Principles of Biochemistry/Amino acids and

proteins

Amino acids are molecules containing an amine cell shape. Other proteins are important in cell signaling,
group(NH2 ), a carboxylic acid group(R-C=O-OH) and immune responses, cell adhesion, and the cell cycle. Pro-
a side-chain( usually denoted as R) that varies between teins are also necessary in animals diets, since animals
dierent amino acids. The key elements of an amino cannot synthesize all the amino acids they need and must
acid are carbon, hydrogen, oxygen, and nitrogen. They obtain essential amino acids from food. Through the pro-
are particularly important in biochemistry, where the cess of digestion, animals break down ingested protein
term usually refers to alpha-amino acids.Proteins are into free amino acids that are then used in metabolism.
biochemical compounds consisting of one or more Proteins were rst described by the Dutch chemist Ger-
polypeptides typically folded into a globular or brous
hardus Johannes Mulder and named by the Swedish
form in a biologically functional way. A polypeptide chemist Jns Jakob Berzelius in 1838. Early nutritional
is a single linear polymer chain of amino acids bonded scientists such as the German Carl von Voit believed that
together by peptide bonds between the carboxyl and protein was the most important nutrient for maintaining
amino groups of adjacent amino acid residues. The the structure of the body, because it was generally be-
sequence of amino acids in a protein is dened by the lieved that esh makes esh. The central role of proteins
sequence of a gene, which is encoded in the genetic code. as enzymes in living organisms was however not fully ap-
In general, the genetic code species 20 standard amino preciated until 1926, when James B. Sumner showed that
acids; however, in certain organisms the genetic code the enzyme urease was in fact a protein.The rst protein to
can include selenocysteineand in certain archaea be sequenced was insulin, by Frederick Sanger, who won
pyrrolysine. Shortly after or even during synthesis, the the Nobel Prize for this achievement in 1958. The rst
residues in a protein are often chemically modied by protein structures to be solved were hemoglobin and myo-
post-translational modication, which alters the physical globin, by Max Perutz and Sir John Cowdery Kendrew,
and chemical properties, folding, stability, activity, and respectively, in 1958. The three-dimensional structures
ultimately, the function of the proteins. Sometimes of both proteins were rst determined by X-ray dirac-
proteins have non-peptide groups attached, which can tion analysis; Perutz and Kendrew shared the 1962 Nobel
be called prosthetic groups or cofactors. Proteins can Prize in Chemistry for these discoveries. Proteins may
also work together to achieve a particular function, and be puried from other cellular components using a vari-
they often associate to form stable complexes. One of ety of techniques such as ultracentrifugation, precipita-
the most distinguishing features of polypeptides is their tion, electrophoresis, and chromatography; the advent of
ability to fold into a globular state, or structure. The genetic engineering has made possible a number of meth-
extent to which proteins fold into a dened structure ods to facilitate purication. Methods commonly used to
varies widely. Some proteins fold into a highly rigid study protein structure and function include immunohis-
structure with small uctuations and are therefore tochemistry, site-directed mutagenesis, nuclear magnetic
considered to be single structure. Other proteins undergo resonance and mass spectrometry. Distributed comput-
large rearrangements from one conformation to another.
ing is a relatively new tool researchers are using to exam-
This conformational change is often associated with a ine the infamously complex interactions that govern pro-
signaling event. Thus, the structure of a protein serves as
tein folding; the statistical analysis techniques employed
a medium through which to regulate either the function to calculate a proteins probable tertiary structure from
of a protein or activity of an enzyme. Not all proteins
its amino acid sequence (primary structure) are well-
requiring a folding process in order to function, as some suited for the distributed computing environment, which
function in an unfolded state[1] .
has made this otherwise prohibitively expensive and time
Like other biological macromolecules such as polysac- consuming problem signicantly more manageable[2] .
charides and nucleic acids, proteins are essential parts
of organisms and participate in virtually every process
within cells. Many proteins are enzymes that catalyze bio-
chemical reactions and are vital to metabolism. Proteins 1 Amino acids
also have structural or mechanical functions, such as actin
and myosin in muscle and the proteins in the cytoskele- There are 22 standard amino acids, but only 21 are
ton, which form a system of scaolding that maintains found in eukaryotes. Of the 22, 20 are directly encoded

