cell Antigens (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..
ShowTOC&rid=rbcantigen.TOC&depth=2) by Laura Dean. Searchable and downloadable online textbook in
the public domain.
• Database of vertebrate erythrocyte sizes (http://www.genomesize.com/cellsize/).
• Red Gold (http://www.pbs.org/wnet/redgold), PBS site containing facts and history

RNA
Ribonucleic acid /raɪbɵ.njuːˌkleɪ.ɪkˈæsɪd/, or RNA, is part of a group
of molecules known as the nucleic acids, which are one of the four
major macromolecules (along with lipids, carbohydrates and proteins)
essential for all known forms of life. Like DNA, RNA is made up of a
long chain of components called nucleotides. Each nucleotide consists
of a nucleobase, a ribose sugar, and a phosphate group. The sequence
of nucleotides allows RNA to encode genetic information. All cellular
organisms use messenger RNA (mRNA) to carry the genetic
information that directs the synthesis of proteins. In addition, many
viruses use RNA instead of DNA as their genetic material.

Some RNA molecules play an active role in cells by catalyzing


biological reactions, controlling gene expression, or sensing and
communicating responses to cellular signals. One of these active
processes is protein synthesis, a universal function whereby mRNA
molecules direct the assembly of proteins on ribosomes. This process
uses transfer RNA (tRNA) molecules to deliver amino acids to the
ribosome, where ribosomal RNA (rRNA) links amino acids together to
form proteins.

The chemical structure of RNA is very similar to that of DNA, with


two differences: (a) RNA contains the sugar ribose, while DNA
A hairpin loop from a pre-mRNA. Highlighted
contains the slightly different sugar deoxyribose (a type of ribose that are the nucleobases (green) and the
lacks one oxygen atom), and (b) RNA has the nucleobase uracil while ribose-phosphate backbone (blue).
DNA contains thymine. Unlike DNA, most RNA molecules are
single-stranded and can adopt very complex three-dimensional structures.
RNA 392

Comparison with DNA


RNA and DNA are both nucleic acids, but differ in three main ways:
• Unlike double-stranded DNA, RNA is a single-stranded molecule in
many of its biological roles and has a much shorter chain of
nucleotides.
• While DNA contains deoxyribose, RNA contains ribose (in
deoxyribose there is no hydroxyl group attached to the pentose ring
in the 2' position). These hydroxyl groups make RNA less stable
than DNA because it is more prone to hydrolysis.
• The complementary base to adenine is not thymine, as it is in DNA,
but rather uracil, which is an unmethylated form of thymine.[1]
Like DNA, most biologically active RNAs, including mRNA, tRNA, Three-dimensional representation of the 50S
rRNA, snRNAs, and other non-coding RNAs, contain ribosomal subunit. RNA is in ochre, protein in
[2] blue. The active site is in the middle (red).
self-complementary sequences that allow parts of the RNA to fold
and pair with itself to form double helices. Analysis of these RNAs has
revealed that they are highly structured. Unlike DNA, their structures do not consist of long double helices but rather
collections of short helices packed together into structures akin to proteins. In this fashion, RNAs can achieve
chemical catalysis, like enzymes.[3] For instance, determination of the structure of the ribosome—an enzyme that
catalyzes peptide bond formation—revealed that its active site is composed entirely of RNA.[4]

Structure
Each nucleotide in RNA contains a ribose sugar, with
carbons numbered 1' through 5'. A base is attached to the 1'
position, in general, adenine (A), cytosine (C), guanine (G),
or uracil (U). Adenine and guanine are purines, cytosine,
and uracil are pyrimidines. A phosphate group is attached to
the 3' position of one ribose and the 5' position of the next.
The phosphate groups have a negative charge each at
physiological pH, making RNA a charged molecule
(polyanion). The bases may form hydrogen bonds between
cytosine and guanine, between adenine and uracil and
between guanine and uracil.[5] However, other interactions
Watson-Crick base pairs in a siRNA (hydrogen atoms are not
are possible, such as a group of adenine bases binding to shown)
each other in a bulge,[6] or the GNRA tetraloop that has a
guanine–adenine base-pair.[5]
RNA 393

An important structural feature of RNA that distinguishes it from DNA


is the presence of a hydroxyl group at the 2' position of the ribose
sugar. The presence of this functional group causes the helix to adopt
the A-form geometry rather than the B-form most commonly observed
in DNA.[7] This results in a very deep and narrow major groove and a
shallow and wide minor groove.[8] A second consequence of the
presence of the 2'-hydroxyl group is that in conformationally flexible
regions of an RNA molecule (that is, not involved in formation of a
double helix), it can chemically attack the adjacent phosphodiester
bond to cleave the backbone.[9]

Chemical structure of RNA

RNA is transcribed with only four bases (adenine, cytosine, guanine


and uracil),[10] but these bases and attached sugars can be modified in
numerous ways as the RNAs mature. Pseudouridine (Ψ), in which the
linkage between uracil and ribose is changed from a C–N bond to a
C–C bond, and ribothymidine (T) are found in various places (the most
notable ones being in the TΨC loop of tRNA).[11] Another notable
modified base is hypoxanthine, a deaminated adenine base whose
nucleoside is called inosine (I). Inosine plays a key role in the wobble
hypothesis of the genetic code.[12]
Secondary structure of a telomerase RNA.
There are nearly 100 other naturally occurring modified
nucleosides,[13] of which pseudouridine and nucleosides with 2'-O-methylribose are the most common.[14] The
specific roles of many of these modifications in RNA are not fully understood. However, it is notable that, in
ribosomal RNA, many of the post-transcriptional modifications occur in highly functional regions, such as the
peptidyl transferase center and the subunit interface, implying that they are important for normal function.[15]
The functional form of single-stranded RNA molecules, just like proteins, frequently requires a specific tertiary
structure. The scaffold for this structure is provided by secondary structural elements that are hydrogen bonds within
the molecule. This leads to several recognizable "domains" of secondary structure like hairpin loops, bulges, and
internal loops.[16] Since RNA is charged, metal ions such as Mg2+ are needed to stabilise many secondary and
tertiary structures.[17]

Synthesis
Synthesis of RNA is usually catalyzed by an enzyme—RNA polymerase—using DNA as a template, a process
known as transcription. Initiation of transcription begins with the binding of the enzyme to a promoter sequence in
the DNA (usually found "upstream" of a gene). The DNA double helix is unwound by the helicase activity of the
enzyme. The enzyme then progresses along the template strand in the 3’ to 5’ direction, synthesizing a
complementary RNA molecule with elongation occurring in the 5’ to 3’ direction. The DNA sequence also dictates
where termination of RNA synthesis will occur.[18]
RNAs are often modified by enzymes after transcription. For example, a poly(A) tail and a 5' cap are added to
eukaryotic pre-mRNA and introns are removed by the spliceosome.
There are also a number of RNA-dependent RNA polymerases that use RNA as their template for synthesis of a new
strand of RNA. For instance, a number of RNA viruses (such as poliovirus) use this type of enzyme to replicate their
genetic material.[19] Also, RNA-dependent RNA polymerase is part of the RNA interference pathway in many
RNA 394

organisms.[20]

Types of RNA

Overview
Messenger RNA (mRNA) is the RNA that carries information from
DNA to the ribosome, the sites of protein synthesis (translation) in the
cell. The coding sequence of the mRNA determines the amino acid
sequence in the protein that is produced.[21] Many RNAs do not code
for protein however (about 97% of the transcriptional output is
non-protein-coding in eukaryotes [22][23][24][25]).

These so-called non-coding RNAs ("ncRNA") can be encoded by their


own genes (RNA genes), but can also derive from mRNA introns.[26]
The most prominent examples of non-coding RNAs are transfer RNA
(tRNA) and ribosomal RNA (rRNA), both of which are involved in the
process of translation.[1] There are also non-coding RNAs involved in
gene regulation, RNA processing and other roles. Certain RNAs are
able to catalyse chemical reactions such as cutting and ligating other
RNA molecules,[27] and the catalysis of peptide bond formation in the
ribosome;[4] these are known as ribozymes.

In translation
Messenger RNA (mRNA) carries information about a protein sequence
Structure of a hammerhead ribozyme, a ribozyme
to the ribosomes, the protein synthesis factories in the cell. It is coded that cuts RNA
so that every three nucleotides (a codon) correspond to one amino acid.
In eukaryotic cells, once precursor mRNA (pre-mRNA) has been transcribed from DNA, it is processed to mature
mRNA. This removes its introns—non-coding sections of the pre-mRNA. The mRNA is then exported from the
nucleus to the cytoplasm, where it is bound to ribosomes and translated into its corresponding protein form with the
help of tRNA. In prokaryotic cells, which do not have nucleus and cytoplasm compartments, mRNA can bind to
ribosomes while it is being transcribed from DNA. After a certain amount of time the message degrades into its
component nucleotides with the assistance of ribonucleases.[21]

Transfer RNA (tRNA) is a small RNA chain of about 80 nucleotides that transfers a specific amino acid to a growing
polypeptide chain at the ribosomal site of protein synthesis during translation. It has sites for amino acid attachment
and an anticodon region for codon recognition that binds to a specific sequence on the messenger RNA chain
through hydrogen bonding.[26]
Ribosomal RNA (rRNA) is the catalytic component of the ribosomes. Eukaryotic ribosomes contain four different
rRNA molecules: 18S, 5.8S, 28S and 5S rRNA. Three of the rRNA molecules are synthesized in the nucleolus, and
one is synthesized elsewhere. In the cytoplasm, ribosomal RNA and protein combine to form a nucleoprotein called
a ribosome. The ribosome binds mRNA and carries out protein synthesis. Several ribosomes may be attached to a
single mRNA at any time.[21] Nearly all the RNA found in a typical eukaryotic cell is rRNA.
Transfer-messenger RNA (tmRNA) is found in many bacteria and plastids. It tags proteins encoded by mRNAs that
lack stop codons for degradation and prevents the ribosome from stalling.[28]
RNA 395

Regulatory RNAs
Several types of RNA can downregulate gene expression by being complementary to a part of an mRNA or a gene's
DNA. MicroRNAs (miRNA; 21-22 nt) are found in eukaryotes and act through RNA interference (RNAi), where an
effector complex of miRNA and enzymes can cleave complementary mRNA, block the mRNA from being
translated, or accelerate its degradation.[29][30] While small interfering RNAs (siRNA; 20-25 nt) are often produced
by breakdown of viral RNA, there are also endogenous sources of siRNAs.[31][32]
siRNAs act through RNA interference in a fashion similar to miRNAs. Some miRNAs and siRNAs can cause genes
they target to be methylated, thereby decreasing or increasing transcription of those genes.[33][34][35] Animals have
Piwi-interacting RNAs (piRNA; 29-30 nt) that are active in germline cells and are thought to be a defense against
transposons and play a role in gametogenesis.[36][37]
Many prokaryotes have CRISPR RNAs, a regulatory system similar to RNA interference.[38] Antisense RNAs are
widespread; most downregulate a gene, but a few are activators of transcription.[39] One way antisense RNA can act
is by binding to an mRNA, forming double-stranded RNA that is enzymatically degraded.[40] There are many long
noncoding RNAs that regulate genes in eukaryotes,[41] one such RNA is Xist, which coats one X chromosome in
female mammals and inactivates it.[42]
An mRNA may contain regulatory elements itself, such as riboswitches, in the 5' untranslated region or 3'
untranslated region; these cis-regulatory elements regulate the activity of that mRNA.[43] The untranslated regions
can also contain elements that regulate other genes.[44]

In RNA processing
Many RNAs are involved in modifying other RNAs. Introns are
spliced out of pre-mRNA by spliceosomes, which contain several
small nuclear RNAs (snRNA),[1] or the introns can be ribozymes that
are spliced by themselves.[45] RNA can also be altered by having its
nucleotides modified to other nucleotides than A, C, G and U. In
eukaryotes, modifications of RNA nucleotides are in general directed
by small nucleolar RNAs (snoRNA; 60-300 nt),[26] found in the Uridine to pseudouridine is a common RNA
nucleolus and cajal bodies. snoRNAs associate with enzymes and modification.
guide them to a spot on an RNA by basepairing to that RNA. These
enzymes then perform the nucleotide modification. rRNAs and tRNAs are extensively modified, but snRNAs and
mRNAs can also be the target of base modification.[46][47] RNA can also be methylated.[48][49]

RNA genomes
Like DNA, RNA can carry genetic information. RNA viruses have genomes composed of RNA that encodes a
number of proteins. The viral genome is replicated by some of those proteins, while other proteins protect the
genome as the virus particle moves to a new host cell. Viroids are another group of pathogens, but they consist only
of RNA, do not encode any protein and are replicated by a host plant cell's polymerase.[50]

In reverse transcription
Reverse transcribing viruses replicate their genomes by reverse transcribing DNA copies from their RNA; these
DNA copies are then transcribed to new RNA. Retrotransposons also spread by copying DNA and RNA from one
another,[51] and telomerase contains an RNA that is used as template for building the ends of eukaryotic
chromosomes.[52]
RNA 396

Double-stranded RNA
Double-stranded RNA (dsRNA) is RNA with two complementary strands, similar to the DNA found in all cells.
dsRNA forms the genetic material of some viruses (double-stranded RNA viruses). Double-stranded RNA such as
viral RNA or siRNA can trigger RNA interference in eukaryotes, as well as interferon response in
vertebrates.[53][54][55]

Key discoveries in RNA biology


Research on RNA has led to many important biological
discoveries and numerous Nobel Prizes. Nucleic acids were
discovered in 1868 by Friedrich Miescher, who called the
material 'nuclein' since it was found in the nucleus.[56] It was
later discovered that prokaryotic cells, which do not have a
nucleus, also contain nucleic acids. The role of RNA in protein
synthesis was suspected already in 1939.[57] Severo Ochoa won
the 1959 Nobel Prize in Medicine (shared with Arthur
Kornberg) after he discovered an enzyme that can synthesize
RNA in the laboratory.[58] However, the enzyme discovered by Robert W. Holley, left, poses with his research team.
Ochoa (polynucleotide phosphorylase) was later shown to be
responsible for RNA degradation, not RNA synthesis.

The sequence of the 77 nucleotides of a yeast tRNA was found by Robert W. Holley in 1965,[59] winning Holley the
1968 Nobel Prize in Medicine (shared with Har Gobind Khorana and Marshall Nirenberg). In 1967, Carl Woese
hypothesized that RNA might be catalytic and suggested that the earliest forms of life (self-replicating molecules)
could have relied on RNA both to carry genetic information and to catalyze biochemical reactions—an RNA
world.[60][61]
During the early 1970s, retroviruses and reverse transcriptase were discovered, showing for the first time that
enzymes could copy RNA into DNA (the opposite of the usual route for transmission of genetic information). For
this work, David Baltimore, Renato Dulbecco and Howard Temin were awarded a Nobel Prize in 1975. In 1976,
Walter Fiers and his team determined the first complete nucleotide sequence of an RNA virus genome, that of
bacteriophage MS2.[62]
In 1977, introns and RNA splicing were discovered in both mammalian viruses and in cellular genes, resulting in a
1993 Nobel to Philip Sharp and Richard Roberts. Catalytic RNA molecules (ribozymes) were discovered in the early
1980s, leading to a 1989 Nobel award to Thomas Cech and Sidney Altman. In 1990 it was found in petunia that
introduced genes can silence similar genes of the plant's own, now known to be a result of RNA interference.[63][64]
At about the same time, 22 nt long RNAs, now called microRNAs, were found to have a role in the development of
C. elegans.[65] Studies on RNA interference gleaned a Nobel Prize for Andrew Fire and Craig Mello in 2006, and
another Nobel was awarded for studies on transcription of RNA to Roger Kornberg in the same year. The discovery
of gene regulatory RNAs has led to attempts to develop drugs made of RNA, such as siRNA, to silence genes.[66]
RNA 397

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External links
• RNA World website (http://www.imb-jena.de/RNA.html) Link collection (structures, sequences, tools,
journals)
• Nucleic Acid Database (http://ndbserver.rutgers.edu/atlas/xray/) Images of DNA, RNA and complexes.
• EteRNA (http://eterna.cmu.edu/content/EteRNA) a game forming RNA by pairing bases.
Starch 400

Starch
Starch

Identifiers

CAS number [1]


9005-25-8  

EC-number [2]
232-679-6

RTECS number GM5090000

Properties

Molecular formula variable

Molar mass variable

Appearance white powder

Density 1.5 g/cm


3

Melting point decomp.

Solubility in water none

Hazards

MSDS [3]
ICSC 1553

EU Index not listed

Autoignition 410 °C
temperature

[4]
  (verify)  (what is:  / ?)
Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
Infobox references

Starch or amylum is a carbohydrate consisting of


a large number of glucose units joined by
glycosidic bonds. This polysaccharide is produced
by all green plants as an energy store. It is the most
common carbohydrate in the human diet and is
contained in large amounts in such staple foods as
potatoes, wheat, maize (corn), rice, and cassava.
Structure of the amylose molecule
Pure starch is a white, tasteless and odorless
powder that is insoluble in cold water or alcohol. It
consists of two types of molecules: the linear and
Starch 401

helical amylose and the branched amylopectin.


Depending on the plant, starch generally contains
20 to 25% amylose and 75 to 80% amylopectin by
weight.[5] Glycogen, the glucose store of animals,
is a more branched version of amylopectin.
Starch is processed to produce many of the sugars
in processed foods. Dissolving starch in warm
water gives wheatpaste, which can be used as a
thickening, stiffening or gluing agent. The biggest
industrial non-food use of starch is as adhesive in
the papermaking process.

Name
Structure of the amylopectin molecule
The word "starch" is derived from Middle English
sterchen, meaning to stiffen. "amylum" is Latin for
starch, from the Greek αμυλον, "amylon" which
means "not ground at a mill". The root amyl is
used in biochemistry for several compounds
related to starch.

History
Starch grains from the rhizomes of Typha (cattails,
bullrushes) as flour have been identified from
Granules of wheat starch, stained with iodine,
grinding stones in Europe dating back to 30,000 photographed through a light microscope
years ago.[6]
Pure extracted wheat starch paste was used in Ancient Egypt possibly to glue papyrus.[7] The extraction of starch is
first described in the Natural History of Pliny the Elder around AD 77-79.[8] Romans used it also in cosmetic creams,
to powder the hair and to thicken sauces. Persians and Indians used it to make dishes similar to gothumai wheat
halva. Rice starch as surface treatment of paper has been used in paper production in China, from 700 AD
onwards.[9]
In addition to starchy plants consumed directly, 66 million tonnes of starch were being produced per year
world-wide by 2008. In the EU this was around 8.5 million tonnes, with around 40% being used for industrial
applications and 60% for food uses,[10] most of the latter as glucose syrups.[11]

Energy store of plants


In photosynthesis, plants use light energy to produce glucose from carbon dioxide. The glucose is stored mainly in
the form of starch granules, in plastids such as chloroplasts and especially amyloplasts. Toward the end of the
growing season, starch accumulates in twigs of trees near the buds. Fruit, seeds, rhizomes, and tubers store starch to
prepare for the next growing season.
Glucose is soluble in water, hydrophilic, binds much water and then takes up much space; glucose in the form of
starch, on the other hand, is not soluble and can be stored much more compactly.
Glucose molecules are bound in starch by the easily hydrolyzed alpha bonds. The same type of bond is found in the
animal reserve polysaccharide glycogen. This is in contrast to many structural polysaccharides such as chitin,
Starch 402

cellulose and peptidoglycan, which are bound by beta bonds and are much more resistant to hydrolysis.

Biosynthesis
Plants produce starch by first converting glucose 1-phosphate to ADP-glucose using the enzyme
glucose-1-phosphate adenylyltransferase. This step requires energy in the form of ATP. The enzyme starch synthase
then adds the ADP-glucose via a 1,4-alpha glycosidic bond to a growing chain of glucose residues, liberating ADP
and creating amylose. Starch branching enzyme introduces 1,6-alpha glycosidic bonds between these chains,
creating the branched amylopectin. The starch debranching enzyme isoamylase removes some of these branches.
Several isoforms of these enzymes exist, leading to a highly complex synthesis process.[12]
Glycogen and amylopectin have the same structure, but the former has about one branch point per ten 1,4-alpha
bonds, compared to about one branch point per thirty 1,4-alpha bonds in amylopectin.[13] Amylopectin is synthesized
from ADP-glucose while mammals and fungi synthesize glycogen from UDP-glucose; for most cases, bacteria
synthesize glycogen from ADP-glucose [14] (analogous to starch).[15]

Properties

Structure
While amylose was traditionally thought to be completely unbranched, it is now known that some of its molecules
contain a few branch points.[16] Although in absolute mass only about one quarter of the starch granules in plants
consist of amylose, there are about 150 times more amylose molecules than amylopectin molecules. Amylose is a
much smaller molecule than amylopectin.
Starch molecules arrange themselves in the plant in semi-crystalline granules. Each plant species has a unique starch
granular size: rice starch is relatively small (about 2μm) while potato starches have larger granules (up to 100μm).
Starch becomes soluble in water when heated. The granules swell and burst, the semi-crystalline structure is lost and
the smaller amylose molecules start leaching out of the granule, forming a network that holds water and increasing
the mixture's viscosity. This process is called starch gelatinization. During cooking the starch becomes a paste and
increases further in viscosity. During cooling or prolonged storage of the paste, the semi-crystalline structure
partially recovers and the starch paste thickens, expelling water. This is mainly caused by retrogradation of the
amylose. This process is responsible for the hardening of bread or staling, and for the water layer on top of a starch
gel (syneresis).
Some cultivated plant varieties have pure amylopectin starch without amylose, known as waxy starches. The most
used is waxy maize, others are glutinous rice and waxy potato starch. Waxy starches have less retrogradation,
resulting in a more stable paste. High amylose starch, amylomaize, is cultivated for the use of its gel strength and for
use as a resistant starch (a starch that resists digestion) in food products.

Hydrolysis
The enzymes that break down or hydrolyze starch into the constituent sugars are known as amylases.
Alpha-amylases are found in plants and in animals. Human saliva is rich in amylase, and the pancreas also secretes
the enzyme. Individuals from populations with a high-starch diet tend to have more amylase genes than those with
low-starch diets;[17] chimpanzees have very few amylase genes.[17] It is possible that turning to a high-starch diet
was a significant event in human evolution.[18]
Beta-amylase cuts starch into maltose units. This process is important in the digestion of starch and is also used in
brewing, where amylase from the skin of seed grains is responsible for converting starch to maltose (Malting,
Mashing).
Starch 403

Dextrinization
If starch is subjected to dry heat, it breaks down to form dextrins, also called "pyrodextrins" in this context. This
break down process is known as dextrinization. (Pyro)dextrins are mainly yellow to brown in color and
dextrinization is partially responsible for the browning of toasted bread.

Chemical tests
Iodine solution is used to test for starch; a dark blue color indicates the presence of starch. The details of this reaction
are not yet fully known, but it is thought that the iodine (I3− and I5− ions) fit inside the coils of amylose, the charge
transfers between the iodine and the starch, and the energy level spacings in the resulting complex correspond to the
absorption spectrum in the visible light region. The strength of the resulting blue color depends on the amount of
amylose present. Waxy starches with little or no amylose present will color red.
Starch indicator solution consisting of water, starch and
iodine is often used in redox titrations: in the presence
of an oxidizing agent the solution turns blue, in the
presence of reducing agent the blue color disappears
because triiodide (I3−) ions break up into three iodide
ions, disassembling the starch-iodine complex. A 0.3%
w/w solution is the standard concentration for a starch
indicator. It is made by adding 3 grams of soluble
starch to 1 liter of heated water; the solution is cooled
before use (starch-iodine complex becomes unstable at
temperatures above 35 °C).

Each species of plant has a unique type of starch Starch, 800x magnified, under polarized light

granules in granular size, shape and crystallization


pattern. Under the microscope, starch grains stained with iodine illuminated from behind with polarized light show a
distinctive Maltese cross effect (also known as extinction cross and birefringence).

Food
Starch is the most common carbohydrate in the human diet and is contained in many staple foods. The major sources
of starch intake worldwide are the cereals (rice, wheat, and maize) and the root vegetables (potatoes and cassava).[19]
Many other starchy foods are grown, some only in specific climates, including acorns, arrowroot, arracacha,
bananas, barley, breadfruit, buckwheat, canna, colacasia, katakuri, kudzu, malanga, millet, oats, oca, polynesian
arrowroot, sago, sorghum, sweet potatoes, rye, taro, chestnuts, water chestnuts and yams, and many kinds of beans,
such as favas, lentils, mung beans, peas, and chickpeas.
Widely used prepared foods containing starch are bread, pancakes, cereals, noodles, pasta, porridge and tortilla.
Digestive enzymes have problems digesting crystalline structures. Raw starch will digest poorly in the duodenum
and small intestine, while bacterial degradation will take place mainly in the colon. When starch is cooked, the
digestibility is increased. Hence, before humans started using fire, eating grains was not a very useful way to get
energy.
Starch gelatinization during cake baking can be impaired by sugar competing for water, preventing gelatinization
and improving texture.
Starch 404

Starch industry
The starch industry extracts and refines starches from seeds, roots and tubers, by wet grinding, washing, sieving and
drying. Today, the main commercial refined starches are cornstarch, tapioca, wheat and potato starch. To a lesser
extent, sources include rice, sweet potato, sago and mung bean. Historically, Florida arrowroot was also
commercialized. To this day, starch is extracted from more than 50 types of plants.
Untreated starch requires heat to thicken or gelatinize. When a starch is pre-cooked, it can then be used to thicken
instantly in cold water. This is referred to as a pregelatinized starch.

Starch sugars
Starch can be hydrolyzed into simpler carbohydrates by acids, various enzymes, or a combination of the two. The
resulting fragments are known as dextrins. The extent of conversion is typically quantified by dextrose equivalent
(DE), which is roughly the fraction of the glycosidic bonds in starch that have been broken.
These starch sugars are by far the most common starch based food ingredient and are used as sweetener in many
drinks and foods. They include:
• Maltodextrin, a lightly hydrolyzed (DE 10–20) starch product used as a bland-tasting filler and thickener.
• Various glucose syrups (DE 30–70), also called corn syrups in the US, viscous solutions used as sweeteners and
thickeners in many kinds of processed foods.
• Dextrose (DE 100), commercial glucose, prepared by the complete hydrolysis of starch.
• High fructose syrup, made by treating dextrose solutions with the enzyme glucose isomerase, until a substantial
fraction of the glucose has been converted to fructose. In the United States, high fructose corn syrup is the
principal sweetener used in sweetened beverages because fructose has better handling characteristics, such as
microbiological stability, and more consistent sweetness/flavor. One kind of high fructose corn syrup, HFCS-55,
is typically sweeter than regular sucrose because it is made with more fructose, while the sweetness of HFCS-42
is on par with sucrose.[20][21]
• Sugar alcohols, such as maltitol, erythritol, sorbitol, mannitol and hydrogenated starch hydrolysate, are
sweeteners made by reducing sugars.

Modified starches
A modified starch is a starch that has been chemically modified to allow the starch to function properly under
conditions frequently encountered during processing or storage, such as high heat, high shear, low pH, freeze/thaw
and cooling.
The modified food starches are E coded according to the International Numbering System for Food Additives
(INS):[22]
• 1400 Dextrin
• 1401 Acid-treated starch
• 1402 Alkaline-treated starch
• 1403 Bleached starch
• 1404 Oxidized starch
• 1405 Starches, enzyme-treated
• 1410 Monostarch phosphate
• 1412 Distarch phosphate
• 1413 Phosphated distarch phosphate
• 1414 Acetylated distarch phosphate
• 1420 Starch acetate
• 1422 Acetylated distarch adipate
• 1440 Hydroxypropyl starch
Starch 405

• 1442 Hydroxypropyl distarch phosphate


• 1443 Hydroxypropyl distarch glycerol
• 1450 Starch sodium octenyl succinate
• 1451 Acetylated oxidized starch
INS 1401, 1402, 1403 and 1405 are in the EU food ingredients without an E-number. Typical modified starches for
technical applications are cationic starches, hydroxyethyl starch and carboxymethylated starches.

Use as food additive


As an additive for food processing, food starches are typically used as thickeners and stabilizers in foods such as
puddings, custards, soups, sauces, gravies, pie fillings, and salad dressings, and to make noodles and pastas.
Gummed sweets such as jelly beans and wine gums are not manufactured using a mold in the conventional sense. A
tray is filled with native starch and leveled. A positive mold is then pressed into the starch leaving an impression of
1000 or so jelly beans. The jelly mix is then poured into the impressions and put into a stove to set. This method
greatly reduces the number of molds that must be manufactured.
Resistant starch is starch that escapes digestion in the small intestine of healthy individuals. High amylose starch
from corn has a higher gelatinization temperature than other types of starch and retains its resistant starch content
through baking, mild extrusion and other food processing techniques. It is used as an insoluble dietary fiber in
processed foods such as bread, pasta, cookies, crackers, pretzels and other low moisture foods. It is also utilized as a
dietary supplement for its health benefits. Published studies have shown that Type 2 resistant corn helps to improve
insulin sensitivity,[23] increases satiety[24] and improves markers of colonic function.[25] It has been suggested that
resistant starch contributes to the health benefits of intact whole grains.[26]
In the pharmaceutical industry, starch is also used as an excipient, as tablet disintegrant or as binder.

Industrial applications

Papermaking
Papermaking is the largest non-food application for
starches globally, consuming millions of metric tons
annually.[10] In a typical sheet of copy paper for
instance, the starch content may be as high as 8%. Both
chemically modified and unmodified starches are used
in papermaking. In the wet part of the papermaking
process, generally called the “wet-end”, the starches
used are cationic and have a positive charge bound to
the starch polymer. These starch derivatives associate
with the anionic or negatively charged paper fibers /
cellulose and inorganic fillers. Cationic starches Starch adhesive
together with other retention and internal sizing agents
help to give the necessary strength properties to the paper web formed in the papermaking process (wet strength),
and to provide strength to the final paper sheet (dry strength).

In the dry end of the papermaking process, the paper web is rewetted with a starch based solution. The process is
called surface sizing. Starches used have been chemically, or enzymatically depolymerized at the paper mill or by
the starch industry (oxidized starch). The size - starch solutions are applied to the paper web by means of various
mechanical presses (size presses). Together with surface sizing agents the surface starches impart additional strength
to the paper web and additionally provide water hold out or "size" for superior printing properties. Starch is also used
Starch 406

in paper coatings as one of the binders for the coating formulations which include a mixture of pigments, binders and
thickeners. Coated paper has improved smoothness, hardness, whiteness and gloss and thus improves printing
characteristics.

Corrugated board adhesives


Corrugated board adhesives are the next largest application of non-food starches globally. Starch glues are mostly
based on unmodified native starches, plus some additive such as borax and caustic soda. Part of the starch is
gelatinized to carry the slurry of uncooked starches and prevent sedimentation. This opaque glue is called a SteinHall
adhesive. The glue is applied on tips of the fluting. The fluted paper is pressed to paper called liner. This is then
dried under high heat, which causes the rest of the uncooked starch in glue to swell/gelatinize. This gelatinizing
makes the glue a fast and strong adhesive for corrugated board production.

Clothing starch
Clothing or laundry starch is a liquid that is prepared by mixing a vegetable starch in water (earlier preparations also
had to be boiled), and is used in the laundering of clothes. Starch was widely used in Europe in the 16th and 17th
centuries to stiffen the wide collars and ruffs of fine linen which surrounded the necks of the well-to-do. During the
19th century and early 20th century, it was stylish to stiffen the collars and sleeves of men's shirts and the ruffles of
girls' petticoats by applying starch to them as the clean clothes were being ironed. Aside from the smooth, crisp
edges it gave to clothing, it served practical purposes as well. Dirt and sweat from a person's neck and wrists would
stick to the starch rather than to the fibers of the clothing, and would easily wash away along with the starch. After
each laundering, the starch would be reapplied. Today, the product is sold in aerosol cans for home use.

Other
Another large non-food starch application is in the construction industry, where starch is used in the gypsum wall
board manufacturing process. Chemically modified or unmodified starches are added to the stucco containing
primarily gypsum. Top and bottom heavyweight sheets of paper are applied to the formulation, and the process is
allowed to heat and cure to form the eventual rigid wall board. The starches act as a glue for the cured gypsum rock
with the paper covering, and also provide rigidity to the board.
Starch is used in the manufacture of various adhesives or glues[27] for book-binding, wallpaper adhesives, paper
sack production, tube winding, gummed paper, envelope adhesives, school glues and bottle labeling. Starch
derivatives, such as yellow dextrins, can be modified by addition of some chemicals to form a hard glue for paper
work; some of those forms use borax or soda ash, which are mixed with the starch solution at 50–70 °C to create a
very good adhesive. Sodium silicate can be added to reinforce these formulae.
• Starch is also used to make some packing peanuts, and some drop ceiling tiles.
• Textile chemicals from starch are used to reduce breaking of yarns during weaving; the warp yarns are sized.
Starch is mainly used to size cotton based yarns. Modified starch is also used as textile printing thickener.
• In the printing industry, food grade starch[28] is used in the manufacture of anti-set-off spray powder used to
separate printed sheets of paper to avoid wet ink being set off.
• Starch is used to produce various bioplastics, synthetic polymers that are biodegradable. An example is polylactic
acid.
• For body powder, powdered corn starch is used as a substitute for talcum powder, and similarly in other health
and beauty products.
• In oil exploration, starch is used to adjust the viscosity of drilling fluid, which is used to lubricate the drill head
and suspend the grinding residue in petroleum extraction.
• Glucose from starch can be further fermented to biofuel corn ethanol using the so called wet milling process.
Today most bioethanol production plants use the dry milling process to ferment corn or other feedstock directly to
Starch 407

ethanol.[29]
• Hydrogen production can use starch as the raw material, using enzymes.[30]

References
[1] http:/ / www. commonchemistry. org/ ChemicalDetail. aspx?ref=9005-25-8
[2] http:/ / ecb. jrc. ec. europa. eu/ esis/ index. php?GENRE=ECNO& ENTREE=232-679-6
[3] http:/ / www. inchem. org/ documents/ icsc/ icsc/ eics1553. htm
[4] http:/ / en. wikipedia. org/ wiki/ Special%3Acomparepages?rev1=455316358& page2=%3AStarch
[5] Brown, W. H.; Poon, T. (2005). Introduction to organic chemistry (3rd ed.). Wiley. ISBN 0-471-44451-0.
[6] Revedin, A.; Aranguren, B.; Becattini, R.; Longo, L.; Marconi, E.; Lippi, M. M.; Skakun, N.; Sinitsyn, A. et al. (2010). "Thirty
thousand-year-old evidence of plant food processing". Proceedings of the National Academy of Sciences 107 (44): 18815–9.
doi:10.1073/pnas.1006993107. PMC 2973873. PMID 20956317.
[7] Pliny the Elder, The Natural History (Pliny), Book XIII, Chapter 26, The paste used in preparation of paper (http:/ / www. perseus. tufts. edu/
cgi-bin/ ptext?doc=Perseus:text:1999. 02. 0137& query=head=#817)
[8] Pliny the Elder, The Natural History (Pliny), Book XIII, Chapter 17, (http:/ / www. perseus. tufts. edu/ hopper/ text?doc=Perseus:text:1999.
02. 0137:book=18:chapter=17)
[9] Hunter, Dard (1947). Papermaking. DoverPublications. p. 194. ISBN 978-0-486-23619-3.
[10] NNFCC Renewable Chemicals Factsheet: Starch (http:/ / www. nnfcc. co. uk/ publications/ nnfcc-renewable-chemicals-factsheet-starch)
[11] International Starch Institute Denmark, Starch production volume (http:/ / www. starch. dk/ isi/ market/ index. asp)
[12] Smith, Alison M. (2001). "The Biosynthesis of Starch Granules". Biomacromolecules 2 (2): 335–41. doi:10.1021/bm000133c.
PMID 11749190.
[13] Stryer, Lubert; Berg, Jeremy Mark; Tymoczko, John L. (2002). "Section 11.2.2" (http:/ / www. ncbi. nlm. nih. gov/ books/ bv.
fcgi?rid=stryer. section. 1517#1522). Biochemistry (http:/ / www. ncbi. nlm. nih. gov/ books/ bv. fcgi?rid=stryer) (5th ed.). San Francisco:
W.H. Freeman. ISBN 0-7167-3051-0. .
[14] http:/ / www. genome. jp/ dbget-bin/ www_bget?C00498
[15] Ball, Steven G.; Matthew K Morell (2003). "FROM BACTERIAL GLYCOGEN TO STARCH: Understanding the Biogenesis of the Plant
Starch Granule" (http:/ / www. annualreviews. org/ doi/ abs/ 10. 1146/ annurev. arplant. 54. 031902. 134927). Annual Review of Plant Biology
54 (1): 207–233. doi:10.1146/annurev.arplant.54.031902.134927. PMID 14502990. .
[16] David R. Lineback, "Starch", in AccessScience@McGraw-Hill.
[17] Perry, George H; Dominy, Nathaniel J; Claw, Katrina G; Lee, Arthur S; Fiegler, Heike; Redon, Richard; Werner, John; Villanea, Fernando
A et al. (2007). "Diet and the evolution of human amylase gene copy number variation". Nature Genetics 39 (10): 1256–60.
doi:10.1038/ng2123. PMC 2377015. PMID 17828263.
[18] Myers, P.Z. (December 11, 2008). "Amylase and human evolution" (http:/ / scienceblogs. com/ pharyngula/ 2008/ 12/
amylase_and_human_evolution. php). .
[19] Anne-Charlotte Eliasson (2004). Starch in food: Structure, function and applications. Woodhead Publishing. ISBN 978-0-8493-2555-7.
[20] Ophardt, Charles. "Sweetners - Introduction" (http:/ / www. elmhurst. edu/ ~chm/ vchembook/ 549sweet. html). Elmhurst College. .
[21] White, John S. (December 2, 2008). "HFCS: How Sweet It Is" (http:/ / www. foodproductdesign. com/ articles/ 2008/ 12/
hfcs-how-sweet-it-is. aspx). .
[22] Modified Starches (http:/ / www. fao. org/ ag/ agn/ jecfa-additives/ specs/ Monograph1/ Additive-287. pdf). CODEX ALIMENTARIUS
published in FNP 52 Add 9 (2001)
[23] Maki, K. C.; Pelkman, C. L.; Finocchiaro, E. T.; Kelley, K. M.; Lawless, A. L.; Schild, A. L.; Rains, T. M. (2012). "Resistant Starch from
High-Amylose Maize Increases Insulin Sensitivity in Overweight and Obese Men". Journal of Nutrition 142 (4): 717–23.
doi:10.3945/jn.111.152975. PMID 22357745.
[24] Bodinham, Caroline L.; Frost, Gary S.; Robertson, M. Denise (2009). "Acute ingestion of resistant starch reduces food intake in healthy
adults". British Journal of Nutrition 103 (6): 917–22. doi:10.1017/S0007114509992534. PMID 19857367.
[25] Nugent, A. P. (2005). "Health properties of resistant starch". Nutrition Bulletin 30: 27–54. doi:10.1111/j.1467-3010.2005.00481.x.
[26] Higgins, Janine A. (2012). "Whole Grains, Legumes, and the Subsequent Meal Effect: Implications for Blood Glucose Control and the Role
of Fermentation". Journal of Nutrition and Metabolism 2012: 1. doi:10.1155/2012/829238. PMC 3205742. PMID 22132324.
[27] "Stuck on Starch: A new wood adhesive" (http:/ / www. ars. usda. gov/ is/ ar/ archive/ apr00/ wood0400. htm). US Department of
Agriculture. 2000. .
[28] "Spray Powder" (http:/ / web. archive. org/ web/ 20070809214841/ http:/ / www. russell-webb. com/ anti_set_off_powder/
soluble_anti-set-off-powder. html). Russell-Webb. Archived from the original (http:/ / www. russell-webb. com/ anti_set_off_powder/
soluble_anti-set-off-powder. html) on 2007-08-09. . Retrieved 2007-07-05.
[29] American coalition for ethanol, Ethanol facilities (http:/ / www. ethanol. org/ index. php?id=37& parentid=8)
[30] Zhang, Y.-H. Percival; Evans, Barbara R.; Mielenz, Jonathan R.; Hopkins, Robert C.; Adams, Michael W.W. (2007). Melis, Anastasios. ed.
"High-Yield Hydrogen Production from Starch and Water by a Synthetic Enzymatic Pathway". PLoS ONE 2 (5): e456.
doi:10.1371/journal.pone.0000456. PMC 1866174. PMID 17520015.
Starch 408

External links
• Starch (http://www.lsbu.ac.uk/water/hysta.html), by Martin Chaplin
• Starch - Stärke (http://www3.interscience.wiley.com/journal/5007532/home), scientific journal on starch

Tissue (biology)
Tissue is a cellular organizational level
intermediate between cells and a complete
organism. A tissue is an ensemble of similar
cells and from the same origin, that together
carry out a specific function. These are
called tissues because of their identical
functioning. Organs are then formed by the
functional grouping together of multiple
tissues.

The study of tissue is known as histology or,


in connection with disease, histopathology.
The classical tools for studying tissues are
the paraffin block in which tissue is
embedded and then sectioned, the
Cross section of sclerenchyma fibers in plant ground tissue
histological stain, and the optical
microscope. In the last couple of decades,
developments in electron microscopy,
immunofluorescence, and the use of frozen
tissue sections have enhanced the detail that
can be observed in tissues. With these tools,
the classical appearances of tissues can be
examined in health and disease, enabling
considerable refinement of clinical diagnosis
and prognosis.

Microscopic view of a histologic specimen of human lung tissue stained with


hematoxylin and eosin.
Tissue (biology) 409

Animal tissues
Animal tissues can be grouped into four basic types: connective,
muscle, nervous, and epithelial. Multiple tissue types comprise organs
and body structures. While all animals can generally be considered to
contain the four tissue types, the manifestation of these tissues can
differ depending on the type of organism. For example, the origin of
the cells comprising a particular tissue type may differ
developmentally for different classifications of animals.

The epithelium in all animals is derived from the ectoderm and


endoderm with a small contribution from the mesoderm, forming the
endothelium, a specialized type of epithelium that comprises the PAS diastase showing the fungus Histoplasma.
vasculature. By contrast, a true epithelial tissue is present only in a
single layer of cells held together via occluding junctions called tight junctions, to create a selectively permeable
barrier. This tissue covers all organismal surfaces that come in contact with the external environment such as the
skin, the airways, and the digestive tract. It serves functions of protection, secretion, and absorption, and is separated
from other tissues below by a basal lamina.

Connective tissue
Connective tissues are fibrous tissues. They are made up of cells separated by non-living material, which is called
extracellular matrix. Connective tissue gives shape to organs and holds them in place. Both blood and bone are
examples of connective tissue. As the name implies, connective tissue serves a "connecting" function. It supports and
binds other tissues. Unlike epithelial tissue, connective tissue typically has cells scattered throughout an extracellular
matrix.

Muscle tissue
Muscle cells form the active contractile tissue of the body known as muscle tissue or muscular tissue. Muscle tissue
functions to produce force and cause motion, either locomotion or movement within internal organs. Muscle tissue is
separated into three distinct categories: visceral or smooth muscle, which is found in the inner linings of organs;
skeletal muscle, in which is found attached to bone providing for gross movement; and cardiac muscle which is
found in the heart, allowing it to contract and pump blood throughout an organism.

Nervous tissue
Cells comprising the central nervous system and peripheral nervous system are classified as neural tissue. In the
central nervous system, neural tissue forms the brain and spinal cord and, in the peripheral nervous system forms the
cranial nerves and spinal nerves, inclusive of the motor neurons. Nervous tissue functions to transmit messages.
===Epithelial tissue===

The epithelial tissues are formed by cells that cover the organ
surfaces such as the surface of the skin, the airways, the reproductive
tract, and the inner lining of the digestive tract. The cells
comprising an epithelial layer are linked via semi-permeable, tight
junctions; hence, this tissue provides a barrier between the external
environment and the organ it covers. In addition to this protective
function, epithelial tissue may also be specialized to function in
secretion and absorption. Epithelial tissue helps to protect organisms
from microorganisms, injury, and fluid loss.
Tissue (biology) 410

functions:
1)the cell of the body surface form the outer layer of skin.
2)inside the body,epitheleal cells forms lining of mouth &
alimentary canal & protect these organ.
3)epithelial tissues help in absorption of water & nutrient.
4)epithelial tissues help in elimination of waste product
The different types of epithelial tissues are as follows:
1)Squamous epithelium,
2)Cuboidal epithelium,
3)Columnar epithelium,
4)Glandular epithelium,
5)Ciliated epithelium,

Plant tissues
Examples of tissue in other multicellular organisms are
vascular tissue in plants, such as xylem and phloem.
Plant tissues are categorized broadly into three tissue
systems: the epidermis, the ground tissue, and the
vascular tissue. Together they are often referred to as
biomass.

• Epidermis - Cells forming the outer surface of the


leaves and of the young plant body.
• Vascular tissue - The primary components of
vascular tissue are the xylem and phloem. These
transport fluid and nutrients internally.
• Ground tissue - Ground tissue is less differentiated
than other tissues. Ground tissue manufactures
Cross-section of a flax plant stem with several layers of different
nutrients by photosynthesis and stores reserve
tissue types:
nutrients. 1. Pith,
Plant tissues can also be divided differently into two 2. Protoxylem,
3. Xylem I,
types:
4. Phloem I,
1. Meristematic tissues 5. Sclerenchyma (bast fibre),
2. Permanent tissues 6. Cortex,
7. Epidermis

Meristematic tissues
Meristematic tissue consists of actively dividing cells, and leads to increase in length and thickness of the plant. The
primary growth of a plant occurs only in certain, specific regions, such as in the tips of stems or roots. It is in these
regions that meristematic tissue is present. Cells in these tissues are roughly spherical or polyhedral, to rectangular in
shape, and have thin cell walls. New cells produced by meristem are initially those of meristem itself, but as the new
cells grow and mature, their characteristics slowly change and they become differentiated as components of the
region of occurrence of meristimatic tissues, they are classified as:

a) Apical Meristem - It is present at the growing tips of stems and roots and increases the length of the
stem and root. They form growing parts at the apices of roots and stems and are responsible for increase
in length,also called primary growth.This meristem is responsible for the linear growth of an organ.
Tissue (biology) 411

b) Lateral Meristem - This meristem consist of cells which mainly divide in one plane and cause the
organ to increase in diameter and growth. Lateral Meristem usually occurs beneath the bark of the tree
in the form of Cork Cambium and in vascular bundles of dicots in the form of vascular cambium. The
activity of this cambium results in the formation of secondary growth.
c) Intercalary Meristem - This meristem is located in between permanent tissues. It is usually present
at the base of node, inter node and on leaf base. They are responsible for growth in length of the
plant.This adds growth in the girth of stem.
The cells of meristematic tissues are similar in structure and have thin and elastic primary cell wall made up of
cellulose. They are compactly arranged without inter-cellular spaces between them. Each cell contains a dense
cytoplasm and a prominent nucleus. Dense protoplasm of meristematic cells contains very few vacuoles. Normally
the meristematic cells are oval, polygonal or rectangular in shape.
Meristemetic tissue cells have a large nucleus with small or no vacuoles, they have no inter cellular spaces.

Permanent tissues
The meristematic tissues that take up a specific role lose the ability to divide. This process of taking up a permanent
shape, size and a function is called cellular differentiation. Cells of meristematic tissue differentiate to form different
types of permanent tissue. There are 3 types of permanent tissues:
1. simple permanent tissues
2. complex permanent tissues
3. special or secretory tissues (glandular)

Simple permanent tissues


These tissues are called simple because they are composed of similar types of cells which have common origin and
function. They are further classified into:
1. Parenchyma
2. Collenchyma
3. Sclerenchyma
4. Epidermis

Parenchyma
Parenchyma (para - beside ;chyma - in filling) is a term used to describe a bulk of a substance. It is used in different
ways in animals and in plants. It consists of relatively unspecialised cells with thin cell walls. They are live cells.
They are usually loosely packed, so that large spaces between cells(intercellular spaces)are found in this tissue. This
tissue provides support to plants and also stores food.In some situations, it contains chlorophyll and performs
photosynthesis, and then it is called chlorenchyma. In aquatic plants,large air cavities are present in parenchyma to
give support to them to float on water. Such a parenchyma type is called aerenchyma.
Tissue (biology) 412

Collenchyma

Collenchyma is Greek word where "Collen" means gum and


"enchyma" means infusion. It is a living tissue of primary body like
Parenchyma. Cells are thin-walled but possess thickening of cellulose
and pectin substances at the corners where number of cells join
together. This tissue gives a tensile strength to the plant and the cells
are compactly arranged and do not have inter-cellular spaces. It occurs
chiefly in hypodermis of stems and leaves. It is absent in monocots and
in roots.

Collenchymatous tissue acts as a supporting tissue in stems of young Cross section of collenchyma cells
plants. It provides mechanical support, elasticity, and tensile strength
to the plant body. It helps in manufacturing sugar and storing it as starch. It is present in margin of leaves and resist
tearing effect of the wind.

Sclerenchyma
Sclerenchyma is Greek word where "Sclrenes" means hard and "enchyma" means infusion. This tissue consists of
thick-walled, dead cells. These cells have hard and extremely thick secondary walls due to uniform distribution of
lignin. Lignin deposition is so thick that the cell walls become strong, rigid and impermeable to water.
Sclerenchymatous cells are closely packed without inter-cellular spaces between them. Thus, they appear as
hexagonal net in transverse section. The cells are cemented with the help of lamella. The middle lamella is a wall
that lies between adjacent cells. Sclerenchymatous cells mainly occur in hypodermis, pericycle, secondary xylem and
phloem. They also occur in endocorp of almond and coconut. It is made of pectin, lignin, protein. The cells of
sclerenchymatous cells can be classified as :
1. Fibres- Fibres are long, elongated sclerenchymatous cells with pointed ends.
2. Sclerides- Sclerenchymatous cells which are short and possess extremely thick, lamellated, lignified walls with
long singular piths. They are called sclerides.
The main function of Sclerenchymatous tissues is to give support to the plant.

Epidermis
The entire surface of the plant consists of a single layer of cells called epidermis or surface tissue. The entire surface
of the plant has this outer layer of epidermis. Hence it is also called surface tissue. Most of the epidermal cells are
relatively flat. the outer and lateral walls of the cell are often thicker than the inner walls. The cells forms a
continuous sheet without inter cellular spaces. It protects all parts of the plant.

Complex permanent tissue


The complex tissue consists of more than one type of cells which work together as a unit. Complex tissues help in
the transportation of organic material,water and mineral up and down the plants. That is why it is also known as
conducting and vascular tissue. The common types of complex permanent tissue are:
• Xylem or wood
• Phloem or bast
Xylem and phloem together form vascular bundles.
Tissue (biology) 413

Xylem
Xylem consists of:
• Tracheid
• Trachea
• Xylem fibers
• Xylem parenchyma
Xylem is a chief, conducting tissue of vascular plants. It is responsible for conduction of water and mineral ions.
Xylem is a very important plant tissue as it is part of the ‘plumbing’ of a plant. Think of bundles of pipes running
along the main axis of stems and roots. It carries water and dissolved substances throughout and consists of a
combination of parenchyma cells, fibers, vessels, tracheids and ray cells. Long tubes made up of individual cells are
the vessels, while vessel members are open at each end. Internally, there may be bars of wall material extending
across the open space. These cells are joined end to end to form long tubes. Vessel members and tracheids are dead
at maturity. Tracheids have thick secondary cell walls and are tapered at the ends. They do not have end openings
such as the vessels. The tracheids ends overlap with each other, with pairs of pits present. The pit pairs allow water
to pass from cell to cell. While most conduction in the xylem is up and down, there is some side-to-side or lateral
conduction via rays. Rays are horizontal rows of long-living parenchyma cells that arise out of the vascular
cambium. In trees, and other woody plants, ray will radiate out from the center of stems and roots and in
cross-section will look like the spokes of a wheel.

Phloem
Phloem consists of:
• Sieve tube
• Sieve cell
• Companion cell
• Phloem fiber
• Phloem parenchyma
Phloem is an equally important plant tissue as it also is part of the ‘plumbing’ of a plant. Primarily, phloem carries
dissolved food substances throughout the plant. This conduction system is composed of sieve-tube member and
companion cells, that are without secondary walls. The parent cells of the vascular cambium produce both xylem and
phloem. This usually also includes fibers, parenchyma and ray cells. Sieve tubes are formed from sieve-tube
members laid end to end. The end walls, unlike vessel members in xylem, do not have openings. The end walls,
however, are full of small pores where cytoplasm extends from cell to cell. These porous connections are called
sieve plates. In spite of the fact that their cytoplasm is actively involved in the conduction of food materials,
sieve-tube members do not have nuclei at maturity. It is the companion cells that are nestled between sieve-tube
members that function in some manner bringing about the conduction of food. Sieve-tube members that are alive
contain a polymer called callose. Callose stays in solution as long at the cell contents are under pressure. As a repair
mechanism, if an insect injures a cell and the pressure drops, the callose will precipitate. However, the callose and a
phloem protein will be moved through the nearest sieve plate where they will form a plug. This prevents further
leakage of sieve tube contents and the injury is not necessarily fatal to overall plant turgor pressure. Phloem
transports food and materials in plants in upwards and downwards as required.
Tissue (biology) 414

References
• Raven, Peter H., Evert, Ray F., & Eichhorn, Susan E. (1986). Biology of Plants (4th ed.). New York: Worth
Publishers. ISBN 0-87901-315-X.