1
2 1 AMINO ACIDS

present in all the amino acid types, and a side chain that
is unique to each type of residue. An exception from this
rule is proline, where the hydrogen atom is replaced by
a bond to the side chain. Because the carbon atom is
bound to four dierent groups it is chiral, however only
one of the isomers occur in biological proteins. Glycine
however, is not chiral since its side chain is a hydro-
gen atom. A simple mnemonic for correct L-form is
CORN": when the C atom is viewed with the H in
front, the residues read CO-R-N in a clockwise direc-
tion.
Isomerism
The standard -amino acids, all but glycine can exist in
A schematic visual model of oxygen-binding process, showing all either of two optical isomers, called L or D amino acids,
four monomers and hemes, and protein chains only as diagra- which are mirror images of each other . While L-amino
matic coils, to facilitate visualization into the molecule. Oxygen acids represent all of the amino acids found in proteins
is not shown in this model, but, for each of the iron atoms, it during translation in the ribosome, D-amino acids are
binds to the iron (red sphere) in the at heme. For example, in found in some proteins produced by enzyme posttrans-
the upper left of the four hemes shown, oxygen binds at the left lational modications after translation and translocation
of the iron atom shown in the upper left of diagram. This causes to the endoplasmic reticulum, as in exotic sea-dwelling
the iron atom to move backward into the heme which holds it (the organisms such as cone snails. They are also abundant
iron moves upward as it binds oxygen, in this illustration), tug-
components of the peptidoglycan cell walls of bacteria,
ging the histidine residue (modeled as a red pentagon on the right
and D-serine may act as a neurotransmitter in the
of the iron) closer, as it does. This, in turn, pulls on the protein
chain holding the histidine. brain. The L and D convention for amino acid con-
guration 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 the-
oretically be synthesized (D-glyceraldehyde is dextroro-
tary; L-glyceraldehyde is levorotary). Alternatively, the
(S) and (R) designators are used to indicate the absolute
stereochemistry. Almost all of the amino acids in pro-
teins are (S) at the carbon, with cysteine being (R) and
glycine non-chiral.Cysteine is unusual since it has a sul-
fur atom at the second position in its side-chain, which
has a larger atomic mass than the groups attached to the
rst carbon which is attached to the -carbon in the other
standard amino acids, thus the (R) instead of (S)[3] .
Zwitterions
The amine and carboxylic acid functional groups found in
amino acids allow it to have amphiprotic properties. At
a certain pH, known as the isoelectric point, an amino
acid has no overall charge since the number of protonated
ammonia groups (positive charges) and deprotonated car-
boxylate groups (negative charges) are equal. The amino
acids all have dierent isoelectric points. The ions pro-
CO-R-N rule
duced at the isoelectric point have both positive and neg-
ative charges and are known as a zwitterion, which comes
from the German word Zwitter meaning hermaphrodite
by the universal genetic code. Humans can synthesize
or hybrid. Amino acids can exist as zwitterions in
11 of these 20 from each other or from other molecules
solids and in polar solutions such as water, but not
of intermediary metabolism. The other 9 must be con-
in the gas phase. Zwitterions have minimal solubility at
sumed in the diet, and so are called essential amino acids;
their isolectric point and an amino acid can be isolated
those are histidine, isoleucine, leucine, lysine, methionine,
by precipitating it from water by adjusting the pH to its
phenylalanine, threonine, tryptophan, and valine. The re-
particular isoelectric point[4] .
maining two, selenocysteine and pyrrolysine, are incor-
porated into proteins by unique synthetic mechanisms. The 20 naturally occurring amino acids have dierent
physical and chemical properties, including their electro-
Each -amino acid consists of a backbone part that is
 3

static charge, pKa, hydrophobicity, size and specic func-

tional groups. These properties play a major role in mold-
ing protein structure. The salient features of amino acids
are described below in the table.