External links
• List of tissues in ExPASy (http://www.expasy.org/cgi-bin/lists?tisslist.txt)

Virology
Virology is the study of viruses and virus-like agents: their structure, classification and evolution, their ways to
infect and exploit host cells for virus reproduction, their interaction with host organism physiology and immunity,
the diseases they cause, the techniques to isolate and culture them, and their use in research and therapy. Virology is
considered to be a subfield of microbiology or of medicine.

Virus structure and classification


A major branch of virology is virus classification. Viruses can be classified according to the host cell they infect:
animal viruses, plant viruses, fungal viruses, and bacteriophages (viruses infecting bacteria, which include the most
complex viruses). Another classification uses the geometrical shape of their capsid (often a helix or an icosahedron)
or the virus's structure (e.g. presence or absence of a lipid envelope). Viruses range in size from about 30 nm to
about 450 nm, which means that most of them cannot be seen with light microscopes. The shape and structure of
viruses has been studied by electron microscopy, NMR spectroscopy, and X-ray crystallography.
The most useful and most widely used classification system distinguishes viruses according to the type of nucleic
acid they use as genetic material and the viral replication method they employ to coax host cells into producing more
viruses:
• DNA viruses (divided into double-stranded DNA viruses and single-stranded DNA viruses),
• RNA viruses (divided into positive-sense single-stranded RNA viruses, negative-sense single-stranded RNA
viruses and the much less common double-stranded RNA viruses),
• reverse transcribing viruses (double-stranded reverse-transcribing DNA viruses and single-stranded
reverse-transcribing RNA viruses including retroviruses).
The latest report by the International Committee on Taxonomy of Viruses (2005) lists 5450 viruses, organized in
over 2,000 species, 287 genera, 73 families and 3 orders.
Virologists also study subviral particles, infectious entities notably smaller and simpler than viruses:
• viroids (naked circular RNA molecules infecting plants),
• satellites (nucleic acid molecules with or without a capsid that require a helper virus for infection and
reproduction), and
• prions (proteins that can exist in a pathological conformation that induces other prion molecules to assume that
same conformation).
Taxa in virology are not necessarily monophyletic, as the evolutionary relationships of the various virus groups
remain unclear. Three hypotheses regarding their origin exist:
1. Viruses arose from non-living matter, separately from yet in parallel to cells, perhaps in the form of
self-replicating RNA ribozymes similar to viroids.
2. Viruses arose by genome reduction from earlier, more competent cellular life forms that became parasites to host
cells and subsequently lost most of their functionality; examples of such tiny parasitic prokaryotes are
Virology 415

Mycoplasma and Nanoarchaea.


3. Viruses arose from mobile genetic elements of cells (such as transposons, retrotransposons or plasmids) that
became encapsulated in protein capsids, acquired the ability to "break free" from the host cell and infect other
cells.
Of particular interest here is mimivirus, a giant virus that infects amoebae and encodes much of the molecular
machinery traditionally associated with bacteria. Is it a simplified version of a parasitic prokaryote, or did it originate
as a simpler virus that acquired genes from its host?
The evolution of viruses, which often occurs in concert with the evolution of their hosts, is studied in the field of
viral evolution.
While viruses reproduce and evolve, they do not engage in metabolism, do not move, and depend on a host cell for
reproduction. The often-debated question of whether they are alive or not is a matter of definition that does not affect
the biological reality of viruses.

Viral diseases and host defenses


One main motivation for the study of viruses is the fact that they cause many important infectious diseases, among
them the common cold, influenza, rabies, measles, many forms of diarrhea, hepatitis, Dengue fever, yellow fever,
polio, smallpox and AIDS. Herpes simplex causes cold sores and genital herpes and is under investigation as a
possible factor in Alzheimer's.
Some viruses, known as oncoviruses, contribute to the development of certain forms of cancer. The best studied
example is the association between Human papillomavirus and cervical cancer: almost all cases of cervical cancer
are caused by certain strains of this sexually transmitted virus. Another example is the association of infection with
hepatitis B and hepatitis C viruses and liver cancer.
Some subviral particles also cause disease: the transmissible spongiform encephalopathies, which include Kuru,
Creutzfeldt-Jakob disease and bovine spongiform encephalopathy ("mad cow disease"), are caused by prions, and
hepatitis D is due to a satellite virus.
The study of the manner in which viruses cause disease is viral pathogenesis. The degree to which a virus causes
disease is its virulence.
When the immune system of a vertebrate encounters a virus, it may produce specific antibodies which bind to the
virus and neutralize its infectivity or mark it for destruction. Antibody presence in blood serum is often used to
determine whether a person has been exposed to a given virus in the past, with tests such as ELISA. Vaccinations
protect against viral diseases, in part, by eliciting the production of antibodies. Monoclonal antibodies, specific to the
virus, are also used for detection, as in fluorescence microscopy.
A second defense of vertebrates against viruses, cell-mediated immunity, involves immune cells known as T cells:
the body's cells constantly display short fragments of their proteins on the cell's surface, and if a T cell recognizes a
suspicious viral fragment there, the host cell is destroyed and the virus-specific T-cells proliferate. This mechanism
is jump-started by certain vaccinations.
RNA interference, an important cellular mechanism found in plants, animals and many other eukaryotes, most likely
evolved as a defense against viruses. An elaborate machinery of interacting enzymes detects double-stranded RNA
molecules (which occur as part of the life cycle of many viruses) and then proceeds to destroy all single-stranded
versions of those detected RNA molecules.
Every lethal viral disease presents a paradox: killing its host is obviously of no benefit to the virus, so how and why
did it evolve to do so? Today it is believed that most viruses are relatively benign in their natural hosts; some viral
infection might even be beneficial to the host.[1] The lethal viral diseases are believed to have resulted from an
"accidental" jump of the virus from a species in which it is benign to a new one that is not accustomed to it (see
zoonosis). For example, viruses that cause serious influenza in humans probably have pigs or birds as their natural
Virology 416

host, and HIV is thought to derive from the benign non-human primate virus SIV.
While it has been possible to prevent (certain) viral diseases by vaccination for a long time, the development of
antiviral drugs to treat viral diseases is a comparatively recent development. The first such drug was interferon, a
substance that is naturally produced by certain immune cells when an infection is detected and stimulates other parts
of the immune system.

Molecular biology research and viral therapy


Bacteriophages, the viruses which infect bacteria, can be relatively easily grown as viral plaques on bacterial
cultures. Bacteriophages occasionally move genetic material from one bacterial cell to another in a process known as
transduction, and this horizontal gene transfer is one reason why they served as a major research tool in the early
development of molecular biology. The genetic code, the function of ribozymes, the first recombinant DNA and
early genetic libraries were all arrived at using bacteriophages. Certain genetic elements derived from viruses, such
as highly effective promoters, are commonly used in molecular biology research today.
Growing animal viruses outside of the living host animal is more difficult. Classically, fertilized chicken eggs have
often been used, but cell cultures are increasingly employed for this purpose today.
Since some viruses that infect eukaryotes need to transport their genetic material into the host cell's nucleus, they are
attractive tools for introducing new genes into the host (known as transformation or transfection). Modified
retroviruses are often used for this purpose, as they integrate their genes into the host's chromosomes.
This approach of using viruses as gene vectors is being pursued in the gene therapy of genetic diseases. An obvious
problem to be overcome in viral gene therapy is the rejection of the transforming virus by the immune system.
Phage therapy, the use of bacteriophages to combat bacterial diseases, was a popular research topic before the advent
of antibiotics and has recently seen renewed interest.
Oncolytic viruses are viruses that preferably infect cancer cells. While early efforts to employ these viruses in the
therapy of cancer failed, there have been reports in 2005 and 2006 of encouraging preliminary results.[2]

Other uses of viruses


A new application of genetically engineered viruses in nanotechnology was recently described; see the uses of
viruses in material science and nanotechnology. For a use in mapping neurons see the applications of pseudorabies in
neuroscience.

History of virology
The word virus appeared in 1599 and originally meant "venom".[3]
A very early form of vaccination known as variolation was developed several thousand years ago in China. It
involved the application of materials from smallpox sufferers in order to immunize others. In 1717 Lady Mary
Wortley Montagu observed the practice in Istanbul and attempted to popularize it in Britain, but encountered
considerable resistance. In 1796 Edward Jenner developed a much safer method, using cowpox to successfully
immunize a young boy against smallpox, and this practice was widely adopted. Vaccinations against other viral
diseases followed, including the successful rabies vaccination by Louis Pasteur in 1886. The nature of viruses
however was not clear to these researchers.
Virology 417

In 1892 Dimitri Ivanovski showed that a disease of tobacco plants,


tobacco mosaic disease, could be transmitted by extracts that were
passed through filters fine enough to exclude even the smallest known
bacteria. In 1898 Martinus Beijerinck repeated Iwanowski's work but
went further and passed the "filterable agent" from plant to plant, found
the action undiminished, and concluded it infectious—replicating in
the host—and thus not a mere toxin. He called it contagium vivum
fluidum.[4] The question of whether the agent was a "living fluid" or a
particle was however still open.

In 1903 it was suggested for the first time that transduction by viruses
might cause cancer. In 1908 Bang and Ellerman showed that a
filterable virus could transmit chicken leukemia, data largely ignored
till the 1930s when leukemia became regarded as cancerous.[5] In 1911
Peyton Rous reported the transmission of chicken sarcoma, a solid
tumor, with a virus, and thus Rous became "father of tumor
virology".[5] The virus was later called Rous sarcoma virus 1 and
understood to be a retrovirus. Several other cancer-causing retroviruses Martinus Beijerinck
have since been described.

The existence of viruses that infect bacteria (bacteriophages) was first recognized by Frederick Twort in 1911, and,
independently, by Felix d'Herelle in 1917. As bacteria could be grown easily in culture, this led to an explosion of
virology research.
The cause of the devastating Spanish flu pandemic of 1918 was initially unclear. In late 1918, French scientists
showed that a "filter-passing virus" could transmit the disease to people and animals, fulfilling Koch's postulates.[6]
While plant viruses and bacteriophages can be grown comparatively easily, animal viruses normally require a living
host animal, which complicates their study immensely. In 1931 it was shown that influenza virus could be grown in
fertilized chicken eggs, a method that is still used today to produce vaccines. In 1937, Max Theiler managed to grow
the yellow fever virus in chicken eggs and produced a vaccine from an attenuated virus strain; this vaccine saved
millions of lives and is still being used today.
Max Delbrück, an important investigator in the area of bacteriophages, described the basic "life cycle" of a virus in
1937: rather than "growing", a virus particle is assembled from its constituent pieces in one step; eventually it leaves
the host cell to infect other cells. The Hershey-Chase experiment in 1952 showed that only DNA and not protein
enters a bacterial cell upon infection with bacteriophage T2. Transduction of bacteria by bacteriophages was first
described in the same year.
In 1949 John F. Enders, Thomas Weller and Frederick Robbins reported growth of poliovirus in cultured human
embryonal cells, the first significant example of an animal virus grown outside of animals or chicken eggs. This
work aided Jonas Salk in deriving a polio vaccine from deactivated polio viruses; this vaccine was shown to be
effective in 1955.
The first virus that could be crystalized and whose structure could therefore be elucidated in detail was tobacco
mosaic virus (TMV), the virus that had been studied earlier by Ivanovski and Beijerink. In 1935, Wendell Stanley
achieved its crystallization for electron microscopy and showed that it remains active even after crystallization. Clear
X-ray diffraction pictures of the crystallized virus were obtained by Bernal and Fankuchen in 1941. Based on such
pictures, Rosalind Franklin proposed the full structure of the tobacco mosaic virus in 1955. Also in 1955, Heinz
Fraenkel-Conrat and Robley Williams showed that purified TMV RNA and its capsid (coat) protein can
self-assemble into functional virions, suggesting that this assembly mechanism is also used within the host cell, as
Delbrück had proposed earlier.
Virology 418

In 1963, the Hepatitis B virus was discovered by Baruch Blumberg who went on to develop a hepatitis B vaccine.
In 1965, Howard Temin described the first retrovirus: a virus whose RNA genome was reverse transcribed into
complementary DNA (cDNA), then integrated into the host's genome and expressed from that template. The viral
enzyme reverse transcriptase, which along with integrase is a distinguishing trait of retroviruses, was first described
in 1970, independently by Howard Temin and David Baltimore. The first retrovirus infecting humans was identified
by Robert Gallo in 1974. Later it was found that reverse transcriptase is not specific to retroviruses; retrotransposons
which code for reverse transcriptase are abundant in the genomes of all eukaryotes. About 10-40% of the human
genome derives from such retrotransposons.
In 1975 the functioning of oncoviruses was clarified considerably. Until that time, it was thought that these viruses
carried certain genes called oncogenes which, when inserted into the host's genome, would cause cancer. Michael
Bishop and Harold Varmus showed that the oncogene of Rous sarcoma virus is in fact not specific to the virus but is
contained in the genome of healthy animals of many species. The oncovirus can switch this pre-existing benign
proto-oncogene on, turning it into a true oncogene that causes cancer.
1976 saw the first recorded outbreak of Ebola hemorrhagic fever, a highly lethal virally transmitted disease.
In 1977, Frederick Sanger achieved the first complete sequencing of the genome of any organism, the bacteriophage
Phi X 174. In the same year, Richard Roberts and Phillip Sharp independently showed that the genes of adenovirus
contain introns and therefore require gene splicing. It was later realized that almost all genes of eukaryotes have
introns as well.
A worldwide vaccination campaign led by the UN World Health Organization resulted in the eradication of smallpox
in 1979.
In 1982, Stanley Prusiner discovered prions and showed that they cause scrapie.
The first cases of AIDS were reported in 1981, and HIV, the retrovirus causing it, was identified in 1983 by Robert
Gallo and Luc Montagnier. Tests detecting HIV infection by detecting the presence of HIV antibody were
developed. Subsequent tremendous research efforts turned HIV into the best studied virus. Human Herpes Virus 8,
the cause of Kaposi's sarcoma which is often seen in AIDS patients, was identified in 1994. Several antiretroviral
drugs were developed in the late 1990s, decreasing AIDS mortality dramatically in developed countries.
The Hepatitis C virus was identified using novel molecular cloning techniques in 1987, leading to screening tests
that dramatically reduced the incidence of post-transfusion hepatitis.[7]
The first attempts at gene therapy involving viral vectors began in the early 1980s, when retroviruses were developed
that could insert a foreign gene into the host's genome. They contained the foreign gene but did not contain the viral
genome and therefore could not reproduce. Tests in mice were followed by tests in humans, beginning in 1989. The
first human studies attempted to correct the genetic disease severe combined immunodeficiency (SCID), but clinical
success was limited. In the period from 1990 to 1995, gene therapy was tried on several other diseases and with
different viral vectors, but it became clear that the initially high expectations were overstated. In 1999 a further
setback occurred when 18-year-old Jesse Gelsinger died in a gene therapy trial. He suffered a severe immune
response after having received an adenovirus vector. Success in the gene therapy of two cases of X-linked SCID was
reported in 2000.[8]
In 2002 it was reported that poliovirus had been synthetically assembled in the laboratory, representing the first
synthetic organism. Assembling the 7741-base genome from scratch, starting with the virus's published RNA
sequence, took about two years. In 2003 a faster method was shown to assemble the 5386-base genome of the
bacteriophage Phi X 174 in 2 weeks.
The giant mimivirus, in some sense an intermediate between tiny prokaryotes and ordinary viruses, was described in
2003 and sequenced in 2004.
The strain of Influenza A virus subtype H1N1 that killed up to 50 million people during the Spanish flu pandemic in
1918 was reconstructed in 2005. Sequence information was pieced together from preserved tissue samples of flu
Virology 419

victims; viable virus was then synthesized from this sequence.[9] The 2009 flu pandemic involved another strain of
Influenza A H1N1, commonly known as "swine flu".
By 1985, Harald zur Hausen had shown that two strains of Human papillomavirus (HPV) cause most cases of
cervical cancer. Two vaccines protecting against these strains were released in 2006.
In 2006 and 2007 it was reported that introducing a small number of specific transcription factor genes into normal
skin cells of mice or humans can turn these cells into pluripotent stem cells, known as Induced Pluripotent Stem
Cells. The technique uses modified retroviruses to transform the cells; this is a potential problem for human therapy
since these viruses integrate their genes at a random location in the host's genome, which can interrupt other genes
and potentially causes cancer.[10]
In 2008, Sputnik virophage was described, the first known virophage: it uses the machinery of a helper virus to
reproduce and inhibits reproduction of that helper virus. Sputnik reproduces in amoeba infected by mamavirus, a
relative of the mimivirus mentioned above and the largest known virus to date.[11]

References
[1] Dimmock NJ, Easton AJ, Leppard K, Introduction to Modern Virology, (Oxford: Blackwell Publishers, 2007), ch 23 "Horizons in human
virology", subch 23.3 "Subtle and insidious virus-host interactions", sec "Virus infections can give their host an evolutionary advantage", p
432 (http:/ / books. google. com/ books?id=E3ntv9XwsFwC& pg=PA432).
[2] Viruses: The new cancer hunters (http:/ / www. isracast. com/ tech_news/ 260106_tech. aspx), IsraCast, 1 March 2006
[3] "Virus" (http:/ / www. merriam-webster. com/ dictionary/ virus), Merriam-Webster, Inc, 2011.
[4] Pennazio S (2007). "Genetics and virology: Two interdisciplinary branches of biology". Rivista di Bilogia 100 (1): 119–46. PMID 17592822.
[5] Van Epps HL (2005). "Peyton Rous: Father of the tumor virus" (http:/ / jem. rupress. org/ content/ 201/ 3/ 320. full. pdf). Journal of
Experimental Medicine 201 (3): 320. doi:10.1084/jem.2013fta. PMC 2213042. PMID 15756727. .
[6] The Medical and Scientific Conceptions of Influenza (http:/ / virus. stanford. edu/ uda/ fluscimed. html), Human Virology at Stanford
[7] 2000 Albert Lasker Award for Clinical Medical Research (http:/ / www. laskerfoundation. org/ awards/ library/ 2000c_cit. shtml), The Lasker
Foundation. Accessed 20 February 2008
[8] Zeger Debyser. A Short Course on Virology / Vectorology / Gene Therapy (http:/ / www. ohsu. edu/ nod/ documents/ week1/ short.
vectorology. pdf), Current Gene Therapy, 2003, 3, 495-499
[9] Kolata, Gina (2005-10-06). "Experts Unlock Clues to Spread of 1918 Flu Virus" (http:/ / www. nytimes. com/ 2005/ 10/ 06/ health/ 06flu.
html?pagewanted=2). The New York Times. ISSN 0362-4331. . Retrieved 2008-02-03.
[10] Stem Cells—This Time without the Cancer (http:/ / www. sciam. com/ article. cfm?id=stem-cells-without-cancer), Scientific American
News, 30 November 2007
[11] "Biggest Known Virus Yields First-Ever Virophage" (http:/ / forms. asm. org/ microbe/ index. asp?bid=61386). Microbe Magazine.
November 2008. .
• Villarreal, L. P. (2005) Viruses and the Evolution of Life. ASM Press, Washington DC ISBN 1-55581-309-7

• Samuel Baron (ed.) (1996) Medical Microbiology, 4th ed., Section 2: Virology (http://www.ncbi.nlm.nih.gov/books/bv.
fcgi?rid=mmed.part.5437) (freely searchable online book)
• Coffin, Hughes, Varmus. (1997) Retroviruses (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..
ShowTOC&rid=rv.TOC&depth=10) (freely searchable online book)

External links and sources


• ICTV: International Committee on Taxonomy of Viruses (http://www.ictvonline.org/) - searchable virus
taxonomy, updated versions in 2007 and 2008. Explanations of the virus species concept and viral taxonomy.
• David Sander: All the Virology on the WWW (http://www.virology.net/) - collection of links, pictures, lecture
notes. Many of the links on this site are broken and it does not appear to be being maintained.
• Online lectures in virology (http://media.med.sc.edu/microbiology2007/) University of South Carolina
• MicrobiologyBytes: Origins of Virology (http://www.microbiologybytes.com/introduction/introduction.html)
• MicrobiologyBytes: The Virology Time Machine (http://www.microbiologybytes.com/tutorials/Time/
Machine.html)
Virology 420

• Timeline of the history of virology (http://medicine.wustl.edu/~virology/timeline.htm), from the Washington


University in St. Louis.
• Wong's Virology (http://virology-online.com).
• Vaccine Research Center (VRC) (http://www.vrc.nih.gov) - Information concerning vaccine research studies
• This Week in Virology Podcast by Vincent Racaniello (http://www.twiv.tv/)
Virus 421

Virus
Viruses

Rotavirus

Virus classification
Group: I–VII
Groups
I: dsDNA viruses
II: ssDNA viruses
III: dsRNA viruses
IV: (+)ssRNA viruses
V: (−)ssRNA viruses
VI: ssRNA-RT viruses
VII: dsDNA-RT viruses

A virus is a small infectious agent that can replicate only inside the living cells of an organism. Viruses can infect all
types of organisms, from animals and plants to bacteria and archaea.[1]
Since Dmitri Ivanovsky's 1892 article describing a non-bacterial pathogen infecting tobacco plants, and the
discovery of the tobacco mosaic virus by Martinus Beijerinck in 1898,[2] about 5,000 viruses have been described in
detail,[3] although there are millions of different types.[4] Viruses are found in almost every ecosystem on Earth and
are the most abundant type of biological entity.[5][6] The study of viruses is known as virology, a sub-speciality of
microbiology.
Virus particles (known as virions) consist of two or three parts: the genetic material made from either DNA or RNA,
long molecules that carry genetic information; a protein coat that protects these genes; and in some cases an
envelope of lipids that surrounds the protein coat when they are outside a cell. The shapes of viruses range from
simple helical and icosahedral forms to more complex structures. The average virus is about one one-hundredth the
size of the average bacterium. Most viruses are too small to be seen directly with an optical microscope.
The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids – pieces
of DNA that can move between cells – while others may have evolved from bacteria. In evolution, viruses are an
important means of horizontal gene transfer, which increases genetic diversity.[7]
Viruses spread in many ways; viruses in plants are often transmitted from plant to plant by insects that feed on plant
sap, such as aphids; viruses in animals can be carried by blood-sucking insects. These disease-bearing organisms are
known as vectors. Influenza viruses are spread by coughing and sneezing. Norovirus and rotavirus, common causes
of viral gastroenteritis, are transmitted by the faecal-oral route and are passed from person to person by contact,
Virus 422

entering the body in food or water. HIV is one of several viruses transmitted through sexual contact and by exposure
to infected blood. The range of host cells that a virus can infect is called its "host range". This can be narrow or, as
when a virus is capable of infecting many species, broad.[8]
Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune
responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral
infection. However, some viruses including those that cause AIDS and viral hepatitis evade these immune responses
and result in chronic infections. Antibiotics have no effect on viruses, but several antiviral drugs have been
developed.

Etymology
The word is from the Latin virus referring to poison and other noxious substances, first used in English in 1392.[9]
Virulent, from Latin virulentus (poisonous), dates to 1400.[10] A meaning of "agent that causes infectious disease" is
first recorded in 1728,[9] before the discovery of viruses by Dmitri Ivanovsky in 1892. The plural is viruses. The
adjective viral dates to 1948.[11] The term virion (plural virions), which dates from 1959,[12] is also used to refer to a
single, stable infective viral particle that is released from the cell and is fully capable of infecting other cells of the
same type.[13]

History
Louis Pasteur was unable to find a causative agent for rabies and
speculated about a pathogen too small to be detected using a
microscope.[14] In 1884, the French microbiologist Charles
Chamberland invented a filter (known today as the Chamberland filter
or Chamberland-Pasteur filter) with pores smaller than bacteria. Thus,
he could pass a solution containing bacteria through the filter and
completely remove them from the solution.[15] In 1892, the Russian
biologist Dmitri Ivanovsky used this filter to study what is now known
as the tobacco mosaic virus. His experiments showed that crushed leaf
extracts from infected tobacco plants remain infectious after filtration.
Ivanovsky suggested the infection might be caused by a toxin produced
by bacteria, but did not pursue the idea.[16] At the time it was thought
that all infectious agents could be retained by filters and grown on a
nutrient medium – this was part of the germ theory of disease.[2] In
1898, the Dutch microbiologist Martinus Beijerinck repeated the
experiments and became convinced that the filtered solution contained
Martinus Beijerinck in his laboratory in 1921
a new form of infectious agent.[17] He observed that the agent
multiplied only in cells that were dividing, but as his experiments did
not show that it was made of particles, he called it a contagium vivum fluidum (soluble living germ) and
re-introduced the word virus.[16] Beijerinck maintained that viruses were liquid in nature, a theory later discredited
by Wendell Stanley, who proved they were particulate.[16] In the same year Friedrich Loeffler and Frosch passed the
first animal virus – agent of foot-and-mouth disease (aphthovirus) – through a similar filter.[13]

In the early 20th century, the English bacteriologist Frederick Twort discovered a group of viruses that infect
bacteria, now called bacteriophages[18] (or commonly phages), and the French-Canadian microbiologist Félix
d'Herelle described viruses that, when added to bacteria on agar, would produce areas of dead bacteria. He accurately
diluted a suspension of these viruses and discovered that the highest dilutions (lowest virus concentrations), rather
than killing all the bacteria, formed discrete areas of dead organisms. Counting these areas and multiplying by the
Virus 423

dilution factor allowed him to calculate the number of viruses in the original suspension.[19] Phages were heralded as
a potential treatment for diseases such as typhoid and cholera, but their promise was forgotten with the development
of penicillin. The study of phages provided insights into the switching on and off of genes, and a useful mechanism
for introducing foreign genes into bacteria.
By the end of the 19th century, viruses were defined in terms of their infectivity, their ability to be filtered, and their
requirement for living hosts. Viruses had been grown only in plants and animals. In 1906, Ross Granville Harrison
invented a method for growing tissue in lymph, and, in 1913, E. Steinhardt, C. Israeli, and R. A. Lambert used this
method to grow vaccinia virus in fragments of guinea pig corneal tissue.[20] In 1928, H. B. Maitland and M. C.
Maitland grew vaccinia virus in suspensions of minced hens' kidneys. Their method was not widely adopted until the
1950s, when poliovirus was grown on a large scale for vaccine production.[21]
Another breakthrough came in 1931, when the American pathologist Ernest William Goodpasture grew influenza
and several other viruses in fertilized chickens' eggs.[22] In 1949, John Franklin Enders, Thomas Weller, and
Frederick Robbins grew polio virus in cultured human embryo cells, the first virus to be grown without using solid
animal tissue or eggs. This work enabled Jonas Salk to make an effective polio vaccine.[23]
The first images of viruses were obtained upon the invention of electron microscopy in 1931 by the German
engineers Ernst Ruska and Max Knoll.[24] In 1935, American biochemist and virologist Wendell Meredith Stanley
examined the tobacco mosaic virus and found it was mostly made of protein.[25] A short time later, this virus was
separated into protein and RNA parts.[26] The tobacco mosaic virus was the first to be crystallised and its structure
could therefore be elucidated in detail. The first X-ray diffraction pictures of the crystallised virus were obtained by
Bernal and Fankuchen in 1941. On the basis of her pictures, Rosalind Franklin discovered the full DNA structure of
the virus in 1955.[27] In the same year, Heinz Fraenkel-Conrat and Robley Williams showed that purified tobacco
mosaic virus RNA and its coat protein can assemble by themselves to form functional viruses, suggesting that this
simple mechanism was probably the means through which viruses were created within their host cells.[28]
The second half of the 20th century was the golden age of virus discovery and most of the over 2,000 recognised
species of animal, plant, and bacterial viruses were discovered during these years.[29] In 1957, equine arterivirus and
the cause of Bovine virus diarrhea (a pestivirus) were discovered. In 1963, the hepatitis B virus was discovered by
Baruch Blumberg,[30] and in 1965, Howard Temin described the first retrovirus. Reverse transcriptase, the key
enzyme that retroviruses use to translate their RNA into DNA, was first described in 1970, independently by Howard
Martin Temin and David Baltimore.[31] In 1983 Luc Montagnier's team at the Pasteur Institute in France, first
isolated the retrovirus now called HIV.[32]