L-Glutamic acid
(Glu / E)

L-Alanine
(Ala / A)

L-Glutamine
(Gln / Q)

L-Arginine
(Arg / R) Glycine
(Gly / G)

L-Asparagine
(Asn / N) L-Histidine
(His / H)

L-Aspartic acid L-Isoleucine

(Asp / D) (Ile / I)

L-Cysteine L-Leucine
(Cys / C) (Leu / L)
4 1 AMINO ACIDS

L-Lysine
(Lys / K)
L-Tryptophan
(Trp / W)

L-Methionine
(Met / M) L-Tyrosine
(Tyr / Y)

L-Valine
L-Phenylalanine (Val / V)
(Phe / F)

L-Selenocysteine
L-Proline (Sec / U)
(Pro / P)

L-Pyrrolysine
(Pyl / O)

1.1 Classication of aminoacids

L-Serine
(Ser / S) The 20 amino acids encoded directly by the genetic code
can be divided into several groups based on their proper-
ties. Important factors are charge, hydrophilicity or hy-
drophobicity, size and functional groups.Amino acids are
usually classied 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.
Protein amino acids are combined into a single
L-Threonine polypeptide chain in a condensation reaction. This
(Thr / T) reaction is catalysed by the ribosome in a process known
as translation.

The 21 amino acids found in eukaryotes, grouped according to
their side-chains pKas and charge at physiological pH 7.4
An -amino acid. The CH atom is omitted in the diagram.
Polar and non polar amino acids and their single and
three letter code
Additionally, there are two additional amino acids which
are incorporated by overriding stop codons:
In addition to the specic amino acid codes, placehold-
ers are used in cases where chemical or crystallographic
analysis of a peptide or protein can not conclusively de-
termine the identity of a residue.
Unk is sometimes used instead of Xaa, but is less stan- digested proteins yielded only oligopeptides, the idea that
dard.
5
Additionally, many non-standard amino acids have a spe-
cic code. For example, several peptide drugs, such as
Bortezomib or MG132 are articially synthesized and re-
tain their protecting groups, which have specic codes.
Bortezomib is Pyz-Phe-boroLeu and MG132 is Z-Leu-
Leu-Leu-al. Additionally, To aid in the analysis of pro-
tein structure, photocrosslinking amino acid analogues
are available. These include photoleucine (pLeu) and
photomethionine (pMet).[5]
2 Structure of protein
A Ramachandran plot generated from the protein PCNA, a hu-
man DNA clamp protein that is composed of both beta sheets and
alpha helices (PDB ID 1AXC). Points that lie on the axes indicate
N- and C-terminal residues for each subunit. The green regions
show possible angle formations that include glycine, while the
blue areas are for formations that don't include glycine.
2.1 Primary structure of protein
The proposal that proteins were linear chains of -amino
acids was made nearly simultaneously by two scientists at
the same conference in 1902, the 74th meeting of the So-
ciety of German Scientists and Physicians, held in Karls-
bad. Franz Hofmeister made the proposal in the morn-
ing, based on his observations of the biuret reaction in
proteins. Hofmeister was followed a few hours later by
Emil Fischer, who had amassed a wealth of chemical de-
tails supporting the peptide-bond model. For complete-
ness, the proposal that proteins contained amide linkages
was made as early as 1882 by the French chemist E. Gri-
maux.
Despite these data and later evidence that proteolytically
proteins were linear, unbranched polymers of amino acids
6 2 STRUCTURE OF PROTEIN

formation, phosphorylations and glycosylations are usu-

ally also considered a part of the primary structure, and
cannot be read from the gene[8] .

A Ramachandran plot (also known as

Ramachandran diagram (, plot), with data points for -
helical residues forming a dense diagonal cluster below and
left of center, around the global energy minimum for backbone
conformation.[6]
was not accepted immediately. Some well-respected sci-
entists such as William Astbury doubted that covalent
bonds were strong enough to hold such long molecules
together; they feared that thermal agitations would shake
such long molecules asunder. Hermann Staudinger faced
similar prejudices in the 1920s when he argued that rub-
ber was composed of macromolecules. Thus, several al-
ternative hypotheses arose. The colloidal protein hy-
pothesis stated that proteins were colloidal assemblies of
smaller molecules. This hypothesis was disproved in the
1920s by ultracentrifugation measurements by Theodor
Svedberg that showed that proteins had a well-dened, re-
producible molecular weight and by electrophoretic mea-
surements by Arne Tiselius that indicated that proteins
were single molecules[7] .
A second hypothesis, the cyclol hypothesis advanced by
Dorothy Wrinch, proposed that the linear polypeptide
underwent a chemical cyclol rearrangement C=O + HN
C(OH)-N that crosslinked its backbone amide groups,
forming a two-dimensional fabric. Other primary struc-
tures of proteins were proposed by various researchers,
such as the diketopiperazine model of Emil Abderhalden
and the pyrrol/piperidine model of Troensegaard in 1942.
Although never given much credence, these alternative
models were nally disproved when Frederick Sanger
successfully sequenced insulin and by the crystallographic
determination of myoglobin and hemoglobin by Max Pe-
rutz and John Kendrew.
The primary structure of peptides and proteins refers to
the linear sequence of its amino acid structural units. The
term primary structure was rst coined by Linderstrm-
Lang in 1951. By convention, the primary structure of 2.2 Secondary structure of protein
a protein is reported starting from the amino-terminal
(N) end to the carboxyl-terminal (C) end. The post- Secondary structure refers to highly regular local sub-
translational modications of protein such as disulde structures. Two main types of secondary structure, the
a Ramachandran map or a Ramachandran
diagram or a [,] plot), developed by
Gopalasamudram Narayana Ramachandran
and Viswanathan Sasisekharan is a way to visu-
alize dihedral angles against of amino acid
residues in protein structure. [9] . It shows the
possible conformations of and angles for a
polypeptide.
Mathematically, the Ramachandran plot is
the visualization of a function f : [, )
[, ) R+ . The domain of this func-
tion is the torus. Hence, the conventional Ra-
machandran plot is a projection of the torus on
the plane, resulting in a distorted view and the
presence of discontinuities. One would expect
that larger side chains would result in more re-
strictions and consequently a smaller allowable
region in the Ramachandran plot. In practice
this does not appear to be the case; only the
methylene group at the position has an in-
uence. Glycine has a hydrogen atom, with
a smaller van der Waals radius, instead of a
methyl group at the position. Hence it is
least restricted and this is apparent in the Ra-
machandran plot for glycine for which the al-
lowable area is considerably larger. In con-
trast, the Ramachandran plot for proline shows
only a very limited number of possible com-
binations of and . The Ramachandran
plot was calculated just before the rst pro-
tein structures at atomic resolution were de-
termined. Forty years later there were tens
of thousands of high-resolution protein struc-
tures determined by X-ray crystallography and
deposited in the Protein Data Bank (PDB).
From one thousand dierent protein chains,
Ramachandran plots of over 200 000 amino
acids were plotted, showing some signicant
dierences, especially for glycine (Hovmller
et al. 2002). The upper left region was found
to be split into two; one to the left containing
amino acids in beta sheets and one to the right
containing the amino acids in random coil of
this conformation. One can also plot the dihe-
dral angles in polysaccharides and other poly-
mers in this fashion. For the rst two protein
side-chain dihedral angles a similar plot is the
Janin Plot.
2.2 Secondary structure of protein
The Hemoglobin molecule has four heme-binding subunits, each
largely made of alpha helices.
alpha helix and the beta strand, were suggested in 1951
by Linus Pauling' and coworkers.[10] . These secondary
structures are dened by patterns of hydrogen bonds be-
tween the main-chain peptide groups. They have a reg-
ular geometry, being constrained to specic values of
the dihedral angles and on the Ramachandran plot.
Both the alpha helix and the beta-sheet represent a way
of saturating all the hydrogen bond donors and acceptors
in the peptide backbone. Some parts of the protein are
ordered but do not form any regular structures. They
should not be confused with random coil, an unfolded
polypeptide chain lacking any xed three-dimensional
structure. Several sequential secondary structures may
form a "supersecondary unit".[11]
Beta-meander motif
Portion of outer surface Protein A of Borrelia burgdorferi
complexed with a murine monoclonal antibody.
Amino acids vary in their ability to form the various sec-
ondary structure elements. Proline and glycine are some-
times known as helix breakers because they disrupt the sheet The rst sheet structure was proposed by
regularity of the helical backbone conformation; how- William Astbury in the 1930s. He proposed the idea of
7
ever, both have unusual conformational abilities and are
commonly found in turns. Amino acids that prefer to
adopt helical conformations in proteins include methio-
nine, alanine, leucine, glutamate and lysine (MALEK