Origins
Viruses are found wherever there is life and have probably existed since living cells first evolved.[33] The origin of
viruses is unclear because they do not form fossils, so molecular techniques have been used to compare the DNA or
RNA of viruses and are a useful means of investigating how they arose.[34] There are three main hypotheses that try
to explain the origins of viruses:[35][36]
Regressive hypothesis
Viruses may have once been small cells that parasitised larger cells. Over time, genes not required by their
parasitism were lost. The bacteria rickettsia and chlamydia are living cells that, like viruses, can reproduce
only inside host cells. They lend support to this hypothesis, as their dependence on parasitism is likely to have
caused the loss of genes that enabled them to survive outside a cell. This is also called the degeneracy
hypothesis,[37][38] or reduction hypothesis.[39]
Cellular origin hypothesis
Some viruses may have evolved from bits of DNA or RNA that "escaped" from the genes of a larger organism.
The escaped DNA could have come from plasmids (pieces of naked DNA that can move between cells) or
Virus 424

transposons (molecules of DNA that replicate and move around to different positions within the genes of the
cell).[40] Once called "jumping genes", transposons are examples of mobile genetic elements and could be the
origin of some viruses. They were discovered in maize by Barbara McClintock in 1950.[41] This is sometimes
called the vagrancy hypothesis,[37][42] or the escape hypothesis.[39]
Coevolution hypothesis
This is also called the virus-first hypothesis[39] and proposes that viruses may have evolved from complex
molecules of protein and nucleic acid at the same time as cells first appeared on earth and would have been
dependent on cellular life for billions of years. Viroids are molecules of RNA that are not classified as viruses
because they lack a protein coat. However, they have characteristics that are common to several viruses and
are often called subviral agents.[43] Viroids are important pathogens of plants.[44] They do not code for
proteins but interact with the host cell and use the host machinery for their replication.[45] The hepatitis delta
virus of humans has an RNA genome similar to viroids but has a protein coat derived from hepatitis B virus
and cannot produce one of its own. It is, therefore, a defective virus and cannot replicate without the help of
hepatitis B virus.[46] In similar manner, the sputnik virophage is dependent on mimivirus, which infects the
protozoan Acanthamoeba castellanii.[47] These viruses that are dependent on the presence of other virus
species in the host cell are called satellites and may represent evolutionary intermediates of viroids and
viruses.[48][49]
In the past, there were problems with all of these hypotheses: the regressive hypothesis did not explain why even the
smallest of cellular parasites do not resemble viruses in any way. The escape hypothesis did not explain the complex
capsids and other structures on virus particles. The virus-first hypothesis contravened the definition of viruses in that
they require host cells.[39] Viruses are now recognised as ancient and to have origins that pre-date the divergence of
life into the three domains.[50] This discovery has led modern virologists to reconsider and re-evaluate these three
classical hypotheses.[50]
The evidence for an ancestral world of RNA cells[51] and computer analysis of viral and host DNA sequences are
giving a better understanding of the evolutionary relationships between different viruses and may help identify the
ancestors of modern viruses. To date, such analyses have not proved which of these hypotheses is correct.[51]
However, it seems unlikely that all currently known viruses have a common ancestor, and viruses have probably
arisen numerous times in the past by one or more mechanisms.[52]
Prions are infectious protein molecules that do not contain DNA or RNA.[53] They can cause infections such as
scrapie in sheep, bovine spongiform encephalopathy ("mad cow" disease) in cattle, and chronic wasting disease in
deer; in humans prionic diseases include Kuru, Creutzfeldt–Jakob disease, and Gerstmann–Sträussler–Scheinker
syndrome.[54] They are able to replicate because some proteins can exist in two different shapes and the prion
changes the normal shape of a host protein into the prion shape. This starts a chain reaction where each prion protein
converts many host proteins into more prions, and these new prions then go on to convert even more protein into
prions; all known prion diseases are fatal. Although prions are fundamentally different from viruses and viroids, their
discovery gives credence to the theory that viruses could have evolved from self-replicating molecules.[55]

Microbiology

Life properties
Opinions differ on whether viruses are a form of life, or organic structures that interact with living organisms. They
have been described as "organisms at the edge of life",[56] since they resemble organisms in that they possess genes
and evolve by natural selection,[57] and reproduce by creating multiple copies of themselves through self-assembly.
Although they have genes, they do not have a cellular structure, which is often seen as the basic unit of life. Viruses
do not have their own metabolism, and require a host cell to make new products. They therefore cannot naturally
reproduce outside a host cell[58] – although bacterial species such as rickettsia and chlamydia are considered living
Virus 425

organisms despite the same limitation.[59][60] Accepted forms of life use cell division to reproduce, whereas viruses
spontaneously assemble within cells. They differ from autonomous growth of crystals as they inherit genetic
mutations while being subject to natural selection. Virus self-assembly within host cells has implications for the
study of the origin of life, as it lends further credence to the hypothesis that life could have started as self-assembling
organic molecules.[1]

Structure
Viruses display a wide diversity of shapes and sizes, called
morphologies. In general, viruses are much smaller than bacteria. Most
viruses that have been studied have a diameter between 20 and 300
nanometres. Some filoviruses have a total length of up to 1400 nm;
their diameters are only about 80 nm.[61] Most viruses cannot be seen
with an optical microscope so scanning and transmission electron
microscopes are used to visualise virions.[62] To increase the contrast
between viruses and the background, electron-dense "stains" are used.
These are solutions of salts of heavy metals, such as tungsten, that Diagram of how a virus capsid can be constructed
scatter the electrons from regions covered with the stain. When virions using multiple copies of just two protein
molecules
are coated with stain (positive staining), fine detail is obscured.
Negative staining overcomes this problem by staining the background
only.[63]

A complete virus particle, known as a virion, consists of nucleic acid surrounded by a protective coat of protein
called a capsid. These are formed from identical protein subunits called capsomeres.[64] Viruses can have a lipid
"envelope" derived from the host cell membrane. The capsid is made from proteins encoded by the viral genome and
its shape serves as the basis for morphological distinction.[65][66] Virally coded protein subunits will self-assemble to
form a capsid, in general requiring the presence of the virus genome. Complex viruses code for proteins that assist in
the construction of their capsid. Proteins associated with nucleic acid are known as nucleoproteins, and the
association of viral capsid proteins with viral nucleic acid is called a nucleocapsid. The capsid and entire virus
structure can be mechanically (physically) probed through atomic force microscopy.[67][68] In general, there are four
main morphological virus types:

RNA coiled in a helix of repeating protein sub-units

Electron micrograph of icosahedral adenovirus


Virus 426

Herpes viruses have a lipid envelope

Helical
These viruses are composed of a single type of capsomer stacked around a central axis to form a helical
structure, which may have a central cavity, or hollow tube. This arrangement results in rod-shaped or
filamentous virions: These can be short and highly rigid, or long and very flexible. The genetic material, in
general, single-stranded RNA, but ssDNA in some cases, is bound into the protein helix by interactions
between the negatively charged nucleic acid and positive charges on the protein. Overall, the length of a
helical capsid is related to the length of the nucleic acid contained within it and the diameter is dependent on
the size and arrangement of capsomers. The well-studied tobacco mosaic virus is an example of a helical
virus.[69]
Icosahedral
Most animal viruses are icosahedral or near-spherical with icosahedral symmetry. A regular icosahedron is the
optimum way of forming a closed shell from identical sub-units. The minimum number of identical capsomers
required is twelve, each composed of five identical sub-units. Many viruses, such as rotavirus, have more than
twelve capsomers and appear spherical but they retain this symmetry. Capsomers at the apices are surrounded
by five other capsomers and are called pentons. Capsomers on the triangular faces are surrounded by six others
and are called hexons.[70] Hexons are in essence flat and pentons, which form the 12 vertices, are curved. The
same protein may act as the subunit of both the pentamers and hexamers or they may be composed of different
proteins.
Prolate
This is an isosahedron elongated along the fivefold axis and is a common arrangement of the heads of
bacteriophages. This structure is composed of a cylinder with a cap at either end.[71]
Envelope
Some species of virus envelop themselves in a modified form of one of the cell membranes, either the outer
membrane surrounding an infected host cell or internal membranes such as nuclear membrane or endoplasmic
reticulum, thus gaining an outer lipid bilayer known as a viral envelope. This membrane is studded with
proteins coded for by the viral genome and host genome; the lipid membrane itself and any carbohydrates
present originate entirely from the host. The influenza virus and HIV use this strategy. Most enveloped viruses
are dependent on the envelope for their infectivity.[72]
Complex
These viruses possess a capsid that is neither purely helical nor purely icosahedral, and that may possess extra
structures such as protein tails or a complex outer wall. Some bacteriophages, such as Enterobacteria phage
T4, have a complex structure consisting of an icosahedral head bound to a helical tail, which may have a
hexagonal base plate with protruding protein tail fibres. This tail structure acts like a molecular syringe,
attaching to the bacterial host and then injecting the viral genome into the cell.[73]
The poxviruses are large, complex viruses that have an unusual morphology. The viral genome is associated with
proteins within a central disk structure known as a nucleoid. The nucleoid is surrounded by a membrane and two
Virus 427

lateral bodies of unknown function. The virus has an outer envelope with a thick layer of protein studded over its
surface. The whole virion is slightly pleiomorphic, ranging from ovoid to brick shape.[74] Mimivirus is the largest
characterised virus, with a capsid diameter of 400 nm. Protein filaments measuring 100 nm project from the surface.
The capsid appears hexagonal under an electron microscope, therefore the capsid is probably icosahedral.[75] In
2011, researchers discovered a larger virus on ocean floor of the coast of Las Cruces, Chile. Provisionally named
Megavirus chilensis, it can be seen with a basic optical microscope. [76]
Some viruses that infect Archaea have complex structures that are unrelated to any other form of virus, with a wide
variety of unusual shapes, ranging from spindle-shaped structures, to viruses that resemble hooked rods, teardrops or
even bottles. Other archaeal viruses resemble the tailed bacteriophages, and can have multiple tail structures.[77]

Genome

Genomic diversity among viruses


Property Parameters

Nucleic acid • DNA


• RNA
• Both DNA and RNA (at different stages in the life cycle)

Shape • Linear
• Circular
• Segmented

Strandedness • Single-stranded
• Double-stranded
• Double-stranded with regions of single-strandedness

Sense • Positive sense (+)


• Negative sense (−)
• Ambisense (+/−)

An enormous variety of genomic structures can be seen among viral species; as a group, they contain more structural
genomic diversity than plants, animals, archaea, or bacteria. There are millions of different types of viruses,[4]
although only about 5,000 of them have been described in detail.[3] A virus has either DNA or RNA genes and is
called a DNA virus or a RNA virus, respectively. The vast majority of viruses have RNA genomes. Plant viruses
tend to have single-stranded RNA genomes and bacteriophages tend to have double-stranded DNA genomes.[78]
Viral genomes are circular, as in the polyomaviruses, or linear, as in the adenoviruses. The type of nucleic acid is
irrelevant to the shape of the genome. Among RNA viruses and certain DNA viruses, the genome is often divided up
into separate parts, in which case it is called segmented. For RNA viruses, each segment often codes for only one
protein and they are usually found together in one capsid. However, all segments are not required to be in the same
virion for the virus to be infectious, as demonstrated by brome mosaic virus and several other plant viruses.[61]
A viral genome, irrespective of nucleic acid type, is almost always either single-stranded or double-stranded.
Single-stranded genomes consist of an unpaired nucleic acid, analogous to one-half of a ladder split down the
middle. Double-stranded genomes consist of two complementary paired nucleic acids, analogous to a ladder. The
virus particles of some virus families, such as those belonging to the Hepadnaviridae, contain a genome that is
partially double-stranded and partially single-stranded.[78]
For most viruses with RNA genomes and some with single-stranded DNA genomes, the single strands are said to be
either positive-sense (called the plus-strand) or negative-sense (called the minus-strand), depending on whether or
not they are complementary to the viral messenger RNA (mRNA). Positive-sense viral RNA is in the same sense as
viral mRNA and thus at least a part of it can be immediately translated by the host cell. Negative-sense viral RNA is
complementary to mRNA and thus must be converted to positive-sense RNA by an RNA-dependent RNA
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polymerase before translation. DNA nomenclature for viruses with single-sense genomic ssDNA is similar to RNA
nomenclature, in that the coding strand for the viral mRNA is complementary to it (−), and the non-coding strand is
a copy of it (+).[78] However, several types of ssDNA and ssRNA viruses have genomes that are ambisense in that
transcription can occur off both strands in a double-stranded replicative intermediate. Examples include
geminiviruses, which are ssDNA plant viruses and arenaviruses, which are ssRNA viruses of animals.[79]
Genome size varies greatly between species. The smallest viral genomes – the ssDNA circoviruses, family
Circoviridae – code for only two proteins and have a genome size of only 2 kilobases; the largest – mimiviruses –
have genome sizes of over 1.2 megabases and code for over one thousand proteins.[80] In general, RNA viruses have
smaller genome sizes than DNA viruses because of a higher error-rate when replicating, and have a maximum upper
size limit.[34] Beyond this limit, errors in the genome when replicating render the virus useless or uncompetitive. To
compensate for this, RNA viruses often have segmented genomes – the genome is split into smaller molecules – thus
reducing the chance that an error in a single-component genome will incapacitate the entire genome. In contrast,
DNA viruses generally have larger genomes because of the high fidelity of their replication enzymes.[81]
Single-strand DNA viruses are an exception to this rule, however, as mutation rates for these genomes can approach
the extreme of the ssRNA virus case.[82]
Viruses undergo genetic change by several mechanisms. These include
a process called genetic drift where individual bases in the DNA or
RNA mutate to other bases. Most of these point mutations are
"silent" – they do not change the protein that the gene encodes – but
others can confer evolutionary advantages such as resistance to
antiviral drugs.[83] Antigenic shift occurs when there is a major change
in the genome of the virus. This can be a result of recombination or
reassortment. When this happens with influenza viruses, pandemics
might result.[84] RNA viruses often exist as quasispecies or swarms of
viruses of the same species but with slightly different genome
nucleoside sequences. Such quasispecies are a prime target for natural
selection.[85]

Segmented genomes confer evolutionary advantages; different strains


of a virus with a segmented genome can shuffle and combine genes
and produce progeny viruses or (offspring) that have unique How antigenic shift, or reassortment, can result in
characteristics. This is called reassortment or viral sex.[86] novel and highly pathogenic strains of human flu

Genetic recombination is the process by which a strand of DNA is


broken and then joined to the end of a different DNA molecule. This can occur when viruses infect cells
simultaneously and studies of viral evolution have shown that recombination has been rampant in the species
studied.[87] Recombination is common to both RNA and DNA viruses.[88][89]
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Replication cycle
Viral populations do not grow through cell division, because they are acellular. Instead, they use the machinery and
metabolism of a host cell to produce multiple copies of themselves, and they assemble in the cell.

A typical virus replication cycle

Some bacteriophages inject their genomes into bacterial cells (not to scale)

The life cycle of viruses differs greatly between species but there are six basic stages in the life cycle of viruses:[90]
• Attachment is a specific binding between viral capsid proteins and specific receptors on the host cellular surface.
This specificity determines the host range of a virus. For example, HIV infects a limited range of human
leucocytes. This is because its surface protein, gp120, specifically interacts with the CD4 molecule – a chemokine
receptor – which is most commonly found on the surface of CD4+ T-Cells. This mechanism has evolved to
favour those viruses that infect only cells in which they are capable of replication. Attachment to the receptor can
induce the viral envelope protein to undergo changes that results in the fusion of viral and cellular membranes, or
changes of non-enveloped virus surface proteins that allow the virus to enter.
• Penetration follows attachment: Virions enter the host cell through receptor-mediated endocytosis or membrane
fusion. This is often called viral entry. The infection of plant and fungal cells is different from that of animal cells.
Plants have a rigid cell wall made of cellulose, and fungi one of chitin, so most viruses can get inside these cells
only after trauma to the cell wall.[91] However, nearly all plant viruses (such as tobacco mosaic virus) can also
move directly from cell to cell, in the form of single-stranded nucleoprotein complexes, through pores called
plasmodesmata.[92] Bacteria, like plants, have strong cell walls that a virus must breach to infect the cell.
However, given that bacterial cell walls are much less thick than plant cell walls due to their much smaller size,
some viruses have evolved mechanisms that inject their genome into the bacterial cell across the cell wall, while
Virus 430

the viral capsid remains outside.[93]


• Uncoating is a process in which the viral capsid is removed: This may be by degradation by viral enzymes or host
enzymes or by simple dissociation; the end-result is the releasing of the viral genomic nucleic acid.
• Replication of viruses involves primarily multiplication of the genome. Replication involves synthesis of viral
messenger RNA (mRNA) from "early" genes (with exceptions for positive sense RNA viruses), viral protein
synthesis, possible assembly of viral proteins, then viral genome replication mediated by early or regulatory
protein expression. This may be followed, for complex viruses with larger genomes, by one or more further
rounds of mRNA synthesis: "late" gene expression is, in general, of structural or virion proteins.
• Following the structure-mediated self-assembly of the virus particles, some modification of the proteins often
occurs. In viruses such as HIV, this modification (sometimes called maturation) occurs after the virus has been
released from the host cell.[94]
• Viruses can be released from the host cell by lysis, a process that kills the cell by bursting its membrane and cell
wall if present: This is a feature of many bacterial and some animal viruses. Some viruses undergo a lysogenic
cycle where the viral genome is incorporated by genetic recombination into a specific place in the host's
chromosome. The viral genome is then known as a "provirus" or, in the case of bacteriophages a "prophage".[95]
Whenever the host divides, the viral genome is also replicated. The viral genome is mostly silent within the host;
however, at some point, the provirus or prophage may give rise to active virus, which may lyse the host cells.[96]
Enveloped viruses (e.g., HIV) typically are released from the host cell by budding. During this process the virus
acquires its envelope, which is a modified piece of the host's plasma or other, internal membrane.[97]
The genetic material within virus particles, and the method by which the material is replicated, varies considerably
between different types of viruses.
DNA viruses
The genome replication of most DNA viruses takes place in the cell's nucleus. If the cell has the appropriate
receptor on its surface, these viruses enter the cell sometimes by direct fusion with the cell membrane (e.g.,
herpesviruses) or – more usually – by receptor-mediated endocytosis. Most DNA viruses are entirely
dependent on the host cell's DNA and RNA synthesising machinery, and RNA processing machinery;
however, viruses with larger genomes may encode much of this machinery themselves. In eukaryotes the viral
genome must cross the cell's nuclear membrane to access this machinery, while in bacteria it need only enter
the cell.[98]
RNA viruses
Replication usually takes place in the cytoplasm. RNA viruses can be placed into four different groups
depending on their modes of replication. The polarity (whether or not it can be used directly by ribosomes to
make proteins) of single-stranded RNA viruses largely determines the replicative mechanism; the other major
criterion is whether the genetic material is single-stranded or double-stranded. All RNA viruses use their own
RNA replicase enzymes to create copies of their genomes.[99]
Reverse transcribing viruses
These have ssRNA (Retroviridae, Metaviridae, Pseudoviridae) or dsDNA (Caulimoviridae, and
Hepadnaviridae) in their particles. Reverse transcribing viruses with RNA genomes (retroviruses), use a DNA
intermediate to replicate, whereas those with DNA genomes (pararetroviruses) use an RNA intermediate
during genome replication. Both types use a reverse transcriptase, or RNA-dependent DNA polymerase
enzyme, to carry out the nucleic acid conversion. Retroviruses integrate the DNA produced by reverse
transcription into the host genome as a provirus as a part of the replication process; pararetroviruses do not,
although integrated genome copies of especially plant pararetroviruses can give rise to infectious virus.[100]
They are susceptible to antiviral drugs that inhibit the reverse transcriptase enzyme, e.g. zidovudine and
lamivudine. An example of the first type is HIV, which is a retrovirus. Examples of the second type are the
Hepadnaviridae, which includes Hepatitis B virus.[101]
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Effects on the host cell


The range of structural and biochemical effects that viruses have on the host cell is extensive.[102] These are called
cytopathic effects.[103] Most virus infections eventually result in the death of the host cell. The causes of death
include cell lysis, alterations to the cell's surface membrane and apoptosis.[104] Often cell death is caused by
cessation of its normal activities because of suppression by virus-specific proteins, not all of which are components
of the virus particle.[105]
Some viruses cause no apparent changes to the infected cell. Cells in which the virus is latent and inactive show few
signs of infection and often function normally.[106] This causes persistent infections and the virus is often dormant
for many months or years. This is often the case with herpes viruses.[107][108] Some viruses, such as Epstein-Barr
virus, can cause cells to proliferate without causing malignancy,[109] while others, such as papillomaviruses, are
established causes of cancer.[110]

Host range
Viruses are by far the most abundant biological entities on Earth and they outnumber all the others put together.[111]
They infect all types of cellular life including animals, plants, bacteria and fungi.[3] However, different types of
viruses can infect only a limited range of hosts and many are species-specific. Some, such as smallpox virus for
example, can infect only one species – in this case humans,[112] and are said to have a narrow host range. Other
viruses, such as rabies virus, can infect different species of mammals and are said to have a broad range.[113] The
viruses that infect plants are harmless to animals, and most viruses that infect other animals are harmless to
humans.[114] The host range of some bacteriophages is limited to a single strain of bacteria and they can be used to
trace the source of outbreaks of infections by a method called phage typing.[115]

Classification
Classification seeks to describe the diversity of viruses by naming and grouping them on the basis of similarities. In
1962, André Lwoff, Robert Horne, and Paul Tournier were the first to develop a means of virus classification, based
on the Linnaean hierarchical system.[116] This system bases classification on phylum, class, order, family, genus, and
species. Viruses were grouped according to their shared properties (not those of their hosts) and the type of nucleic
acid forming their genomes.[117] Later the International Committee on Taxonomy of Viruses was formed. However,
viruses are not classified on the basis of phylum or class, as their small genome size and high rate of mutation makes
it difficult to determine their ancestry beyond Order. As such, the Baltimore Classification is used to supplement the
more traditional hierarchy.

ICTV classification
The International Committee on Taxonomy of Viruses (ICTV) developed the current classification system and wrote
guidelines that put a greater weight on certain virus properties to maintain family uniformity. A unified taxonomy (a
universal system for classifying viruses) has been established. The 7th lCTV Report formalised for the first time the
concept of the virus species as the lowest taxon (group) in a branching hierarchy of viral taxa.[118] However, at
present only a small part of the total diversity of viruses has been studied, with analyses of samples from humans
finding that about 20% of the virus sequences recovered have not been seen before, and samples from the
environment, such as from seawater and ocean sediments, finding that the large majority of sequences are
completely novel.[119]
The general taxonomic structure is as follows:
Order (-virales)
Family (-viridae)
Subfamily (-virinae)
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Genus (-virus)
Species (-virus)
In the current (2011) ICTV taxonomy, six orders have been established, the Caudovirales, Herpesvirales,
Mononegavirales, Nidovirales, Picornavirales and Tymovirales. A seventh order Ligamenvirales has also been
proposed. The committee does not formally distinguish between subspecies, strains, and isolates. In total there are 6
orders, 87 families, 19 subfamilies, 349 genera, about 2,284 species and over 3,000 types yet
unclassified.[120][121][122]

Baltimore classification
The Nobel Prize-winning biologist David Baltimore devised the
Baltimore classification system.[31][123] The ICTV classification
system is used in conjunction with the Baltimore classification system
in modern virus classification.[124][125][126]
The Baltimore classification of viruses is based on the mechanism of
mRNA production. Viruses must generate mRNAs from their genomes
to produce proteins and replicate themselves, but different mechanisms
are used to achieve this in each virus family. Viral genomes may be
single-stranded (ss) or double-stranded (ds), RNA or DNA, and may or
may not use reverse transcriptase (RT). In addition, ssRNA viruses
may be either sense (+) or antisense (−). This classification places The Baltimore Classification of viruses is based
viruses into seven groups: on the method of viral mRNA synthesis.

• I: dsDNA viruses (e.g. Adenoviruses, Herpesviruses, Poxviruses)


• II: ssDNA viruses (+)sense DNA (e.g. Parvoviruses)
• III: dsRNA viruses (e.g. Reoviruses)
• IV: (+)ssRNA viruses (+)sense RNA (e.g. Picornaviruses, Togaviruses)
• V: (−)ssRNA viruses (−)sense RNA (e.g. Orthomyxoviruses, Rhabdoviruses)
• VI: ssRNA-RT viruses (+)sense RNA with DNA intermediate in life-cycle (e.g. Retroviruses)
• VII: dsDNA-RT viruses (e.g. Hepadnaviruses)
As an example of viral classification, the chicken pox virus, varicella zoster (VZV), belongs to the order
Herpesvirales, family Herpesviridae, subfamily Alphaherpesvirinae, and genus Varicellovirus. VZV is in Group I of
the Baltimore Classification because it is a dsDNA virus that does not use reverse transcriptase.
Virus 433

Role in human disease


Examples of common human diseases caused by viruses include the
common cold, influenza, chickenpox and cold sores. Many serious
diseases such as ebola, AIDS, avian influenza and SARS are caused by
viruses. The relative ability of viruses to cause disease is described in
terms of virulence. Other diseases are under investigation as to whether
they too have a virus as the causative agent, such as the possible
connection between human herpesvirus 6 (HHV6) and neurological
diseases such as multiple sclerosis and chronic fatigue syndrome.[129]
There is controversy over whether the bornavirus, previously thought
to cause neurological diseases in horses, could be responsible for
psychiatric illnesses in humans.[130]
Overview of the main types of viral infection and
Viruses have different mechanisms by which they produce disease in [127][128]
the most notable species involved
an organism, which depends largely on the viral species. Mechanisms
at the cellular level primarily include cell lysis, the breaking open and subsequent death of the cell. In multicellular
organisms, if enough cells die, the whole organism will start to suffer the effects. Although viruses cause disruption
of healthy homeostasis, resulting in disease, they may exist relatively harmlessly within an organism. An example
would include the ability of the herpes simplex virus, which causes cold sores, to remain in a dormant state within
the human body. This is called latency[131] and is a characteristic of the herpes viruses including Epstein-Barr virus,
which causes glandular fever, and varicella zoster virus, which causes chickenpox and shingles. Most people have
been infected with at least one of these types of herpes virus.[132] However, these latent viruses might sometimes be
beneficial, as the presence of the virus can increase immunity against bacterial pathogens, such as Yersinia
pestis.[133]

Some viruses can cause lifelong or chronic infections, where the viruses continue to replicate in the body despite the
host's defence mechanisms.[134] This is common in hepatitis B virus and hepatitis C virus infections. People
chronically infected are known as carriers, as they serve as reservoirs of infectious virus.[135] In populations with a
high proportion of carriers, the disease is said to be endemic.[136]

Epidemiology
Viral epidemiology is the branch of medical science that deals with the transmission and control of virus infections
in humans. Transmission of viruses can be vertical, that is from mother to child, or horizontal, which means from
person to person. Examples of vertical transmission include hepatitis B virus and HIV where the baby is born already
infected with the virus.[137] Another, more rare, example is the varicella zoster virus, which, although causing
relatively mild infections in humans, can be fatal to the foetus and new-born baby.[138]
Horizontal transmission is the most common mechanism of spread of viruses in populations. Transmission can occur
when: body fluids are exchanged during sexual activity, e.g., HIV; blood is exchanged by contaminated transfusion
or needle sharing, e.g., hepatitis C; exchange of saliva by mouth, e.g., Epstein-Barr virus; contaminated food or
water is ingested, e.g., norovirus; aerosols containing virions are inhaled, e.g., influenza virus; and insect vectors
such as mosquitoes penetrate the skin of a host, e.g., dengue. The rate or speed of transmission of viral infections
depends on factors that include population density, the number of susceptible individuals, (i.e., those not
immune),[139] the quality of healthcare and the weather.[140]
Epidemiology is used to break the chain of infection in populations during outbreaks of viral diseases.[141] Control
measures are used that are based on knowledge of how the virus is transmitted. It is important to find the source, or
sources, of the outbreak and to identify the virus. Once the virus has been identified, the chain of transmission can
sometimes be broken by vaccines. When vaccines are not available sanitation and disinfection can be effective.
Virus 434

Often infected people are isolated from the rest of the community and those that have been exposed to the virus
placed in quarantine.[142] To control the outbreak of foot-and-mouth disease in cattle in Britain in 2001, thousands of
cattle were slaughtered.[143] Most viral infections of humans and other animals have incubation periods during which
the infection causes no signs or symptoms.[144] Incubation periods for viral diseases range from a few days to weeks
but are known for most infections.[145] Somewhat overlapping, but mainly following the incubation period, there is a
period of communicability; a time when an infected individual or animal is contagious and can infect another person
or animal.[146] This too is known for many viral infections and knowledge the length of both periods is important in
the control of outbreaks.[147] When outbreaks cause an unusually high proportion of cases in a population,
community or region they are called epidemics. If outbreaks spread worldwide they are called pandemics.[148]

Epidemics and pandemics


Native American populations were devastated by contagious diseases,
in particular, smallpox, brought to the Americas by European colonists.
It is unclear how many Native Americans were killed by foreign
diseases after the arrival of Columbus in the Americas, but the
numbers have been estimated to be close to 70% of the indigenous
population. The damage done by this disease significantly aided
European attempts to displace and conquer the native population.[149]

A pandemic is a worldwide epidemic. The 1918 flu pandemic, which Transmission electron microscope image of a
recreated 1918 influenza virus
lasted until 1919, was a category 5 influenza pandemic caused by an
unusually severe and deadly influenza A virus. The victims were often
healthy young adults, in contrast to most influenza outbreaks, which predominantly affect juvenile, elderly, or
otherwise-weakened patients.[150] Older estimates say it killed 40–50 million people,[151] while more recent research
suggests that it may have killed as many as 100 million people, or 5% of the world's population in 1918.[152]

Most researchers believe that HIV originated in sub-Saharan Africa during the 20th century;[153] it is now a
pandemic, with an estimated 38.6 million people now living with the disease worldwide.[154] The Joint United
Nations Programme on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimate that AIDS has
killed more than 25 million people since it was first recognised on June 5, 1981, making it one of the most
destructive epidemics in recorded history.[155] In 2007 there were 2.7 million new HIV infections and 2 million
HIV-related deaths.[156]
Several highly lethal viral pathogens are members of the Filoviridae.
Filoviruses are filament-like viruses that cause viral hemorrhagic fever,
and include the ebola and marburg viruses. The Marburg virus
attracted widespread press attention in April 2005 for an outbreak in
Angola. Beginning in October 2004 and continuing into 2005, the
outbreak was the world's worst epidemic of any kind of viral
hemorrhagic fever.[157]

Marburg virus
Cancer
Viruses are an established cause of cancer in humans and other species. Viral cancers occur only in a minority of
infected persons (or animals). Cancer viruses come from a range of virus families, including both RNA and DNA
viruses, and so there is no single type of "oncovirus" (an obsolete term originally used for acutely transforming
retroviruses). The development of cancer is determined by a variety of factors such as host immunity[158] and
mutations in the host.[159] Viruses accepted to cause human cancers include some genotypes of human
papillomavirus, hepatitis B virus, hepatitis C virus, Epstein-Barr virus, Kaposi's sarcoma-associated herpesvirus and
Virus 435

human T-lymphotropic virus. The most recently discovered human cancer virus is a polyomavirus (Merkel cell
polyomavirus) that causes most cases of a rare form of skin cancer called Merkel cell carcinoma.[160] Hepatitis
viruses can develop into a chronic viral infection that leads to liver cancer.[161][162] Infection by human
T-lymphotropic virus can lead to tropical spastic paraparesis and adult T-cell leukemia.[163] Human papillomaviruses
are an established cause of cancers of cervix, skin, anus, and penis.[164] Within the Herpesviridae, Kaposi's
sarcoma-associated herpesvirus causes Kaposi's sarcoma and body cavity lymphoma, and Epstein–Barr virus causes
Burkitt's lymphoma, Hodgkin’s lymphoma, B lymphoproliferative disorder, and nasopharyngeal carcinoma.[165]
Merkel cell polyomavirus closely related to SV40 and mouse polyomaviruses that have been used as animal models
for cancer viruses for over 50 years.[166]

Host defence mechanisms


The body's first line of defence against viruses is the innate immune system. This comprises cells and other
mechanisms that defend the host from infection in a non-specific manner. This means that the cells of the innate
system recognise, and respond to, pathogens in a generic way, but, unlike the adaptive immune system, it does not
confer long-lasting or protective immunity to the host.[167]
RNA interference is an important innate defence against viruses.[168] Many viruses have a replication strategy that
involves double-stranded RNA (dsRNA). When such a virus infects a cell, it releases its RNA molecule or
molecules, which immediately bind to a protein complex called dicer that cuts the RNA into smaller pieces. A
biochemical pathway called the RISC complex is activated, which degrades the viral mRNA and the cell survives the
infection. Rotaviruses avoid this mechanism by not uncoating fully inside the cell and by releasing newly produced
mRNA through pores in the particle's inner capsid. The genomic dsRNA remains protected inside the core of the
virion.[169][170]
When the adaptive immune system of a vertebrate encounters a virus, it produces specific antibodies that bind to the
virus and render it non-infectious. This is called humoral immunity. Two types of antibodies are important. The first,
called IgM, is highly effective at neutralizing viruses but is produced by the cells of the immune system only for a
few weeks. The second, called IgG, is produced indefinitely. The presence of IgM in the blood of the host is used to
test for acute infection, whereas IgG indicates an infection sometime in the past.[171] IgG antibody is measured when
tests for immunity are carried out.[172]
A second defence of vertebrates against viruses is called cell-mediated
immunity and involves immune cells known as T cells. The body's
cells constantly display short fragments of their proteins on the cell's
surface, and, if a T cell recognises a suspicious viral fragment there,
the host cell is destroyed by killer T cells and the virus-specific T-cells
proliferate. Cells such as the macrophage are specialists at this antigen
presentation.[173] The production of interferon is an important host
Two rotaviruses: the one on the right is coated
defence mechanism. This is a hormone produced by the body when with antibodies that stop its attaching to cells and
viruses are present. Its role in immunity is complex; it eventually stops infecting them
the viruses from reproducing by killing the infected cell and its close
neighbours.[174]

Not all virus infections produce a protective immune response in this way. HIV evades the immune system by
constantly changing the amino acid sequence of the proteins on the surface of the virion. These persistent viruses
evade immune control by sequestration, blockade of antigen presentation, cytokine resistance, evasion of natural
killer cell activities, escape from apoptosis, and antigenic shift.[175] Other viruses, called neurotropic viruses, are
disseminated by neural spread where the immune system may be unable to reach them.
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Prevention and treatment


Because viruses use vital metabolic pathways within host cells to replicate, they are difficult to eliminate without
using drugs that cause toxic effects to host cells in general. The most effective medical approaches to viral diseases
are vaccinations to provide immunity to infection, and antiviral drugs that selectively interfere with viral replication.

Vaccines
Vaccination is a cheap and effective way of preventing infections by viruses. Vaccines were used to prevent viral
infections long before the discovery of the actual viruses. Their use has resulted in a dramatic decline in morbidity
(illness) and mortality (death) associated with viral infections such as polio, measles, mumps and rubella.[176]
Smallpox infections have been eradicated.[177] Vaccines are available to prevent over thirteen viral infections of
humans,[178] and more are used to prevent viral infections of animals.[179] Vaccines can consist of live-attenuated or
killed viruses, or viral proteins (antigens).[180] Live vaccines contain weakened forms of the virus, which do not
cause the disease but, nonetheless, confer immunity. Such viruses are called attenuated. Live vaccines can be
dangerous when given to people with a weak immunity, (who are described as immunocompromised), because in
these people, the weakened virus can cause the original disease.[181] Biotechnology and genetic engineering
techniques are used to produce subunit vaccines. These vaccines use only the capsid proteins of the virus. Hepatitis
B vaccine is an example of this type of vaccine.[182] Subunit vaccines are safe for immunocompromised patients
because they cannot cause the disease.[183] The yellow fever virus vaccine, a live-attenuated strain called 17D, is
probably the safest and most effective vaccine ever generated.[184]

Antiviral drugs

Guanosine

The guanosine analogue Aciclovir

Antiviral drugs are often nucleoside analogues, (fake DNA building-blocks), which viruses mistakenly incorporate
into their genomes during replication. The life-cycle of the virus is then halted because the newly synthesised DNA
is inactive. This is because these analogues lack the hydroxyl groups, which, along with phosphorus atoms, link
together to form the strong "backbone" of the DNA molecule. This is called DNA chain termination.[185] Examples
of nucleoside analogues are aciclovir for Herpes simplex virus infections and lamivudine for HIV and Hepatitis B
virus infections. Aciclovir is one of the oldest and most frequently prescribed antiviral drugs.[186] Other antiviral
drugs in use target different stages of the viral life cycle. HIV is dependent on a proteolytic enzyme called the HIV-1
protease for it to become fully infectious. There is a large class of drugs called protease inhibitors that inactivate this
enzyme.
Hepatitis C is caused by an RNA virus. In 80% of people infected, the disease is chronic, and without treatment, they
are infected for the remainder of their lives. However, there is now an effective treatment that uses the nucleoside
analogue drug ribavirin combined with interferon.[187] The treatment of chronic carriers of the hepatitis B virus by
using a similar strategy using lamivudine has been developed.[188]
Virus 437

Infection in other species


Viruses infect all cellular life and, although viruses occur universally, each cellular species has its own specific range
that often infect only that species.[189] Some viruses, called satellites, can replicate only within cells that have
already been infected by another virus.[47] Viruses are important pathogens of livestock. Diseases such as
foot-and-mouth disease and bluetongue are caused by viruses.[190] Companion animals such as cats, dogs, and
horses, if not vaccinated, are susceptible to serious viral infections. Canine parvovirus is caused by a small DNA
virus and infections are often fatal in pups.[191] Like all invertebrates, the honey bee is susceptible to many viral
infections.[192] However, most viruses co-exist harmlessly in their host and cause no signs or symptoms of disease.[2]

Plants
There are many types of plant virus, but often they cause only a loss of
yield, and it is not economically viable to try to control them. Plant
viruses are often spread from plant to plant by organisms, known as
vectors. These are normally insects, but some fungi, nematode worms,
and single-celled organisms have been shown to be vectors. When
control of plant virus infections is considered economical, for perennial
fruits, for example, efforts are concentrated on killing the vectors and
removing alternate hosts such as weeds.[193] Plant viruses are harmless
to humans and other animals because they can reproduce only in living
plant cells.[194]
Peppers infected by mild mottle virus
Plants have elaborate and effective defence mechanisms against
viruses. One of the most effective is the presence of so-called
resistance (R) genes. Each R gene confers resistance to a particular virus by triggering localised areas of cell death
around the infected cell, which can often be seen with the unaided eye as large spots. This stops the infection from
spreading.[195] RNA interference is also an effective defence in plants.[196] When they are infected, plants often
produce natural disinfectants that kill viruses, such as salicylic acid, nitric oxide, and reactive oxygen molecules.[197]

Plant virus particles or virus-like particles (VLPs) have applications in both biotechnology and nanotechnology. The
capsids of most plant viruses are simple and robust structures and can be produced in large quantities either by the
infection of plants or by expression in a variety of heterologous systems. Plant virus particles can be modified
genetically and chemically to encapsulate foreign material and can be incorporated into supramolecular structures for
use in biotechnology.[198]
Virus 438

Bacteria
Bacteriophages are a common and diverse group of viruses and are the most
abundant form of biological entity in aquatic environments – there are up to ten
times more of these viruses in the oceans than there are bacteria,[199] reaching
levels of 250,000,000 bacteriophages per millilitre of seawater.[200] These
viruses infect specific bacteria by binding to surface receptor molecules and then
entering the cell. Within a short amount of time, in some cases just minutes,
bacterial polymerase starts translating viral mRNA into protein. These proteins
go on to become either new virions within the cell, helper proteins, which help
assembly of new virions, or proteins involved in cell lysis. Viral enzymes aid in
the breakdown of the cell membrane, and, in the case of the T4 phage, in just
over twenty minutes after injection over three hundred phages could be Transmission electron micrograph of
released.[201] multiple bacteriophages attached to a
bacterial cell wall
The major way bacteria defend themselves from bacteriophages is by producing
enzymes that destroy foreign DNA. These enzymes, called restriction endonucleases, cut up the viral DNA that
bacteriophages inject into bacterial cells.[202] Bacteria also contain a system that uses CRISPR sequences to retain
fragments of the genomes of viruses that the bacteria have come into contact with in the past, which allows them to
block the virus's replication through a form of RNA interference.[203][204] This genetic system provides bacteria with
acquired immunity to infection.

Archaea
Some viruses replicate within archaea: these are double-stranded DNA viruses with unusual and sometimes unique
shapes.[5][77] These viruses have been studied in most detail in the thermophilic archaea, particularly the orders
Sulfolobales and Thermoproteales.[205] Defences against these viruses may involve RNA interference from repetitive
DNA sequences within archaean genomes that are related to the genes of the viruses.[206][207]

Role in aquatic ecosystems


A teaspoon of seawater contains about one million viruses.[208] They are essential to the regulation of saltwater and
freshwater ecosystems.[209] Most of these viruses are bacteriophages, which are harmless to plants and animals. They
infect and destroy the bacteria in aquatic microbial communities, comprising the most important mechanism of
recycling carbon in the marine environment. The organic molecules released from the bacterial cells by the viruses
stimulates fresh bacterial and algal growth.[210]
Microorganisms constitute more than 90% of the biomass in the sea. It is estimated that viruses kill approximately
20% of this biomass each day and that there are 15 times as many viruses in the oceans as there are bacteria and
archaea. Viruses are the main agents responsible for the rapid destruction of harmful algal blooms,[211] which often
kill other marine life.[212] The number of viruses in the oceans decreases further offshore and deeper into the water,
where there are fewer host organisms.[213]
The effects of marine viruses are far-reaching; by increasing the amount of photosynthesis in the oceans, viruses are
indirectly responsible for reducing the amount of carbon dioxide in the atmosphere by approximately 3 gigatonnes of
carbon per year.[213]
Like any organism, marine mammals are susceptible to viral infections. In 1988 and 2002, thousands of harbor seals
were killed in Europe by phocine distemper virus.[214] Many other viruses, including caliciviruses, herpesviruses,
adenoviruses and parvoviruses, circulate in marine mammal populations.[213]
Virus 439

Role in evolution
Viruses are an important natural means of transferring genes between different species, which increases genetic
diversity and drives evolution.[7] It is thought that viruses played a central role in the early evolution, before the
diversification of bacteria, archaea and eukaryotes and at the time of the last universal common ancestor of life on
Earth.[215] Viruses are still one of the largest reservoirs of unexplored genetic diversity on Earth.[213]

Applications

Life sciences and medicine


Viruses are important to the study of molecular and cell biology as they provide
simple systems that can be used to manipulate and investigate the functions of
cells.[216] The study and use of viruses have provided valuable information about
aspects of cell biology.[217] For example, viruses have been useful in the study of
genetics and helped our understanding of the basic mechanisms of molecular
genetics, such as DNA replication, transcription, RNA processing, translation,
protein transport, and immunology.

Geneticists often use viruses as vectors to introduce genes into cells that they are
studying. This is useful for making the cell produce a foreign substance, or to
study the effect of introducing a new gene into the genome. In similar fashion,
virotherapy uses viruses as vectors to treat various diseases, as they can
specifically target cells and DNA. It shows promising use in the treatment of
Scientist studying the H5N1
cancer and in gene therapy. Eastern European scientists have used phage therapy
influenza virus
as an alternative to antibiotics for some time, and interest in this approach is
increasing, because of the high level of antibiotic resistance now found in some
[218]
pathogenic bacteria. Expression of heterologous proteins by viruses is the basis of several manufacturing
processes that are currently being used for the production of various proteins such as vaccine antigens and
antibodies. Industrial processes have been recently developed using viral vectors and a number of pharmaceutical
proteins are currently in pre-clinical and clinical trials.[219]

Materials science and nanotechnology


Current trends in nanotechnology promise to make much more versatile use of viruses. From the viewpoint of a
materials scientist, viruses can be regarded as organic nanoparticles. Their surface carries specific tools designed to
cross the barriers of their host cells. The size and shape of viruses, and the number and nature of the functional
groups on their surface, is precisely defined. As such, viruses are commonly used in materials science as scaffolds
for covalently linked surface modifications. A particular quality of viruses is that they can be tailored by directed
evolution. The powerful techniques developed by life sciences are becoming the basis of engineering approaches
towards nanomaterials, opening a wide range of applications far beyond biology and medicine.[220]
Because of their size, shape, and well-defined chemical structures, viruses have been used as templates for
organizing materials on the nanoscale. Recent examples include work at the Naval Research Laboratory in
Washington, D.C., using Cowpea Mosaic Virus (CPMV) particles to amplify signals in DNA microarray based
sensors. In this application, the virus particles separate the fluorescent dyes used for signalling to prevent the
formation of non-fluorescent dimers that act as quenchers.[221] Another example is the use of CPMV as a nanoscale
breadboard for molecular electronics.[222]
Virus 440

Synthetic viruses
Many viruses can be synthesized de novo ("from scratch") and the first synthetic virus was created in 2002.[223]
Although somewhat of a misconception, it is not the actual virus that is synthesized, but rather its DNA genome (in
case of a DNA virus), or a cDNA copy of its genome (in case of RNA viruses). For many virus families the naked
synthetic DNA or RNA (once enzymatically converted back from the synthetic cDNA) is infectious when introduced
into a cell. That is, they contain all the necessary information to produce new viruses. This technology is now being
used to investigate novel vaccine strategies.[224] The ability to synthesize viruses has far-reaching consequences,
since viruses can no longer be regarded as extinct, as long as the information of their genome sequence is known and
permissive cells are available. Currently, the full-length genome sequences of 2408 different viruses (including
smallpox) are publicly available at an online database, maintained by the National Institutes of Health.[225]

Weapons
The ability of viruses to cause devastating epidemics in human societies has led to the concern that viruses could be
weaponised for biological warfare. Further concern was raised by the successful recreation of the infamous 1918
influenza virus in a laboratory.[226] The smallpox virus devastated numerous societies throughout history before its
eradication. There are officially only two centers in the world that keep stocks of smallpox virus – the Russian
Vector laboratory, and the United States Centers for Disease Control.[227] But fears that it may be used as a weapon
are not totally unfounded;[227] the vaccine for smallpox has sometimes severe side-effects – during the last years
before the eradication of smallpox disease more people became seriously ill as a result of vaccination than did people
from smallpox[228] – and smallpox vaccination is no longer universally practiced.[229] Thus, much of the modern
human population has almost no established resistance to smallpox.[227]

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Bibliography
• Collier, Leslie; Balows, Albert; Sussman, Max (1998) Topley and Wilson's Microbiology and Microbial
Infections ninth edition, Volume 1, Virology, volume editors: Mahy, Brian and Collier, Leslie. Arnold. ISBN
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External links
• ViralZone (http://viralzone.expasy.org/) A Swiss Institute of Bioinformatics resource for all viral families,
providing general molecular and epidemiological information
• David Baltimore online Seminar: "Introduction to Viruses and HIV" (http://www.ibioseminars.org/lectures/
global-health-a-energy/david-baltimore.html)
• Ari Helenius online seminar: "Virus entry" (http://www.ibioseminars.org/lectures/bio-mechanisms/
ari-helenius-part-1.html)
• "A Gazillion Tiny Avatars" (http://opinionator.blogs.nytimes.com/2009/12/15/a-gazillion-tiny-avatars/),
article on viruses by Olivia Judson, NY Times, Dec 15, 2009
• Khan Academy, video lecture (http://www.khanacademy.org/video/viruses?playlist=Biology)
• Viruses (http://www.mdpi.com/journal/viruses/) – an Open Access journal
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Bacteriology  Source: http://en.wikipedia.org/w/index.php?oldid=499874245  Contributors: 12.52, Belovedfreak, Edward Gordon Gey, Ellmist, Jeronimo, Jmeppley, LittleT889, Penn Station,
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Biochemistry  Source: http://en.wikipedia.org/w/index.php?oldid=496474736  Contributors: 168..., 203.20.98.xxx, 217.228.14.xxx, 2pac 2007, 52G, A8UDI, APH, Abductive, AdamRetchless,
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Biological membrane  Source: http://en.wikipedia.org/w/index.php?oldid=484548716  Contributors: 168..., Aceofhearts1968, Adashiel, Adrian J. Hunter, Aejohnst, Alan Liefting, Alansohn,
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Blood  Source: http://en.wikipedia.org/w/index.php?oldid=500595402  Contributors: ))ECB((, 2112 rush, 21655, 334a, 3idiot, 64ereye, A D 13, A8UDI, Abdoiu, Abductive,
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Article Sources and Contributors 451

Blood cell  Source: http://en.wikipedia.org/w/index.php?oldid=499922971  Contributors: 123Hedgehog456, Ajc, Amorymeltzer, Andonic, Antonio Lopez, AxelBoldt, Bacardimayne, Basawala,
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Cell (biology)  Source: http://en.wikipedia.org/w/index.php?oldid=499397153  Contributors: .:Ajvol:., 041744, 168..., 1pezguy, 1tinyboo, 2004-12-29T22:45Z, 209.234.79.xxx, 2D, 2help,
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Cell nucleus  Source: http://en.wikipedia.org/w/index.php?oldid=497594382  Contributors: 129.186.19.xxx, 1STstringcorner, 444et, 54gsze4ghz5, A D 13, AMK152, AShin1130, Aaron north,
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Cell wall  Source: http://en.wikipedia.org/w/index.php?oldid=500771133  Contributors: 28421u2232nfenfcenc, Adambiswanger1, Adenosine, Ahoerstemeier, Aidaneggs, AlexiusHoratius,
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Article Sources and Contributors 454

Cellular microbiology  Source: http://en.wikipedia.org/w/index.php?oldid=418266014  Contributors: Carbonrodney, CommonsDelinker, Mild Bill Hiccup, Pixie, Stephen Morley, 1 anonymous
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Collagen  Source: http://en.wikipedia.org/w/index.php?oldid=498718455  Contributors: 28bytes, AWeenie, Adeez, AdrianaW, Aestin, Aeusoes1, Alansohn, Algumacoisaqq, Andrew Nutter,
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Zzuuzz, 471 anonymous edits

Connective tissue  Source: http://en.wikipedia.org/w/index.php?oldid=501085523  Contributors: (jarbarf), A. B., AC+79 3888, AS, Addshore, AdjustShift, Afra Ullah, Ahoerstemeier, Arcadian,
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Copolymer  Source: http://en.wikipedia.org/w/index.php?oldid=498238413  Contributors: Ahering@cogeco.ca, AllGloryToTheHypnotoad, Bdodo1992, Bidabidabee, Bryan Derksen, Ceyockey,
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Cytoplasm  Source: http://en.wikipedia.org/w/index.php?oldid=500383764  Contributors: 129.128.164.xxx, 168..., 1exec1, 2D, A3RO, Aaron north, Abc518, Ac352, Ace258, Acroterion,
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DNA  Source: http://en.wikipedia.org/w/index.php?oldid=501214862  Contributors: (, (jarbarf), -Majestic-, 168.., 168..., 169, 17Drew, 2over0, 3dscience, 4u1e, 62.253.64.xxx, 7434be, 84user, A
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Article Sources and Contributors 455

GordonWatts, GorillaWarfare, Gracenotes, Graeme Bartlett, GraemeL, Grafikm fr, Graft, Graham87, GrahamColm, Grandegrandegrande, GregorB, Grover cleveland, Gurko, Gustav von
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Zoicon5, Zouavman Le Zouave, Zsinj, Zven, Zynwyx, 1413 anonymous edits

Fecal fat test  Source: http://en.wikipedia.org/w/index.php?oldid=489230340  Contributors: Alteripse, Arcadian, BRSM, Countincr, Cyrius, Davidruben, DawnOfDark, Deathawk, Diberri,
HollyAm, Infrangible, Kd4ttc, Longhair, Ntennis, RedWolf, Samir, Scwlong, Shaddack, Some standardized rigour, Tristanb, Uthbrian, WhatamIdoing, 6 anonymous edits

Flow cytometry  Source: http://en.wikipedia.org/w/index.php?oldid=500986465  Contributors: 1111scientist, Aaron carass, Aelindor, Alan Liefting, Alansohn, Alboyle, Andycjp, Anthonyhcole,
Antibody2000, Arcadian, Arch dude, Beetstra, Bender235, Bensaccount, Big Bob the Finder, Bisc import, Borislav Dopudja, Brim, Btyner, Bwbrian, Carandraug, Chaz1066, Chm.bath,
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Wouterstomp, Wyvyrn, Xandi, Yserarau, ‫ﺗﺮﺟﻤﺎﻥ‬05, 256 anonymous edits