in amino-acid 1-letter codes); by contrast, the large aro-
matic residues (tryptophan, tyrosine and phenylalanine)
and C-branched amino acids (isoleucine, valine, and
threonine) prefer to adopt -strand conformations. How-
ever, these preferences are not strong enough to produce
a reliable method of predicting secondary structure from
sequence alone.Secondary structure in proteins consists
of local inter-residue interactions mediated by hydrogen
bonds, or not. The most common secondary structures
are alpha helices and beta sheets. Other helices, such as
the 310 helix and helix, are calculated to have energet-
ically favorable hydrogen-bonding patterns but are rarely
if ever observed in natural proteins except at the ends of
helices due to unfavorable backbone packing in the center
of the helix[12] .
helix
The amino acids in an helix are arranged in a right-
handed helical structure where each amino acid residue
corresponds to a 100 turn in the helix (i.e., the helix
has 3.6 residues per turn), and a translation of 1.5
(0.15 nm) along the helical axis. (Short pieces of left-
handed helix sometimes occur with a large content of
achiral glycine amino acids, but are unfavorable for the
other normal, biological L-amino acids.) The pitch of
the alpha-helix (the vertical distance between one con-
secutive turn of the helix) is 5.4 (0.54 nm) which is
the product of 1.5 and 3.6. What is most important is
that the N-H group of an amino acid forms a hydro-
gen bond with the C=O group of the amino acid four
residues earlier; this repeated hydrogen bonding is the
most prominent characteristic of an -helix. Ocial in-
ternational nomenclature species two ways of dening
-helices, rule 6.2 in terms of repeating , torsion an-
gles and rule 6.3 in terms of the combined pattern of
pitch and hydrogen bonding. Dierent amino-acid se-
quences have dierent propensities for forming -helical
structure. Methionine, alanine, leucine, uncharged glu-
tamate, and lysine (MALEK in the amino-acid 1-letter
codes) all have especially high helix-forming propensi-
ties, whereas proline and glycine have poor helix-forming
propensities. Proline either breaks or kinks a helix, both
because it cannot donate an amide hydrogen bond (hav-
ing no amide hydrogen), and also because its sidechain
interferes sterically with the backbone of the preceding
turn - inside a helix, this forces a bend of about 30 in
the helix axis. However, proline is often seen as the rst
residue of a helix, presumably due to its structural rigid-
ity. At the other extreme, glycine also tends to disrupt he-
lices because its high conformational exibility makes it
entropically expensive to adopt the relatively constrained
-helical structure[13] .
8 2
Representation of a beta hairpin
Greek-key motif in protein structure.
hydrogen bonding between the peptide bonds of parallel Coiled coils
or antiparallel extended strands. However, Astbury did
STRUCTURE OF PROTEIN
not have the necessary data on the bond geometry of the
amino acids in order to build accurate models, especially
since he did not then know that the peptide bond was pla-
nar. A rened version was proposed by Linus Pauling and
Robert Corey in 1951.
The sheet (also -pleated sheet) is the second form of
regular secondary structure in proteins, only somewhat
less common than alpha helix. Beta sheets consist of
beta strands connected laterally by at least two or three
backbone hydrogen bonds, forming a generally twisted,
pleated sheet. A beta strand (also strand) is a stretch of
polypeptide chain typically 3 to 10 amino acids long with
backbone in an almost fully extended conformation.
A very simple structural motif involving sheets is the
hairpin, in which two antiparallel strands are linked by
a short loop of two to ve residues, of which one is fre-
quently a glycine or a proline, both of which can assume
the unusual dihedral-angle conformations required for a
tight turn. However, individual strands can also be linked
in more elaborate ways with long loops that may contain
alpha helices or even entire protein domains[14] .
Greek key motif The Greek key motif consists of four ad-
jacent antiparallel strands and their linking loops. It con-
sists of three antiparallel strands connected by hairpins,
while the fourth is adjacent to the rst and linked to the
third by a longer loop. This type of structure forms easily
during the protein folding process.[15][16] It was named af-
ter a pattern common to Greek ornamental artwork (see
meander (art))[17] .
The -- motif Due to the chirality of their component
amino acids, all strands exhibit a right-handed twist ev-
ident in most higher-order sheet structures. In particu-
lar, the linking loop between two parallel strands almost
always has a right-handed crossover chirality, which is
strongly favored by the inherent twist of the sheet. This
linking loop frequently contains a helical region, in which
case it is called a -- motif. A closely related motif
called a --- motif forms the basic component of the
most commonly observed protein tertiary structure, the
TIM barrel[18] .
-meander motif A simple supersecondary protein topol-
ogy composed of 2 or more consecutive antiparallel -
strands linked together by hairpin loops.[19][20] This mo-
tif is common in -sheets and can be found in sev-
eral structural architectures including -barrels and -
propellers[21] .
Psi-loop motif The psi-loop, -loop, motif consists of
two antiparallel strands with one strand in between that is
connected to both by hydrogen bonds.[22] There are four
possible strand topologies for single -loops as cited by
Hutchinson et al. (1990). This motif is rare as the pro-
cess resulting in its formation seems unlikely to occur dur-
ing protein folding. The -loop was rst identied in the
aspartic protease family.[23]
2.2 Secondary structure of protein 9