Glucose  Source: http://en.wikipedia.org/w/index.php?oldid=500836066  Contributors: *drew, .:Ajvol:., 217.99.96.xxx, 78Laura, Acalamari, Acdx, Acroterion, Addihockey10, Ado, Aeriform,
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Glycogen  Source: http://en.wikipedia.org/w/index.php?oldid=497441259  Contributors: 28421u2232nfenfcenc, AThing, Adamcieslicki, Agathoclea, Ahda, Ahltorp, Akamad, Akxcskier, Ale jrb,
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Article Sources and Contributors 456

Liaocyed, Lijealso, Looxix, MR Deidra, Magnus Manske, Mattbrundage, McDogm, Michael Shields, Mikael Häggström, Mike Rosoft, Mj455972007, Mjharrison, Mmortal03, Narayanese, Ng.j,
Nihiltres, Nirmos, Nutriveg, Nxl256, Ohnoitsjamie, P.s. hua, PDH, Peter K., Physchim62, Pinethicket, Poktirity, Pro crast in a tor, Reconsider the static, Renato Caniatti, RexNL, Rfc1394,
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XxClayTheBossxX, XxNeXuSxX, Zombiejesus, Zuma212, Zynwyx, ~K, 이형주, 283 anonymous edits

Glycoprotein  Source: http://en.wikipedia.org/w/index.php?oldid=497427256  Contributors: (무단팔극권), Abergabe, Abstraktn, Alterrabe, Antelan, Aoso0ck, Arcadian, Bomac, Borgx,
Bybbyy, C5health, Calvero JP, CanadianLinuxUser, Chrislk02, Christian75, Cjb88, ClashofAges, Closedmouth, DMY, Dave Runger, Denisarona, DisillusionedBitterAndKnackered, Download,
Drphilharmonic, Dysprosia, Edgar181, Ekem, Ergosterol, Fenice, Glenn, Glycoform, Gregorius Pilosus, Gurch, Harry watson, Ianml, J.delanoy, JFb, Jefffire, Jfdwolff, Jonkerz, Kdruhl,
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TheAMmollusc, TheTito, TimVickers, Tony1, Vainamainien, Wintermut3, Wk muriithi, Wynler, ZabMilenko, Zfr, 100 anonymous edits

Histology  Source: http://en.wikipedia.org/w/index.php?oldid=493173577  Contributors: 13alexander, 2004-12-29T22:45Z, 217.99.96.xxx, APH, Aacruzr, Abulkasam, AdjustShift,
Ahoerstemeier, Alansohn, Alessandro f2001, Alex.tan, Anclation, Andre Engels, Andres, Antandrus, Arcadian, Benjiboi, Beowulf.1000, Bio geekz, Bobblewik, CDN99, CTPhilosopher, Cellpath,
Ceyockey, Chale14, Chmod007, Chris the speller, Chrisscrewball, Clicketyclack, Cncs wikipedia, Coffee, Conversion script, Correogsk, Ctalab, Cuahl, Cutler, DARTH SIDIOUS 2, DRosenbach,
DavidMuskett, Davidiad, Delirium, Delldot, Demicx, Digital Tsukasa, DocWatson42, Dr. Kasem, Eleassar777, EmmanuelM, Emmanuelm, Emperorbma, Enchanter, Eran of Arcadia, Fenkys,
Galaxiaad, Glenn, Glossologistsucks, Gogo Dodo, HaroldLHammond, Hgvinc, Hovea, Hu12, Hveziris, Iridescent, JAKiernan, JeremyA, Jfraser, Jhomtaz, Jll, John Vandenberg, Jonkerz,
Juliancolton, Just James, Kaboytes, Kalaiarasy, KaurJmeb, Kjkolb, Klopfleisch, Kostisl, Kpjas, Kricxjo, LLDMart, Lexor, LuK3, MER-C, Magnus Manske, Mattopaedia, Mav, Metju, Meyer's
Histology, Michi zh, Mickchy2k, Mike Dillon, Mike Rosoft, Mike Serfas, Mild Bill Hiccup, Mr.Bip, Mrskristyn, Mycroft7, NawlinWiki, Ncurrier, Nihola, Nk, Nlu, Northerncedar, Novangelis,
Nqn, Nuujinn, Obafgkm, Origamiemensch, P. S. Burton, Phansen, Plasmic Physics, Psychofox, Ranveig, Renato Caniatti, RexNL, Robert M. Hunt, Robert brand, Roberta F., Rodrigja, Rogerva,
Rotational, Ryan, Ryomaandres, SCEhardt, ST47, ScAvenger, Schnurrbart, Selket, Shoeofdeath, Shportin1, Silvamad, Sitarius, Sjschen, SkyWalker, Snek01, Sp33dyphil, SpuriousQ,
Staphylococcus314, SunCreator, Sunray, Tastyecats, Technidata, TenOfAllTrades, The Thing That Should Not Be, Thehumorous, Tiddly Tom, Tjcheckley, Tobby72, Toddst1, Treisijs, Trigger
hippie77, Troberts 1234, Tryptofish, Uranium-junkie, Valodzka, Vinnie Della Speranza, WahreJakob, Wavelength, WikHead, Wimt, Wolfkeeper, Yerpo, Zfr, Zonethree, 257 anonymous edits

Immunohistochemistry  Source: http://en.wikipedia.org/w/index.php?oldid=496422681  Contributors: 9banDH, Adrian J. Hunter, AkashAD, Alboyle, Andreenka, Antibody123, Arcadian,
Belizefan, Bioinformin, Bjwebb, Brianga, CDN99, Chaz1066, Chris the speller, Clicketyclack, Crystallina, DO11.10, Danrichjohn, Dr Aaron, E.01, Eitch, Graham87, Gustavocarra, IHCPro,
ITBlair, Immuno, Imoen, Isaacdealey, Ixfd64, Jfdwolff, Johnuniq, Jonakimmen, Jonkerz, Ju66l3r, Kereish, Kkmurray, Lexor, Lozadamunoz, MER-C, Matchups, Monen1985, Natarajanganesan,
Nephron, Novangelis, Onepebble, Peak, Potcherboy, Promethean, RDBrown, Radagast83, Rdbrady, Rich Farmbrough, Rjwilmsi, Runningamok, Rustavo, SCEhardt, Saimhe, Salsb, Shaddack,
Shell Kinney, Skullers, Slarson, Spudgun, Stephen Spencer, Swharden, Tabletop, Travis.jennings, Vogon77, Xris0, Zkaleem, Zouden, Клеткин, ‫ﻣﺎﻧﻲ‬, 125 anonymous edits

Immunology  Source: http://en.wikipedia.org/w/index.php?oldid=501030978  Contributors: APH, AbinoamJr, Adavallou, Aetkin, Alansohn, Andreadb, Andres, Andries, Antigrandiose,
Anurag.00197, Arcadian, Argon233, Ariedartin, ArmadilloFromHell, Art LaPella, AxelBoldt, Bact, Boghog, Bratsche, Brtlabs, Caltas, Celefin, Cforrester101, Christian List, Cinik, Connelly,
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TylerDurden8823, VX, Verbal, Versageek, Violask81976, Wavelength, Wikicrat, Wouterstomp, Yan rowe, Ymei, Ymerino, Yobol, Yohan, Youssefsan, ZayZayEM, Zeno Gantner, Zhou Yu,
Zigger, ZimZalaBim, Тиверополник, 217 anonymous edits

Lipid  Source: http://en.wikipedia.org/w/index.php?oldid=499773122  Contributors: 168..., 27 Juni, 52 Pickup, 61 88 131 149a, A8UDI, Actam, Adambro, Addshore, AeonicOmega,
Ahoerstemeier, Aitias, Albert galiza, Alice Davidson, Alteripse, Anaxial, Andrewx96, Andycjp, Andymc, Antandrus, Aranherunar, Arcadian, Arthena, Artichoker, Ashill, Ashleyisachild,
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CharlotteWebb, Choij, Chrislk02, Christian75, Cimex, Clicketyclack, ClockworkSoul, Compaddict11, Conversion script, Coppertwig, Costas78, Courcelles, Crazynas, Cruccone,
Curiousgeorgethemonkey, DARTH SIDIOUS 2, DVD R W, Daf, Dakilla15, Dan4636, Daniel Cliff, Daniel5127, Dannyhoffman, DarkHorizon, Darklilac, Darth Panda, Dave6, Dcoetzee,
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Fireice, Frankenpuppy, Freiddie, GFP, Garzo, Giants27, Giftlite, Giraffedata, Glane23, Gomm, Gurch, Gustavb, Gwernol, HaeB, Haham hanuka, Hapsiainen, Hardrada, Harvy2004, Headbomb,
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Jedidan747, Jesse V., Jfdwolff, JimBrownish, JimVC3, JinJian, Joanjoc, JoeAnderson, Jrtayloriv, Jvcallaway, Kajasudhakarababu, Kandar, Karada, Karol Langner, Katgabrielle, Keilana, Kelly
Katula, King003, Knopfkind, Kruusamägi, Krylonblue83, Kupirijo, Kuru, LeaveSleaves, Lemchesvej, Lennert B, Leptonsoup337, Lir, Lmaps, Loren.wilton, Lunchboxhero, Lunkwill42,
MEHMEHMEHMEH, MER-C, MZMcBride, Mac, Madfalcon108, Madhero88, Magnus Manske, Mani1, Marc Venot, Marj Tiefert, Markacohen, Maryrebecca, Matanya (renamed),
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Ichiro, Yelsaimery, Zephyris, Zzuuzz, ‫ﮐﺎﺷﻒ ﻋﻘﯿﻞ‬, आशीष भटनागर, 855 anonymous edits

Lipopolysaccharide  Source: http://en.wikipedia.org/w/index.php?oldid=497384003  Contributors: Aceofhearts1968, Adenosine, Aestasis, Alan Liefting, Alansohn, Arcadian, AxelBoldt, Bjh21,
BunnyNMontreal, Calvinchong, CanisRufus, Cburnett, Chikiss, Colincbn, DO11.10, DRosenbach, Diberri, Dr.saptarshi, Drphilharmonic, Eras-mus, Eug, Fawcett5, Firsfron, Gak, GargoyleMT,
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Spike0xFF, Tdlogan, TestPilot, Untrue Believer, Vojtech.dostal, Voriig Kye, Wikijens, Wootini, YUL89YYZ, 90 anonymous edits

Metabolism  Source: http://en.wikipedia.org/w/index.php?oldid=499924644  Contributors: - ), .:Ajvol:., A. Parrot, A8UDI, AVand, Aaaaaactually, Aacac, Ababababa1, Acroterion, Adam
Hasheesh, AdjustShift, Adrian J. Hunter, Agentilini, Ahoerstemeier, Aitias, Alai, Alan Au, Alan Liefting, Alex.muller, Algumacoisaqq, Allstarecho, Alpha1337Saint, Amaher, Ampersand777,
Anaxial, AndreasJS, Andrew6906, Androstachys, Anna Lincoln, Antandrus, Arcadian, Aremith, ArielGold, Arthena, AshLin, Ashleyisachild, BD2412, BarretB, Batmanand, Beetstra,
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Article Sources and Contributors 457

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Zirconscot, 544 anonymous edits

Microbial ecology  Source: http://en.wikipedia.org/w/index.php?oldid=490744571  Contributors: Alan Liefting, Arch o median, Avenged Eightfold, Bendzh, Bioguz, Camrn86, Darrien, Enajy,
Epipelagic, Estevezj, Gidip, Ilyanassa, Jaellee, Jesse V., Jneufeld, LeeHunter, Levineps, MG55T, Munita Prasad, Northamerica1000, OldakQuill, Oscar Evans, PatVanHove, R'n'B, Radiant!,
Rjwilmsi, Rotcaeroib, Sabedon, Stemonitis, Tardigrade, Thesquire, Touchstone42, Triddle, Unara, Wavelength, 15 anonymous edits

Microbial genetics  Source: http://en.wikipedia.org/w/index.php?oldid=496468181  Contributors: Avalon, Bhawani Gautam, Correogsk, Drmies, Epbr123, Jethero, Maksud3, Melaen, PDH,
Romanov1, Sarahj2107, Skapur, Zzuuzz, 8 anonymous edits

Microbiology  Source: http://en.wikipedia.org/w/index.php?oldid=499857043  Contributors: 5 albert square, AJCann, AJim, APH, Achaemenes, AdRock, AdamRetchless, Adodda05, Advanced,
Afluent Rider, Alan Liefting, Alpha male wolf, AlphaEta, Anclation, Andreadb, AnmaFinotera, AnnaJune, Antandrus, Anthonyhcole, Anypodetos, April kathleen, Arcadian,
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Mitochondrion  Source: http://en.wikipedia.org/w/index.php?oldid=500054715  Contributors: 168..., 24.12.199.xxx, A-giau, A30382, Aaron Schulz, Across the miles, Adenosine, AdjustShift,
Ado, Adriaan, Adrian.benko, Aeioun, Ahaffa, Aitias, Alansohn, Alcmaeonid, Algumacoisaqq, Allen4names, Alumunum, Amarrg, Anaraug, Anclation, AndyZ, AnkhMorpork, Anomalocaris,
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Wells, TimVickers, Tofutwitch11, Tom Lougheed, Tomiko72, Tomm490, Tommy2010, Toniwikipendia, Traxs7, Triguy11, Trintith, Trusilver, Tunzinette, Turkilas, TyA, Tycho,
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Wayne Slam, Wayward, Where next Columbus?, Why Not A Duck, Wikid77, Wikieditor06, WikipedianMarlith, WillowW, Winhunter, Wknight94, Woohookitty, Wowcody, Writ Keeper,
WriterHound, Xestia, Xlaxplaya, Xris0, Yabti, Yaffley, Yamamoto Ichiro, Yunshui, Yuorme, Zafiroblue05, Zephyris, Zero sharp, Zocky, Zoicon5, Zzuuzz, Zzyzx11, Σ, ‫ﻗﯿﺼﺮﺍﻧﯽ‬, තඹරු විජේසේකර,
1431 anonymous edits

Molecular microbiology  Source: http://en.wikipedia.org/w/index.php?oldid=491952473  Contributors: Alan Liefting, Bhawani Gautam, Guettarda, Headbomb, JeremyA, Jesse V.,
Micron.ac.uk, Nagelfar, Nono64, Rich Farmbrough, Rjwilmsi, Skier Dude, TableManners, Touchstone42, 6 anonymous edits

Morphology (biology)  Source: http://en.wikipedia.org/w/index.php?oldid=498500819  Contributors: 11sharpshot, Adan, Alcmaeonid, Andycjp, ArnoLagrange, Bento00, Binary TSO, Bonás,
Chenli, Ciphers, Clicketyclack, Coopersk, Daniel Mietchen, Dinesh smita, Drgarden, Drussey, Dysmorodrepanis, Eleassar, Elrodriguez, EncycloPetey, Farmasistudent, FiverBeyond,
Fryed-peach, Funkamatic, Giancarlodessi, Ginkgo100, Gits (Neo), HCA, HappyVR, Hellknowz, J.delanoy, Jack Merridew, Jethero, Jim1138, JinJ, Jj137, Johnkeats, Johnuniq, Jonkerz,
Kalaiarasy, KimvdLinde, Kungfuadam, LeaveSleaves, Leptictidium, Lol n00b yuiop, Lowellian, Molono8, Mzajac, Nath1012, Neoteen13, Pine, Ragesoss, Revery, Richard001, Rmashhadi,
SP-KP, Sankeman, Sfwhip, Shakiestone, Skippan, Skittleys, Some jerk on the Internet, Standinguptoit, The Rationalist, Troop350, Tsop, TyA, WardXmodem, Wickey-nl, Z10x, 68 anonymous
edits

Mucin  Source: http://en.wikipedia.org/w/index.php?oldid=493301073  Contributors: Altenmann, Arcadian, Art Carlson, Banus, Boghog, Chochopk, Delldot, Doseiai2, Icairns, Iloveyoupm,
Japanese Searobin, JohnJohn, LLDMart, Nbauman, Nephron, Nightstallion, Nono64, Openlander, Orbst, R'n'B, Rjwilmsi, Several Pending, Sfahey, Shaddack, Smith609, Thialfi, Trickrick2001,
Uthbrian, Vinne2, Zeeexsixare, 35 anonymous edits
Article Sources and Contributors 458

Mycology  Source: http://en.wikipedia.org/w/index.php?oldid=492743377  Contributors: APH, Aitias, Alan Rockefeller, Altenmann, Anam Gumnam, Anclation, Archenzo, Ashishbhatnagar72,
Bejnar, Ben Ben, Bettymnz4, BlueCanoe, Bluechedd, Bomac, Cacycle, Carl Francis, Cburnett, Cinik, Clementina, Cliff smith, Cohesion, Comesturnruler, Constructive editor, Conversion script,
Coolidays, DVD R W, Dalving, Darth Panda, Dbachmann, Dbollard99, Debivort, Denisarona, Dismas, Dj Capricorn, Doremo, Douglas Whitaker, Dullhunk, Duncharris, Dygituljunky,
Edwinstearns, Eedo Bee, Eog1916, Ericsteinert, Filipe1997, FireBrandon, Friviere, Gabrielbodard, Gc1234567, Graywright, Grendelkhan, Haham hanuka, HappyCamper, Hayabusa future,
Heliocybe, Helloclint, Helmoony, HiDrNick, Hojimachong, Icairns, Iohannes Animosus, Island, J Milburn, Jac16888, Jackol, Jag123, Jatlas, Jauhienij, Jerzy, Jonkerz, Josh Parris, Jvbishop,
Karl-Henner, Keahapana, Kelovy, KingTT, Kkkdc, Kristaga, Lexor, MER-C, MacTire02, Macronencer, Malcolm Farmer, MannLib, MarcusRP, Marshman, Mayumashu, Mboverload, Michael
Snow, Mikael Häggström, Mmxx, Monkeynoze, Mordicai, Mycologyauthor, Mycota, Mycowizard, Mykoweb, Nemetona, Netalarm, Philip Trueman, Piano non troppo, Pir, Portillo, Preposteruss,
Ravinpa, Reedy, Rjwilmsi, Rm1271, Romanfall, Rossami, STGM, Santista1982, Sasata, Shoujun, SilkTork, Some jerk on the Internet, Spellcast, Stemonitis, Sungai pelek guy, Tail, Tchoutoye,
Tennoutdoorsman, The cattr, Tim1357, Timo Honkasalo, Touchstone42, Weeman04, Williamb, Wimt, WojPob, YAYsocialism, Ykhwong, आशीष भटनागर, 134 anonymous edits

Myofibril  Source: http://en.wikipedia.org/w/index.php?oldid=495429310  Contributors: Alai, Angela, Arcadian, Blainster, Bobo192, Buzybeez, Ceyockey, ClockworkSoul, Cntras,
CommonsDelinker, Daarznieks, Datofm, Dictabeard, Doodle77, FrankTobia, Glagolev, HCA, Hooperbloob, James McNally, Kubra, Lexor, Lir, Lynntyler, MER-C, MONGO, Mabrewski,
MarkN, Merovingian, Moralis, Nbauman, NightWolf1298, Nsaa, Nyq, PFHLai, Poccil, Postglock, Raul654, Rodolfo Hermans, Segv11, Slashme, Slawojarek, THEN WHO WAS PHONE?,
Template namespace initialisation script, Trixt, Tyciol, Urzică, Vervin, Y12J, Zzuuzz, ‫ﻣﺎﻧﻲ‬, 67 anonymous edits

Nerve  Source: http://en.wikipedia.org/w/index.php?oldid=500721218  Contributors: *drew, 168..., A8UDI, ABF, AHands, Albert12Sanchez, Alex.muller, Alksub, Alphachimp, Altzinn,
Andycjp, Antandrus, Anthonygalvann111, Anthonyhcole, Arcadian, Arsenalthefootballchampions, Audriusa, AvicAWB, Az1568, Barzkar, Basharh, Bcasterline, Bemoeial, Bento00, Bobo192,
Bonadea, BuzyBody, Cabe6403, Calaka, CapitalR, Catgut, Cerealkiller13, Chikinpotato11, Chirality, Christopher Parham, CommonsDelinker, Conversion script, CyberRaptor, Dan D. Ric,
Daniel 1992, Doctorstacy, Dominus, Don Gosiewski, Donarreiskoffer, Drgarden, Dspradau, Ducducpham, Dysepsion, El0i, Emperorbma, Energy Dome, Epingchris, Erdal Ronahi, ErdemTuzun,
Erikhansson1, Eubulides, Everyking, Extransit, Ezeu, Femto, Flyer22, Fredwerner, Friedo, FuelWagon, Fuzzform, Gdarin, Geni, Geniac, Getwood, Ghakko, Giftlite, Gockyman, Gogo Dodo,
Graham87, Hadarot, Hazard-SJ, Hqb, II MusLiM HyBRiD II, Icephoenix26, IronGargoyle, Isnow, Jabronimus, Jacklee, Jafeluv, Jahnavisatyan, Jak123, Jamesooders, Jasontn, Jauhienij,
Jclemens, Jerryseinfeld, Joehall45, Jossi, Jumbuck, Kenichikun, Killer 12341234, KnowledgeOfSelf, Kraftlos, Ksanyi, Kunzalicious, Ld100, Lentando, Lexor, Locos epraix, Looie496,
Loren.wilton, Lova Falk, Lsan08, Mailer diablo, Marc Venot, Marek69, Martarius, Massimo Macconi, Maxxicum, McSly, Mclowes, Mentifisto, Mesoderm, Mgw854, Mikael Häggström,
Milhojas, Mintleaf, Misza13, MrArifnajafov, Neifion, Nephron, Nerdygeek101, Ngantengyuen, NickGorton, Nlu, NormanEinstein, Onco p53, OwenX, Pat Payne, Patrick, Peter bertok, Philip
Trueman, Philopp, Pinethicket, Pjbflynn, Posix memalign, PrestonH, Promethean, Pwsimporter, Quirk, R'n'B, Rbanzai, Read-write-services, ResearchRave, Riley Huntley, Rivertorch,
Roastytoast, Robinatron, Robinmeeee, Rror, Runningonbrains, Sanguinity, Satori Son, Sayeth, SchfiftyThree, Sci0x, Senator Palpatine, Sietse Snel, Sortie, Spangineer, Squirt2711, StarryEyes,
Strongsauce, Super-Magician, Tcncv, Techman224, Teles, The Anome, The Thing That Should Not Be, TheEgyptian, Thegreatandpowerfulsimonseville, Tide rolls, TigerShark, Tomdo08, Tosha,
Tregoweth, Tryptofish, Tsa1093, WLU, Wafulz, Williamhooligan, Yangat, Yidisheryid, Yuckfoo, Zachbe, Zandperl, Σ, ‫יוסי‬, ‫ﻓﯿﺰﯾﻮﺗﺮﺍﭘﯿﺴﺖ ﺍﺑﺮﺍﻫﯿﻢ ﺑﺮﺯﮐﺎﺭ‬, ‫ﮐﺎﺷﻒ ﻋﻘﯿﻞ‬, 370 anonymous edits

Nissl body  Source: http://en.wikipedia.org/w/index.php?oldid=474496008  Contributors: Arcadian, Bender235, Brim, EerieNight, Elleckz, Enix150, Hut 6.5, Iv0202, KenyaSong, KrmartinCA,
Lenrodman, Lovebeingme, Lynntyler, Manfi, Mikael Häggström, Riffle, Skimsu, SkyWalker, Stepa, Tameamseo, Velella, Zoz, 18 anonymous edits

Nucleic acid  Source: http://en.wikipedia.org/w/index.php?oldid=500032024  Contributors: 168..., 2 of 8, A4, Abrech, Acelgoyobis, Adam Bishop, Addshore, Agathman, Alansohn, Alboyle,
Alex43223, Alexius08, Anclation, Andre Engels, Angela, Anthere, Antony-22, Antzervos, Aoi, Arakunem, Araucaria, Arbitrarily0, Armin Straub, Astronautics, AxelBoldt, BD2412,
Babyranks17, Barticus88, Beethoven's DNA, Beetstra, Bensaccount, Bobchicken9, Bobo192, Bongwarrior, BrightStarSky, CDN99, CL, CLW, Cacycle, Cadiomals, Can't sleep, clown will eat
me, Careless hx, Ceyockey, Chanoyu, ChaosR, Chillowack, ChrisCork, ChrisGualtieri, ChrisHodgesUK, Ciphers, Conversion script, Courcelles, Cpeditorial, Cyan, DARTH SIDIOUS 2,
Daniel5127, DarkFalls, DerHexer, Desireader, Discospinster, Dng267, Dposse, Dungodung, Dysprosia, EconoPhysicist, Ed Poor, Ellmist, Emw, Forluvoft, Frankenpuppy, Franz Bryan,
FreplySpang, G3pro, Gaia Octavia Agrippa, GeeJo, Gentgeen, GeorgeLouis, Giftlite, Gilliam, Gogo Dodo, GraemeL, Graft, Grunty Thraveswain, Gurch, Gwernol, Hede2000, Hellow yo,
Hellowhy, Hephaestos, Hu, Hydrogen Iodide, I dream of horses, Ianis G. Vasilev, Inka 888, It Is Me Here, J Di, J.delanoy, JForget, JMBurke1791, James086, Jauhienij, Jhannah, Joanjoc, John
Mackenzie Burke, John R Murray, JonMoulton, JonRichfield, Josh Cherry, Josh Grosse, Julesd, K3f3rn, Kablammo, Kalaiarasy, Kandar, Kbdank71, Keegan, Kierano, KimvdLinde, Kkmurray,
Kocio, Kpjas, Kyle 290, LAX, La goutte de pluie, Laurascudder, Leonard Vertighel, Lexor, Lfh, Liamdaly620, Lir, Looie496, Luna Santin, LyXX, M80forYOU, Magog the Ogre 2,
Marudubshinki, Maurice Carbonaro, Mav, Maxxicum, Mendaliv, Miaow Miaow, Mikegrant, Misza13, Mlouns, My76Strat, Mygerardromance, Narayanese, Narsil, NellieBly,
NewEnglandYankee, Ngourlie, Nirmos, Nk, Nposs, NuclearWarfare, Omicronpersei8, Onco p53, OrangeDog, OrenBochman, Oxymoron83, P99am, Pakaran, Petergans, Petrb, Pgan002, Pharaoh
of the Wizards, Philip Trueman, Piano non troppo, Pinethicket, Pobregatita, Polypipe Wrangler, Popnose, Possum, Ppgardne, Ppntori, Preston.hussey, Pschemp, RJaguar3, Rcej, Res2216firestar,
Rifleman 82, Rjwilmsi, Ronhjones, Royalmate1, SJP, Salamurai, Salvio giuliano, Scharks, Schmutz MDPI, Sciurinæ, Seba5618, Sgpsaros, ShellCoder, Shuipzv3, Simeon H, Sintaku,
SixPurpleFish, Skizzik, Smack, Smaug123, Snoyes, Sonicology, SpikeToronto, Squidonius, Stephen5406, Stewartadcock, Str1977, Strathallen, Tad Lincoln, Talon Artaine, Teles, The Thing That
Should Not Be, TheTito, Thehelpfulone, Thingg, Tide rolls, Tim1357, TimVickers, TimonyCrickets, Tobby72, Tommy2010, Trevor MacInnis, Tuganax, U.S.A.U.S.A.U.S.A., Ugen64, Uncle
Dick, User A1, VIOLENTRULER, Vary, Versus22, Violetriga, Vrenator, W3bj3d1, Waggers, Wayne Slam, Widefox, Wikipedia addict101, Wimt, Wisdom89, Wysprgr2005, Xdenizen,
Yachtsman1, Yk Yk Yk, Yngvadottir, Yoenit, Ziusudra, 625 anonymous edits

Organelle  Source: http://en.wikipedia.org/w/index.php?oldid=499164740  Contributors: 090-chall, 168... DNA edit war, 1pezguy, 2004-12-29T22:45Z, 212.134.69.xxx, 28bytes, AVand,
ActivExpression, Adenosine, Alansohn, Alfie66, Amantine, Anclation, Andre Engels, Andy120290, Andycjp, Antionne1, Arcadian, Avoided, BKalesti, Badanedwa, Beno1000, Bensaccount,
Bernie Sanders' DNA, Bggoldie, Bhumiya, Bidabadi, Billare, Bio geekz, Biologos, Bjarki S, Blake-, Blanchardb, Blaxthos, Bleebie84105, Blue Danube, Bobo192, Boing! said Zebedee, Bomac,
Bozartas, Breakyunit, Brian Crawford, CSWarren, Caladont, CanisRufus, Capricorn42, Careless hx, Carmichael, Catgut, Cathardic, Cdcdoc, Chaos, Chaser, Chizeng, Ckatz, ClamDip,
ClockworkSoul, Clohse17, Conversion script, Corrigen, Courcelles, Cp111, Cspurrier, Csörföly D, DVdm, Daniel5127, Dark Samus, DarkAudit, Darkwind6000, Debresser, Decumanus,
Deflective, Deor, DerHexer, Dgw, Dietzel65, Discospinster, DivineAlpha, Dogposter, Doug swisher, Download, Drphilharmonic, Drsrisenthil, Dullhunk, Duncharris, Durova, Dwayne,
Edittingdude, Efe, Elapied, Enochlau, Epbr123, Eribro, Eric-Wester, Evanreyes, Excirial, Extrablue, Faradayplank, Farid2053, Ferengi, Forever Dusk, Fraggle81, Freakofnurture, FreeKresge,
G3pro, Gabbe, George W Bush's DNA, Gholam, Giftlite, Gilliam, Glassofwateronthecounter, Gogo Dodo, GoingBatty, GrandpaDoc, Gustafave, Guyd, Hadal, Hal0 g33k101, Halmstad, Harry
Reid's DNA, Hello32020, Hotcrocodile, Hurricane111, Hydrogen Iodide, II MusLiM HyBRiD II, IRP, IW.HG, Ilmari Karonen, Ilyanep, Intelati, Iridescent, Ixfd64, J.delanoy, JForget, JaGa,
Jackol, Jmcollier, John Ensign's DNA, John Owens' DNA, John the ripper, John254, Johnny Isakson's DNA, Jon Kyl's DNA, Jon Porter's DNA, JonathonSimister, JulianC, Jusdafax,
Justinsomnia, KEN SALAZAR'S DNA, KGasso, Kay Dekker, Kazkaskazkasako, Kazvorpal, Kelly Martin, Kinaro, Kpjas, Kupirijo, Kurtispj, Kville105125, Kwamikagami, Kwiki, L'Aquatique,
LadyofHats, LeeG, Lexor, Lilceez, Lir, Livitup, Low-frequency internal, Lozeldafan, Luna Santin, Magnus Manske, Magog the Ogre, Marcelivan, Mark91, MarkS, Martial75, Martious, Mato,
Matthew Yeager, Mav, Mentifisto, Mhking, MichaK, Michael Hardy, MichaelBillington, Micromagnets, Middlemanmaster, MidgleyDJ, Midgrid, Mikael Häggström, Mike2vil, Misscutie27,
Mononomic, Monterey Bay, Mormegil, Mostermann, Mrpepsidrink, Mschel, N2e, Nakon, NawlinWiki, Necessary Evil, Nehrams2020, Neocrypticzero, New Jack Swing, NewEnglandYankee,
Nickptar, NilsTycho, OnePt618, PFHLai, Paul Foxworthy, Pauli133, Paxsimius, Pb30, Pepper, Philopp, Piano non troppo, Pinethicket, Plindenbaum, Postglock, Princess Clown, Prodego,
Proofreader77, R. S. Shaw, RA0808, Rama's Arrow, Rcej, Ready, Realricanboy123, Reaper Eternal, Res2216firestar, Rettetast, Rexkim, Rhd, Riana, Rishaj, Rjwilmsi, Roemmdal, Ronhjones,
Scjessey, Seegoon, Senator Palpatine, Sephiroth BCR, Shadowjams, Shakarun1, Shanes, Sharkface217, Shelly berkeley's DNA, Shlomke, Skarebo, Skizzik, Slates22, Sludtke42, Smartiger,
Snapish, Snigbrook, Snowolf, Soliloquial, Soralin, Spamburgler, Steinsky, Stephenb, Stevenr123, Stwalkerster, Suriel1981, Svick, Sylverfysh, Synchronism, Tangotango, Td321, Ted Steven's
DNA, Teles, Template namespace initialisation script, Tetigit, The Thing That Should Not Be, Theccy, Thingg, Tide rolls, TimVickers, Tohd8BohaithuGh1, Tom Delay's DNA, Tom Lougheed,
TomasBat, Tombo, Tomgally, Tommy2010, TravisTX, Treygdor, Triwbe, Tryptofish, Tyrol5, Vacio, Vrenator, Wavelength, WereSpielChequers, WikiDao, WikiFew, Wikieditor06, Wikipelli,
Wondpook, Wouterstomp, X!, Yamamoto Ichiro, Yourexhalekiss, ZX81, Zzuuzz, ‫ﮐﺎﺷﻒ ﻋﻘﯿﻞ‬, 百 家 姓 之 四, 736 anonymous edits

Parasitology  Source: http://en.wikipedia.org/w/index.php?oldid=497579979  Contributors: APH, Ahmed O.Soliman, Ahoerstemeier, Allmightyduck, Allstarecho, Anclation, Anilocra, Arcadian,
Ary29, BD2412, Bact, Borgx, Ccgrimm, Cleduc, Cmdrjameson, D6, Danger, Ddb3, Durova, Dysmorodrepanis, Ezmindegy, Felizdenovo, Ida Shaw, Jivee Blau, Joelmills, Jurriaan Schulman,
KBi, Kristenq, Kubra, Lexor, Maurreen, Mayooranathan, Mayumashu, McDogm, Methcub, Mikael Häggström, Moreschi, Mornarine, Mr.Z-man, Normand.cyr, Petecarney, Phlebas,
Plommespiser, Sam Hocevar, Scvblwxq, Snek01, Stelligent, Tonicthebrown, TurboCamel, TylerDurden8823, Ugen64, Vet1978, Wdfarmer, Wickey-nl, Xeno, YuriSuassuna, ‫ﻣﺤﺒﻮﺏ ﻋﺎﻟﻢ‬, आशीष
भटनागर, 76 anonymous edits

Peptidoglycan  Source: http://en.wikipedia.org/w/index.php?oldid=495508496  Contributors: 2004-12-29T22:45Z, 24Adrianus, A More Perfect Onion, Alice.odin, Anclation, AndyZ,
AnnaFrance, Arcadian, Ariliand, B20180, Blue520, Boston, Bryan Derksen, CDN99, Caltas, Carl Wivagg, Cburnett, ClockworkSoul, Conversion script, Daevatgl, Dende81, Drphilharmonic,
Edgar181, EerieNight, EncycloPetey, Equendil, Eras-mus, Eubulides, Eyal Bairey, Fredil Yupigo, Graham87, Harrisd5917, Hodja Nasreddin, Isnow, Jeppelbaum, Johannordholm, Jonasbinding,
Jusdafax, Kinglz, Kupirijo, Leptonsoup337, Lexor, Leyo, Mac Davis, Magn0lia, Magnus Manske, MarcoTolo, Marj Tiefert, Mcstrother, Michael Hardy, Mouagip, Mushin, Mårten Berglund,
Naddy, Omid Parto, Our Phellap, PDH, Psora, Rich Farmbrough, Rjwilmsi, Roo72, Shadowjams, Shikuto.ai, Smack, Spencerw, Startrixtriplexxx, Steve98052, Steveking 89, The Anome,
Touchstone42, Tranio24, Truthflux, Twooars, Uazikoff, Unsldsovereignty, Vrenator, WeigelaPen, Wickey-nl, WolfmanSF, Yikrazuul, 121 anonymous edits

Plant  Source: http://en.wikipedia.org/w/index.php?oldid=500877497  Contributors: 1nic, 321mister, Abductive, Acalamari, Accurizer, Ace ETP, Adam McMaster, Adambro, Adashiel,
Adenosine, Adsomvilay, Agong1, Agrihouse, Ahoerstemeier, Alan Liefting, Aleksa Lukic, Ali, Alink, Almafeta, Almog6564, Altenmann, Alwolff55, AmiDaniel, Anclation, Andre Engels,
Andrew R. White, Andrewjlockley, Andrewpmk, Andris, Androstachys, Andux, Andyjsmith, Anger22, Angielaj, Anna Frodesiak, Anomalocaris, Antandrus, AnthonyBryars, AntiVan, Antonrojo,
Anwar saadat, AquamarineOnion, Arcadian, Arfan, Arjun01, Arjuna316, Arkuat, Arnorian, Arsalan daudi, Art LaPella, Ashley Y, Ashmoo, Astropithicus, AtomicDragon, AuburnPilot, Aude,
Autocracy, AxelBoldt, AxiomShell, Banes, BanyanTree, Barbara Shack, Barklund, Barneca, Barticus88, BaseballDetective, Bdiscoe, Bdwolverine87, Bearly541, Bearman4, Beezhive, Benbest,
Bendzh, Bensaccount, Bergsten, BerneyBoy, Bewareofdog, Bibliomaniac15, Billare, Bleach926, Bobblewik, Bobianite, Bobisbob, Bobo192, Bomac, Bongwarrior, BorgQueen, BorisTM,
Article Sources and Contributors 459

Borislav, Bosniak, Brainster 101, Branddobbe, Brastein, Briséis, Bubba hotep, C.Fred, CIreland, Caca, Cadiomals, Caltas, Calvin Limuel, Can't sleep, clown will eat me, CanDo, CapitalR,
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Halsteadk, Hapsiainen, Hardyplants, Hattes, Hdt83, Hdurina, Heegoop, Heimstern, Helikophis, HelloMojo, HenkvD, Henriette, HenryLi, Hephaestos, Heron, Heyitschrisss, Hi112233, Hi332211,
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JesseGarrett, Jhagadurn, Jiddisch, JinJian, Jkyser, JoJan, Joan-of-arc, JoanneB, JoeSmack, JohnnyMrNinja, Jolt76, Josh Grosse, Joyous!, Jpatros, Junglecat, Jurj, Juzeris, Jwanders, Jyril,
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Protein  Source: http://en.wikipedia.org/w/index.php?oldid=497287353  Contributors: 021-adilk, 162.129.26.xxx, 168..., 200itlove, 8472, A K AnkushKumar, A-giau, AA, ABF, Aarktica, Aaron
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Ahoerstemeier, Aitias, Ajraddatz, Alansohn, Aldocella, Ale jrb, Ancheta Wis, Anclation, Andonic, AndreNatas, Andres, Anthonyhcole, Apparition11, Arcadian, Arthena, Atlantia, Av99,
Avicennasis, Avoided, AwamerT, Bailo26, Barzkar, Bezenek, Bjarki S, Blanchardb, Blaxthos, Boateng Albert Boamah, Boky, Bomac, BrightStarSky, Brookie, BuzyBody, CLW, Call me Bubba,
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SIDIOUS 2, Daparsnips, DarekarAshish, Datofm, Dcfleck, Defender of torch, Denisarona, Discospinster, Dixiewolf, DrewBY, Drmies, Dullhunk, EPM, ESkog, Ecs-Tactic, Eleassar,
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WikiTome, Wikinomane, Wikipelli, Wimt, Woggly, Yakudza, Yersinia, Yidisheryid, Yxabelle, Yyy, Zapril, 百 家 姓 之 四, 739 anonymous edits
Article Sources and Contributors 462

Virology  Source: http://en.wikipedia.org/w/index.php?oldid=497277715  Contributors: *drew, A2Kafir, APH, Adacot, Ajc, Anclation, Andres, Arcadian, AxelBoldt, Bact, Ben davison,
Biruitorul, Bryan Derksen, CDN99, CanisRufus, Ccacsmss, Chris the speller, Clarince63, Conversion script, Corvus cornix, Cpl Syx, DTOx, DWaterson, Dalt54321, Dr. Ahmed Sofy, Eeekster,
Eequor, Elizium23, Emersoni, Espresso Addict, Fingerz, Freddekl, Funkyferret7, Gogo Dodo, GoldCityDance, GrahamColm, Gurch, Gzuckier, Headbomb, Icestorm815, Jackol, Jaho, Jesanj, Jo
Wright WB, Jonathan Williams, JuanitaJP, Keitei, Keskiyonaurinko, KillerChihuahua, Kubra, Kusername, Lagalag, Lexor, Lightmouse, Linus M., Llort, Marek69, MichaelJanich, Mikael
Häggström, MrOllie, MrTroy, Msh210, Mushin, NatureA16, NewEnglandYankee, Nima Baghaei, Nina Gerlach, Nirajm, Noneus, Ohnoitsjamie, Paranormal Skeptic, Pedro, Proserepair,
Pzoxicuvybtnrm, Quicksilvre, Ratemonth, Read-write-services, RekishiEJ, Rettetast, Rhys, Rje, Rob Hooft, Romanskolduns, Savant13, Shirik, Spellcast, Spencer, Svetovid, TableManners,
Tgv8925, TheEgyptian, Tide rolls, Timrollpickering, Tonicthebrown, Touchstone42, Vedran12, Velvetron, Wetman, Wimt, Woohookitty, आशीष भटनागर, 127 anonymous edits

Virus  Source: http://en.wikipedia.org/w/index.php?oldid=501176039  Contributors: 14harkinsd, 16@r, 1diot, 216.254.9.xxx, 21655, 24.108.233.xxx, 28421u2232nfenfcenc, 5ko, AC+79 3888,
AJtheeditor, AManWithNoPlan, Abb3w, Abce2, AdamRetchless, Addshore, Adenosine, Agricolaplenus, Ahoerstemeier, Ahunt, Alacante45, AlanH, Alansohn, Alex.tan, Alice.odin, AlphaEta,
Amakuru, Ameliawantsto69u, Anclation, AndrewMc, Andrewlp1991, Androstachys, Andypandy.UK, AnemoneProjectors, Aniten21, Anna Lincoln, Anomalocaris, Anonymous Dissident,
Anonymous editor, Antandrus, Antares42, Anurag Garg, Apostrophe, Apparition11, AquamarineOnion, Arcadian, Arch dude, Archola, Ark2120, Art LaPella, Artichoker, Ashley Y, Assela,
Aubrey Moore, AxelBoldt, Azhyd, Azumeimiya ivanette, BGManofID, BSL4.BioHazard, Badgernet, Badonkadonk xo, Bawolff, Bazookafox1, Bcartolo, Bcorr, Beaumont, Ben-Zin, Beno1000,
Bernopedia, Bigdaddyeor, Bigsandtiny123, Bil101eilay, BinaryTed, Biologie2000, Blanchardb, Blehfu, Blitterbug, Bluemask, Bobblewik, Bobus Builderus, Bomac, Bongwarrior, Bookermorgan,
Boothy443, Boznia, Bradfordandrew, Braincricket, Brandmeister, Brandmeister (old), Brighterorange, Brion VIBBER, Brossj54, Bryan Derksen, Bubbachuck, Buffalosoldier92, Bugtrio,
Buzz-tardis, Bvinee, Bwrs, Cactus Guru, Calmer Waters, Caltas, Camw, Can't sleep, clown will eat me, Canadianbob, CanisRufus, Capricorn42, Captain Infinity, Captain-n00dle, Carmichael,
Carnildo, Cavan, CenozoicEra, Ceramic2metal, Ceyockey, Chairman S., Chaojoker, Charles Matthews, CharlotteWebb, Chasingsol, Chewienoo, Chitomcgee, Chooper, Christopher Parham,
Chriswiki, Chrononaut, Chun-hian, ChyranandChloe, Cimex, Ckatz, Clam0p, ClockworkSoul, Clovis Sangrail, Cohesion, Colin, CommonsDelinker, Confiteordeo, Conversion script, Correogsk,
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Washburnmav, Wavelength, Wayne Slam, Wayward, WereSpielChequers, WesleyChartrand, What!?Why?Who?, Wickey-nl, Wiki alf, Wikiborg, Wikipelli, Wikitarwin, Wilke, WillowW,
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Xmort, Xraven92, Yamaguchi先 生, Ymerino, Ynaztiw, ZScarpia, Zahid Abdassabur, Zav, Zeamays, Zentropa, Zhou Yu, Zodon, Zoicon5, Zomitra, Zsinj, Zuleeema, と あ る 白 い 猫, 达
伟, 1597 anonymous edits
Image Sources, Licenses and Contributors 463

Image Sources, Licenses and Contributors


Image:AminoAcidball.svg  Source: http://en.wikipedia.org/w/index.php?title=File:AminoAcidball.svg  License: Public Domain  Contributors: Edgar181, TimVickers, Wutsje, YassineMrabet, 2
anonymous edits
Image:Amino Acids.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_Acids.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Dancojocari
File:Loudspeaker.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Loudspeaker.svg  License: Public Domain  Contributors: Bayo, Gmaxwell, Husky, Iamunknown, Mirithing,
Myself488, Nethac DIU, Omegatron, Rocket000, The Evil IP address, Wouterhagens, 19 anonymous edits
Image:Lysine fisher struct num.png  Source: http://en.wikipedia.org/w/index.php?title=File:Lysine_fisher_struct_num.png  License: GNU Free Documentation License  Contributors:
User:Ppfk
Image:D+L-Alanine.gif  Source: http://en.wikipedia.org/w/index.php?title=File:D+L-Alanine.gif  License: Public Domain  Contributors: Antonsusi, Ayacop, Edgar181, Jahobr, SharkD, 2
anonymous edits
Image:Amino acid zwitterions.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_acid_zwitterions.png  License: GNU Free Documentation License  Contributors: TimVickers
Image:Protein-primary-structure.png  Source: http://en.wikipedia.org/w/index.php?title=File:Protein-primary-structure.png  License: Public Domain  Contributors: National Human Genome
Research Institute (NHGRI)
Image:L-selenocysteine-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:L-selenocysteine-2D-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27
Image:Beta alanine comparison.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta_alanine_comparison.png  License: GNU Free Documentation License  Contributors:
Dr.saptarshi, Edgar181, 1 anonymous edits
Image:Strecker Amino Acid Synthesis Scheme.png  Source: http://en.wikipedia.org/w/index.php?title=File:Strecker_Amino_Acid_Synthesis_Scheme.png  License: Public Domain
 Contributors: ~K
Image:Peptidformationball.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Peptidformationball.svg  License: Public Domain  Contributors: Karol007, Marek Mazurkiewicz,
PatríciaR, Rocket000, YassineMrabet, 2 anonymous edits
File:Amino acid catabolism revised.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_acid_catabolism_revised.png  License: Creative Commons Zero  Contributors:
BrendonWSmith
file:EscherichiaColi NIAID.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:EscherichiaColi_NIAID.jpg  License: Public domain  Contributors: Credit: Rocky Mountain
Laboratories, NIAID, NIH
File:Speaker Icon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Speaker_Icon.svg  License: Public Domain  Contributors: Blast, G.Hagedorn, Mobius, Tehdog, 2 anonymous edits
File:Antoni van Leeuwenhoek.png  Source: http://en.wikipedia.org/w/index.php?title=File:Antoni_van_Leeuwenhoek.png  License: Public Domain  Contributors: J. Verkolje
File:Bacterial morphology diagram.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Bacterial_morphology_diagram.svg  License: Public Domain  Contributors: Mariana Ruiz
LadyofHats
File:Thermophilic bacteria.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Thermophilic_bacteria.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
User:Amateria1121
File:Relative scale.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Relative_scale.svg  License: Public Domain  Contributors: Created by TimVickers, vectorized by Fvasconcellos
File:Average prokaryote cell- en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Average_prokaryote_cell-_en.svg  License: Public Domain  Contributors: Mariana Ruiz Villarreal,
LadyofHats
File:Carboxysome 3 images.png  Source: http://en.wikipedia.org/w/index.php?title=File:Carboxysome_3_images.png  License: Creative Commons Attribution 3.0  Contributors: Prof. Todd O.
Yeates, UCLA Dept. of Chem. and Biochem.
File:EMpylori.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:EMpylori.jpg  License: Copyrighted free use  Contributors: Yutaka Tsutsumi, M.D. Professor Department of Pathology
Fujita Health University School of Medicine
File:Gram Stain Anthrax.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Gram_Stain_Anthrax.jpg  License: Public Domain  Contributors: Croquant, DO11.10, Dark journey, Ewen,
NEON ja, Yuval Madar, 1 anonymous edits
File:Bluegreen algae.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bluegreen_algae.jpg  License: Public Domain  Contributors: Original uploader was TimVickers at en.wikipedia
File:Binary fission anim.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Binary_fission_anim.gif  License: GNU Free Documentation License  Contributors: User:ZabMilenko
File:E.-coli-growth.gif  Source: http://en.wikipedia.org/w/index.php?title=File:E.-coli-growth.gif  License: Creative Commons Attribution 3.0  Contributors: Stewart EJ, Madden R, Paul G,
Taddei F
File:Flagellum base diagram en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Flagellum_base_diagram_en.svg  License: Public Domain  Contributors: LadyofHats
File:Streptococcus mutans Gram.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Streptococcus_mutans_Gram.jpg  License: Creative Commons Attribution-ShareAlike 3.0
Unported  Contributors: Y tambe
Image:Collapsed_tree_labels_simplified.png  Source: http://en.wikipedia.org/w/index.php?title=File:Collapsed_tree_labels_simplified.png  License: Public Domain  Contributors: Original
uploader was TimVickers at en.wikipedia
File:SalmonellaNIAID.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:SalmonellaNIAID.jpg  License: Public domain  Contributors: Cecil, Copydays, Dark journey, Gammy, Muriel
Gottrop, NEON ja, Smooth O, Taragui, 2 anonymous edits
File:Bacterial infections and involved species.png  Source: http://en.wikipedia.org/w/index.php?title=File:Bacterial_infections_and_involved_species.png  License: Public Domain
 Contributors: Mikael Häggström
File:Gerty Theresa Radnitz Cori (1896-1957) and Carl Ferdinand Cori.jpg  Source:
http://en.wikipedia.org/w/index.php?title=File:Gerty_Theresa_Radnitz_Cori_(1896-1957)_and_Carl_Ferdinand_Cori.jpg  License: unknown  Contributors: Smithsonian Institution from United
States
Image:Sucrose-inkscape.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Sucrose-inkscape.svg  License: GNU Free Documentation License  Contributors: Don A. Carlson
Image:Fat triglyceride shorthand formula.PNG  Source: http://en.wikipedia.org/w/index.php?title=File:Fat_triglyceride_shorthand_formula.PNG  License: Public Domain  Contributors:
Wolfgang Schaefer
Image:DNA chemical structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_chemical_structure.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported
 Contributors: Hystrix, Madprime, Wickey, 5 anonymous edits
Image:Beta-D-Glucose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-Glucose.svg  License: Public Domain  Contributors: Yikrazuul
Image:Saccharose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Saccharose.svg  License: Public Domain  Contributors: Booyabazooka, Calvero, Edgar181, 1 anonymous edits
Image:Cellulose-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cellulose-2D-skeletal.png  License: Public Domain  Contributors: Benjah-bmm27, Edgar181, Slashme
Image:1GZX Haemoglobin.png  Source: http://en.wikipedia.org/w/index.php?title=File:1GZX_Haemoglobin.png  License: GNU Free Documentation License  Contributors: Original uploader
was Zephyris at en.wikipedia
Image:Amino acids 1.png  Source: http://en.wikipedia.org/w/index.php?title=File:Amino_acids_1.png  License: GNU Free Documentation License  Contributors: Arria Belli,
CommonsDelinker, CommonsDelinkerHelper, Edgar181, Karelj, Matanya (usurped), OsamaK, 1 anonymous edits
Image:Schematic relationship between biochemistry, genetics and molecular biology.svg  Source:
http://en.wikipedia.org/w/index.php?title=File:Schematic_relationship_between_biochemistry,_genetics_and_molecular_biology.svg  License: Creative Commons Attribution-ShareAlike 3.0
Unported  Contributors: OldakQuill, PatríciaR
File:Phospholipids aqueous solution structures.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Phospholipids_aqueous_solution_structures.svg  License: Public Domain
 Contributors: Mariana Ruiz Villarreal ,LadyofHats
File:Blood smear.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Blood_smear.jpg  License: GNU Free Documentation License  Contributors: Jacklee, Reytan, Santosga, Snek01, 1
anonymous edits
File:Red White Blood cells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Red_White_Blood_cells.jpg  License: Public Domain  Contributors: Electron Microscopy Facility at The
National Cancer Institute at Frederick (NCI-Frederick)
Image Sources, Licenses and Contributors 464

File:Blutkreislauf.png  Source: http://en.wikipedia.org/w/index.php?title=File:Blutkreislauf.png  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Infrogmation, Jacklee,
Mardetanha, Phrood, Str4nd, Wst, 10 anonymous edits
Image:Humanbood600x.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Humanbood600x.jpg  License: Creative Commons Attribution-Share Alike  Contributors: John Alan Elson
Image:320frogblood600x2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:320frogblood600x2.jpg  License: Creative Commons Attribution-Share Alike  Contributors: John Alan
Elson
Image:320fishblood600x2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:320fishblood600x2.jpg  License: Creative Commons Attribution-Share Alike  Contributors: John Alan
Elson
File:1GZX Haemoglobin.png  Source: http://en.wikipedia.org/w/index.php?title=File:1GZX_Haemoglobin.png  License: GNU Free Documentation License  Contributors: Original uploader
was Zephyris at en.wikipedia
File:Heme.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Heme.svg  License: Public Domain  Contributors: User:Lennert B
File:Blut-EDTA.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Blut-EDTA.jpg  License: GNU Free Documentation License  Contributors: User:JHeuser, User:JHeuser,
User:JHeuser
File:Diagram of the human heart (cropped).svg  Source: http://en.wikipedia.org/w/index.php?title=File:Diagram_of_the_human_heart_(cropped).svg  License: Creative Commons
Attribution-ShareAlike 3.0 Unported  Contributors: User:Yaddah
File:Oxyhaemoglobin dissociation curve.png  Source: http://en.wikipedia.org/w/index.php?title=File:Oxyhaemoglobin_dissociation_curve.png  License: Public Domain  Contributors: Original
uploader was Ratznium at en.wikipedia Later versions were uploaded by Aaronsharpe at en.wikipedia.
File:Bleeding finger.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bleeding_finger.jpg  License: Creative Commons Attribution 2.0  Contributors: Dodo, FlickreviewR, Grafite,
Nilfanion, Southgeist
File:Bloodbags.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bloodbags.jpg  License: Creative Commons Attribution-Sharealike 2.0  Contributors: User "montuno" on Flickr
File:Red and white human blood cells as seen under a microscope using a blue slide stain.jpg  Source:
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File:Gray252.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gray252.png  License: Public Domain  Contributors: User Magnus Manske on en.wikipedia
Image:Illu compact spongy bone.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Illu_compact_spongy_bone.jpg  License: Public Domain  Contributors: SEER
Image:Caput femoris cortex medulla.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Caput_femoris_cortex_medulla.jpg  License: Public Domain  Contributors: Stevenfruitsmaak
File:Bertazzo S SEM deproteined bone - cranium rat - x10k.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bertazzo_S_SEM_deproteined_bone_-_cranium_rat_-_x10k.jpg
 License: Public Domain  Contributors: User:Sbertazzo
File:Woven bone matrix.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Woven_bone_matrix.jpg  License: Public Domain  Contributors: Robert M. Hunt. Original uploader was
Robert M. Hunt at en.wikipedia
File:Illu long bone.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Illu_long_bone.jpg  License: Public Domain  Contributors: Denniss, Hellerhoff, Jacklee, Lennert B, Patho, 1
anonymous edits
File:Bone growth.png  Source: http://en.wikipedia.org/w/index.php?title=File:Bone_growth.png  License: Public Domain  Contributors: derivative work: Chaldor (talk) Illu_bone_growth.jpg:
Fuelbottle
Image:Gray72-en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Gray72-en.svg  License: Public Domain  Contributors: Mysid
File:Bone marrow WBC.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:Bone_marrow_WBC.JPG  License: Creative Commons Attribution-Share Alike  Contributors: Bobjgalindo
Image:acute leukemia-ALL.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Acute_leukemia-ALL.jpg  License: GNU Free Documentation License  Contributors: Original uploader
was VashiDonsk at en.wikipedia
Image:Bone marrow biopsy.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Bone_marrow_biopsy.jpg  License: Public Domain  Contributors: Photographer’s Mate 2nd Class Chad
McNeeley
Image:Markkloesschensuppe.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Markkloesschensuppe.jpg  License: Public Domain  Contributors: 1029man, AlexanderDreyer,
Monstourz
Image:Lactose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Lactose.svg  License: Public Domain  Contributors: Calvero.
Image:D-glucose color coded.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glucose_color_coded.png  License: Public Domain  Contributors: Original uploader was
ClockworkSoul at en.wikipedia
Image:Alpha-D-glucopyranose-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-glucopyranose-2D-skeletal.png  License: Public Domain  Contributors:
Benjah-bmm27, Wickey-nl
Image:Beta-D-glucopyranose-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-glucopyranose-2D-skeletal.png  License: Public Domain  Contributors:
Benjah-bmm27, Wickey-nl
Image:Glucose Fisher to Haworth.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose_Fisher_to_Haworth.gif  License: GNU Free Documentation License  Contributors:
Wikimuzg
Image:sucrose 3Dprojection.png  Source: http://en.wikipedia.org/w/index.php?title=File:Sucrose_3Dprojection.png  License: Public Domain  Contributors: glycoform
Image:starchy-foods..jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Starchy-foods..jpg  License: Public Domain  Contributors: Bestiasonica, Kilom691, Knutux,
Nachcommonsverschieber, Shizhao, 3 anonymous edits
File:Wilson1900Fig2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Wilson1900Fig2.jpg  License: Public Domain  Contributors: Edmund Beecher Wilson
Image:celltypes.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Celltypes.svg  License: Public Domain  Contributors: Science Primer (National Center for Biotechnology
Information). Vectorized by Mortadelo2005.
Image:Average prokaryote cell- en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Average_prokaryote_cell-_en.svg  License: Public Domain  Contributors: Mariana Ruiz
Villarreal, LadyofHats
Image:Animal cell structure en.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Animal_cell_structure_en.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)
Image:Plant cell structure svg.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Plant_cell_structure_svg.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)
File:DAPIMitoTrackerRedAlexaFluor488BPAE.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:DAPIMitoTrackerRedAlexaFluor488BPAE.jpg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: IP69.226.103.13
Image:Diagram human cell nucleus no text.png  Source: http://en.wikipedia.org/w/index.php?title=File:Diagram_human_cell_nucleus_no_text.png  License: Public Domain  Contributors:
Mariana Ruiz Villarreal LadyofHats. Original uploader was Peter Znamenskiy at en.wikipedia
Image:Endomembrane system diagram no text nucleus.png  Source: http://en.wikipedia.org/w/index.php?title=File:Endomembrane_system_diagram_no_text_nucleus.png  License: Public
domain  Contributors: Peter Znamenskiy at en.wikipedia
Image:Proteinsynthesis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Proteinsynthesis.png  License: Public Domain  Contributors: Incnis Mrsi, Laikayiu, 1 anonymous edits
Image:PD-icon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:PD-icon.svg  License: Public Domain  Contributors: Alex.muller, Anomie, Anonymous Dissident, CBM, MBisanz,
Quadell, Rocket000, Strangerer, Timotheus Canens, 1 anonymous edits
Image:NIEHScell.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:NIEHScell.jpg  License: Public Domain  Contributors: US Government
Image:FluorescentCells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:FluorescentCells.jpg  License: Public Domain  Contributors: Amada44, DO11.10, Emijrp, Hannes Röst,
Liaocyed, NEON ja, Origamiemensch, Sentausa, Splette, Timur lenk, Tolanor, Túrelio, 8 anonymous edits
Image:Electronmicroscopynhlbi.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Electronmicroscopynhlbi.jpg  License: Public Domain  Contributors: U. S. government
Image:Drosophila m oogenesis.png  Source: http://en.wikipedia.org/w/index.php?title=File:Drosophila_m_oogenesis.png  License: GNU Free Documentation License  Contributors:
Dysmachus, Mindmatrix, Superborsuk
Image:Cell membrane detailed diagram 4.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Cell_membrane_detailed_diagram_4.svg  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: derivative work: Dhatfield (talk) Cell_membrane_detailed_diagram_3.svg: *derivative work: Dhatfield (talk) Cell_membrane_detailed_diagram.svg:
LadyofHats Mariana Ruiz
Image Sources, Licenses and Contributors 465

Image:Fluid Mosaic.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Fluid_Mosaic.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported  Contributors: Jerome
Walker
Image:Alpha Intercalated Cell Cartoon.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha_Intercalated_Cell_Cartoon.svg  License: Creative Commons Attribution 3.0
 Contributors: Rswarbrick
Image:Membrane lipids.png  Source: http://en.wikipedia.org/w/index.php?title=File:Membrane_lipids.png  License: Public Domain  Contributors: BorisTM, Gwernol, WOSlinker, 2
anonymous edits
Image:HeLa Hoechst 33258.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:HeLa_Hoechst_33258.jpg  License: unknown  Contributors: -
Image:biological cell.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Biological_cell.svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: MesserWoland
Szczepan1990
File:Leeuwenhoek1719RedBloodCells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Leeuwenhoek1719RedBloodCells.jpg  License: Public Domain  Contributors: Antoni van
Leeuwenhoek
Image:Flemming1882Tafel1Fig14.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Flemming1882Tafel1Fig14.jpg  License: Public Domain  Contributors: Walther Flemming.
Professor der Anatomie in Kiel.
Image:Diagram human cell nucleus.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Diagram_human_cell_nucleus.svg  License: Public Domain  Contributors: Mariana Ruiz
LadyofHats
Image:NuclearPore crop.svg  Source: http://en.wikipedia.org/w/index.php?title=File:NuclearPore_crop.svg  License: Creative Commons Attribution-Sharealike 2.5  Contributors:
User:Adenosine, User:LadyofHats
Image:MouseChromosomeTerritoriesBMC Cell Biol6-44Fig2e.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MouseChromosomeTerritoriesBMC_Cell_Biol6-44Fig2e.jpg
 License: Creative Commons Attribution 2.0  Contributors: Robert Mayer, Alessandro Brero, Johann von Hase, Timm Schroeder, Thomas Cremer, Steffen Dietzel
Image:Micrograph of a cell nucleus.png  Source: http://en.wikipedia.org/w/index.php?title=File:Micrograph_of_a_cell_nucleus.png  License: Public Domain  Contributors: User:Opabinia
regalis, User:PNG crusade bot, User:Remember the dot
File:Transcription label en.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Transcription_label_en.jpg  License: GNU Free Documentation License  Contributors: InfoCan, Jacopo
Werther, TimVickers, 1 anonymous edits
Image:RanGTPcycle.png  Source: http://en.wikipedia.org/w/index.php?title=File:RanGTPcycle.png  License: unknown  Contributors: Shao at uk.wikipedia
File:Mitosis-fluorescent.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mitosis-fluorescent.jpg  License: Public domain  Contributors: Deadstar, Glenn, Hikke, Kam Solusar, Liné1,
Monkeybait, Mortadelo2005, Opabinia regalis, Pieter Kuiper, Sanbec, Steveprutz, Túrelio, 10 anonymous edits
Image:redbloodcells.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Redbloodcells.jpg  License: Public domain  Contributors: Dietzel65, Habj, Ranveig, Shizhao, Simon Shek,
Solon, Sundar, Thuresson
Image:Chr2 orang human.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Chr2_orang_human.jpg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Verena
Schubel, Stefan Müller, Department Biologie der Ludwig-Maximilians-Universität München.
Image:MouseChromosomeTerritoriesBMC Cell Biol6-44Fig2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MouseChromosomeTerritoriesBMC_Cell_Biol6-44Fig2.jpg
 License: Creative Commons Attribution 2.0  Contributors: Robert Mayer, Alessandro Brero, Johann von Hase, Timm Schroeder, Thomas Cremer, Steffen Dietzel
Image:PLoSBiol3.5.Fig1bNucleus46Chromosomes.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:PLoSBiol3.5.Fig1bNucleus46Chromosomes.jpg  License: Creative Commons
Attribution 2.5  Contributors: Andreas Bolzer, Gregor Kreth, Irina Solovei, Daniela Koehler, Kaan Saracoglu, Christine Fauth, Stefan Müller, Roland Eils, Christoph Cremer, Michael R.
Speicher, Thomas Cremer
Image:Eukaryota cell strucutre.PNG  Source: http://en.wikipedia.org/w/index.php?title=File:Eukaryota_cell_strucutre.PNG  License: Public Domain  Contributors: Giac83, Ies, LadyofHats,
Lukipuk, Matthias M., Sundance Raphael, 4 anonymous edits
Image:Plant cell wall diagram.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Plant_cell_wall_diagram.svg  License: Public Domain  Contributors: LadyofHats
Image:Diatoms.png  Source: http://en.wikipedia.org/w/index.php?title=File:Diatoms.png  License: Creative Commons Attribution 2.5  Contributors: Images courtesy of Mary Ann Tiffany, San
Diego State University.
Image:Chitin.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Chitin.svg  License: Public Domain  Contributors: Dschanz
Image:Gram-positive cellwall-schematic.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gram-positive_cellwall-schematic.png  License: GNU Free Documentation License
 Contributors: Original uploader was Twooars at en.wikipedia
Image:SalmonellaNIAID.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:SalmonellaNIAID.jpg  License: Public domain  Contributors: Cecil, Copydays, Dark journey, Gammy,
Muriel Gottrop, NEON ja, Smooth O, Taragui, 2 anonymous edits
Image:Collagentriplehelix.png  Source: http://en.wikipedia.org/w/index.php?title=File:Collagentriplehelix.png  License: GNU Free Documentation License  Contributors: User:Vossman
File:Tropocollagen cross-linkage lysyl oxidase (EN).svg  Source: http://en.wikipedia.org/w/index.php?title=File:Tropocollagen_cross-linkage_lysyl_oxidase_(EN).svg  License: Creative
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Image:Unraveling Collagen.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Unraveling_Collagen.jpg  License: GNU Free Documentation License  Contributors: Julianva, Magog
the Ogre
Image:Lfg_polymer_milk.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Lfg_polymer_milk.jpg  License: Creative Commons Attribution 3.0  Contributors: Achim Hering
Image:Copolymers.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Copolymers.svg  License: GNU Free Documentation License  Contributors: Mankash (talk); original image by
en:User:V8rik
File:Stereobl.png  Source: http://en.wikipedia.org/w/index.php?title=File:Stereobl.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Materialscientist
File:Sbs block copolymer.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Sbs_block_copolymer.jpg  License: Public Domain  Contributors: InsufficientData, Lymantria, Peterlewis
Image:SBSstructure.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:SBSstructure.jpg  License: Public Domain  Contributors: BenFrantzDale, Peterlewis
Image:Localisations02eng.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Localisations02eng.jpg  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Jeremy
Simpson and Rainer Pepperkok
File:DNA Structure+Key+Labelled.pn NoBB.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_Structure+Key+Labelled.pn_NoBB.png  License: Creative Commons
Attribution-Sharealike 3.0  Contributors: Zephyris
File:ADN animation.gif  Source: http://en.wikipedia.org/w/index.php?title=File:ADN_animation.gif  License: Public Domain  Contributors: brian0918™
Image:Speakerlink.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Speakerlink.svg  License: Creative Commons Attribution 3.0  Contributors: Woodstone. Original uploader was
Woodstone at en.wikipedia
File:DNA chemical structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_chemical_structure.svg  License: Creative Commons Attribution-ShareAlike 3.0 Unported
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File:DNA orbit animated static thumb.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA_orbit_animated_static_thumb.png  License: GNU Free Documentation License
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File:DNA-ligand-by-Abalone.png  Source: http://en.wikipedia.org/w/index.php?title=File:DNA-ligand-by-Abalone.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
P99am
File:GC DNA base pair.svg  Source: http://en.wikipedia.org/w/index.php?title=File:GC_DNA_base_pair.svg  License: Public Domain  Contributors: Isilanes
File:AT DNA base pair.svg  Source: http://en.wikipedia.org/w/index.php?title=File:AT_DNA_base_pair.svg  License: Public Domain  Contributors: Isilanes
File:A-DNA, B-DNA and Z-DNA.png  Source: http://en.wikipedia.org/w/index.php?title=File:A-DNA,_B-DNA_and_Z-DNA.png  License: GNU Free Documentation License  Contributors:
Original uploader was Richard Wheeler (Zephyris) at en.wikipedia
File:Parallel telomere quadruple.png  Source: http://en.wikipedia.org/w/index.php?title=File:Parallel_telomere_quadruple.png  License: GNU Free Documentation License  Contributors:
Thomas Splettstoesser
File:Branch-dna.png  Source: http://en.wikipedia.org/w/index.php?title=File:Branch-dna.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Original uploader was Peter
K. at en.wikipedia
Image Sources, Licenses and Contributors 466

File:Multi-branch-dna.png  Source: http://en.wikipedia.org/w/index.php?title=File:Multi-branch-dna.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: . Original
uploader was Peter K. at en.wikipedia
File:Cytosin.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Cytosin.svg  License: Public Domain  Contributors: NEUROtiker
File:5-Methylcytosine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:5-Methylcytosine.svg  License: Public Domain  Contributors: Yikrazuul (talk)
File:Thymin.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Thymin.svg  License: Public Domain  Contributors: NEUROtiker
File:Benzopyrene DNA adduct 1JDG.png  Source: http://en.wikipedia.org/w/index.php?title=File:Benzopyrene_DNA_adduct_1JDG.png  License: GNU Free Documentation License
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File:T7 RNA polymerase.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:T7_RNA_polymerase.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
User:Splette
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Image:D-glucose-chain-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glucose-chain-3D-balls.png  License: Public Domain  Contributors: Benjah-bmm27
File:Yes check.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Yes_check.svg  License: Public Domain  Contributors: Anomie
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File:Glucose metabolism.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose_metabolism.svg  License: Public Domain  Contributors: Mikael Häggström
image:D-glucose wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:D-glucose_wpmp.png  License: Public Domain  Contributors: Richard Wheeler (Zephyris)
image:Alpha-D-glucose-6-phosphate wpmp.png  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-glucose-6-phosphate_wpmp.png  License: Public Domain  Contributors:
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image:Biochem_reaction_arrow_foward_YYNN_horiz_med.png  Source: http://en.wikipedia.org/w/index.php?title=File:Biochem_reaction_arrow_foward_YYNN_horiz_med.png  License:
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File:DGlucose Fischer.svg  Source: http://en.wikipedia.org/w/index.php?title=File:DGlucose_Fischer.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Christopher
King
File:Alpha-D-Glucopyranose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-Glucopyranose.svg  License: Public Domain  Contributors: NEUROtiker
File:Beta-D-Glucopyranose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-Glucopyranose.svg  License: Public Domain  Contributors: NEUROtiker
File:Alpha-D-Glucofuranose.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-Glucofuranose.svg  License: Public Domain  Contributors: NEUROtiker
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File:Alpha-D-glucose-from-xtal-1979-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:Alpha-D-glucose-from-xtal-1979-3D-balls.png  License: Public Domain
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File:Beta-D-glucose-from-xtal-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:Beta-D-glucose-from-xtal-3D-balls.png  License: Public Domain  Contributors: Ben Mills
File:Glucose 2.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose_2.jpg  License: Public domain  Contributors: Paul Nasca
File:Glycogen structure.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycogen_structure.svg  License: Public Domain  Contributors: Mikael Häggström
File:Glycogen spacefilling model.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Glycogen_spacefilling_model.jpg  License: Public Domain  Contributors: CeresVesta
Image:Glykogen.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glykogen.svg  License: Public Domain  Contributors: NEUROtiker
File:Glycogen phosphorylase2.png  Source: http://en.wikipedia.org/w/index.php?title=File:Glycogen_phosphorylase2.png  License: Public Domain  Contributors: Jmun7616
Image:Glicoprotein.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glicoprotein.svg  License: Public domain  Contributors: Kosi Gramatikoff, User:Stannered
Image:Glykoproteine Zucker.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Glykoproteine_Zucker.svg  License: Public Domain  Contributors: Yikrazuul
File:Microscope with stained slide.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Microscope_with_stained_slide.jpg  License: GNU Free Documentation License  Contributors:
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File:Emphysema H and E.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Emphysema_H_and_E.jpg  License: Creative Commons Attribution 2.0  Contributors: Bestiasonica,
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File:Cajal-va.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Cajal-va.jpg  License: Public Domain  Contributors: Butko, Chrislb, Docu, Fastfission, Sanbec, 4 anonymous edits
Image:immunohistochemistry.png  Source: http://en.wikipedia.org/w/index.php?title=File:Immunohistochemistry.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors:
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Image:Kidney cd10 ihc.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Kidney_cd10_ihc.jpg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Nephron
File:Monocyte.png  Source: http://en.wikipedia.org/w/index.php?title=File:Monocyte.png  License: GNU Free Documentation License  Contributors: Arcadian, Bobjgalindo, Joey-das-WBF,
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Image Sources, Licenses and Contributors 467

File:Phosphatidyl-Ethanolamine.png  Source: http://en.wikipedia.org/w/index.php?title=File:Phosphatidyl-Ethanolamine.png  License: Public Domain  Contributors: Original uploader was
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File:Sphingomyelin-horizontal-2D-skeletal.png  Source: http://en.wikipedia.org/w/index.php?title=File:Sphingomyelin-horizontal-2D-skeletal.png  License: Public Domain  Contributors:
Benjah-bmm27, 1 anonymous edits
File:Kdo2-lipidA.png  Source: http://en.wikipedia.org/w/index.php?title=File:Kdo2-lipidA.png  License: Creative Commons Attribution-Sharealike 3.0  Contributors: en:User:Lmaps and
User:TimVickers
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image:LPS-Assembly.svg  Source: http://en.wikipedia.org/w/index.php?title=File:LPS-Assembly.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Mike Jones
image:LPS-Transport.svg  Source: http://en.wikipedia.org/w/index.php?title=File:LPS-Transport.svg  License: Creative Commons Attribution-Sharealike 3.0  Contributors: Mike Jones
Image:Toll-like receptor pathways revised.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Toll-like_receptor_pathways_revised.jpg  License: Public Domain  Contributors:
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File:ATP-3D-vdW.png  Source: http://en.wikipedia.org/w/index.php?title=File:ATP-3D-vdW.png  License: Public Domain  Contributors: Benjah-bmm27, Daniel78, 1 anonymous edits
File:Trimyristin-3D-vdW.png  Source: http://en.wikipedia.org/w/index.php?title=File:Trimyristin-3D-vdW.png  License: Public Domain  Contributors: Benjah-bmm27
File:Glucose Fisher to Haworth.gif  Source: http://en.wikipedia.org/w/index.php?title=File:Glucose_Fisher_to_Haworth.gif  License: GNU Free Documentation License  Contributors:
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File:Catabolism schematic.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Catabolism_schematic.svg  License: Public Domain  Contributors: Tim Vickers, vectorized by
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File:A thaliana metabolic network.png  Source: http://en.wikipedia.org/w/index.php?title=File:A_thaliana_metabolic_network.png  License: Public Domain  Contributors: Original uploader
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File:SantoriosMeal.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:SantoriosMeal.jpg  License: Public Domain  Contributors: Original uploader was Wetman at en.wikipedia
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File:Anton van Leeuwenhoek.png  Source: http://en.wikipedia.org/w/index.php?title=File:Anton_van_Leeuwenhoek.png  License: Public Domain  Contributors: Jan Verkolje (1650—1693)
File:Tableau Louis Pasteur.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Tableau_Louis_Pasteur.jpg  License: Public Domain  Contributors: Christophe.Finot,
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File:Animal mitochondrion diagram en (edit).svg  Source: http://en.wikipedia.org/w/index.php?title=File:Animal_mitochondrion_diagram_en_(edit).svg  License: Public Domain
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Image:MitochondrionCAM.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:MitochondrionCAM.jpg  License: Public domain  Contributors: Original uploader was Carmmann (talk)
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Image:Chondrocyte- calcium stain.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Chondrocyte-_calcium_stain.jpg  License: Creative Commons Attribution-Sharealike 3.0
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work: Shanel (talk) Mitochondrial_DNA_de.svg: translation by Knopfkind; layout by jhc
File:Caprella_mutica_male_morphology.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Caprella_mutica_male_morphology.jpg  License: Creative Commons
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Image:Adenocarcinoma on pap test 1.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Adenocarcinoma_on_pap_test_1.jpg  License: Creative Commons Attribution-Sharealike 3.0
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File:Mycena leaiana var. australis.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Mycena_leaiana_var._australis.jpg  License: Creative Commons Attribution-Sharealike 3.0
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File:Gray636.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gray636.png  License: Public Domain  Contributors: Arcadian
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Image:Gray626.png  Source: http://en.wikipedia.org/w/index.php?title=File:Gray626.png  License: Public Domain  Contributors: Arcadian, Origamiemensch
File:RNA-comparedto-DNA thymineAndUracilCorrected.png  Source: http://en.wikipedia.org/w/index.php?title=File:RNA-comparedto-DNA_thymineAndUracilCorrected.png  License:
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Image:Carboxysomes EM.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Carboxysomes_EM.jpg  License: Creative Commons Attribution 3.0  Contributors: Tsai Y, Sawaya MR,
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File:Black fly.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Black_fly.jpg  License: Public Domain  Contributors: United States Department of Agriculture
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Image:Mureine.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Mureine.svg  License: Public Domain  Contributors: Mouagip
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File:Haeckel Siphoneae.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Haeckel_Siphoneae.jpg  License: Public Domain  Contributors: CommonsDelinker, Dysmorodrepanis,
Homonihilis, Ragesoss, Thiotrix, Vonvon, 2 anonymous edits
File:Ferns02.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Ferns02.jpg  License: unknown  Contributors: Amada44, Bdk, Fir0002
File:Petrified forest log 1 md.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Petrified_forest_log_1_md.jpg  License: Creative Commons Attribution-Sharealike 2.5  Contributors:
User:Moondigger
File:Leaf 1 web.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Leaf_1_web.jpg  License: Public Domain  Contributors: Ies, Ranveig, Red devil 666, Rocket000, WeFt,
Überraschungsbilder
File:Eenbruinigherfstblad.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Eenbruinigherfstblad.jpg  License: Public Domain  Contributors: Ischa1
File:Dead plant in pots.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Dead_plant_in_pots.jpg  License: Creative Commons Attribution-Sharealike 2.0  Contributors: vetcw3
File:Plant cell structure svg.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Plant_cell_structure_svg.svg  License: Public Domain  Contributors: LadyofHats (Mariana Ruiz)
File:VFT ne1.JPG  Source: http://en.wikipedia.org/w/index.php?title=File:VFT_ne1.JPG  License: Creative Commons Attribution-Sharealike 2.5  Contributors: Aroche, BRUTE,
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File:Potato plant.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Potato_plant.jpg  License: Public Domain  Contributors: Scott Bauer
File:Timber DonnellyMills2005 SeanMcClean.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Timber_DonnellyMills2005_SeanMcClean.jpg  License: GNU Free Documentation
License  Contributors: Original uploader was SeanMack at en.wikipedia
File:Taxus wood.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Taxus_wood.jpg  License: GNU Free Documentation License  Contributors: MPF
Image:Single Polymer Chains AFM.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Single_Polymer_Chains_AFM.jpg  License: Creative Commons Attribution-Sharealike 3.0
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Image:Polymer Branch.svg  Source: http://en.wikipedia.org/w/index.php?title=File:Polymer_Branch.svg  License: Public Domain  Contributors: Ilmari Karonen
Image:RAFT Architecture.png  Source: http://en.wikipedia.org/w/index.php?title=File:RAFT_Architecture.png  License: Public Domain  Contributors: Chem538w10grp4
Image:stable neck MDPE.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Stable_neck_MDPE.jpg  License: Public Domain  Contributors: Crosslink
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Image:polyethene monomer.png  Source: http://en.wikipedia.org/w/index.php?title=File:Polyethene_monomer.png  License: GNU Free Documentation License  Contributors: Wiki User
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Image:Chlorine attack1.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Chlorine_attack1.jpg  License: Public Domain  Contributors: Peterlewis
Image:Ozone cracks in tube1.jpg  Source: http://en.wikipedia.org/w/index.php?title=File:Ozone_cracks_in_tube1.jpg  License: Public Domain  Contributors: Peterlewis
Image:Cellulose-Ibeta-from-xtal-2002-3D-balls.png  Source: http://en.wikipedia.org/w/index.php?title=File:Cellulose-Ibeta-from-xtal-2002-3D-balls.png  License: Public Domain
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