Psi-loop motif
Portion of Carboxypeptidase A.

The possibility of coiled coils for -keratin was proposed

by Francis Crick in 1952 as well as mathematical meth-
ods for determining their structure. Remarkably, this was
soon after the structure of the alpha helix was suggested
in 1951 by Linus Pauling and coworkers.
Coiled coils usually contain a repeated pattern, hxxhcxc,
of hydrophobic (h) and charged (c) amino-acid residues,
referred to as a heptad repeat. The positions in the hep-
tad repeat are usually labeled abcdefg, where a and d
are the hydrophobic positions, often being occupied by
isoleucine, leucine or valine. Folding a sequence with this
repeating pattern into an alpha-helical secondary struc-
ture causes the hydrophobic residues to be presented as
a 'stripe' that coils gently around the helix in left-handed
fashion, forming an amphipathic structure. The most fa-
vorable way for two such helices to arrange themselves
in the water-lled environment of the cytoplasm is to
wrap the hydrophobic strands against each other sand-
wiched between the hydrophilic amino acids. It is thus
the burial of hydrophobic surfaces, that provides the ther-
modynamic driving force for the oligomerization. The
packing in a coiled-coil interface is exceptionally tight,
with almost complete van der Waals contact between the
side chains of the a and d residues. This tight packing
was originally predicted by Francis Crick in 1952 and
is referred to as Knobs into holes packing. The -helices The four levels of protein structure, from top to bottom: primary
may be parallel or anti-parallel, and usually adopt a left- structure, secondary structure (-sheet left, right -helix), tertiary
handed super-coil. Although disfavored, a few right- and quartary structure.
handed coiled coils have also been observed in nature and
in designed proteins[24] .
10 3 TYPES OF PROTEIN

2.3 Tertiary structure of protein merase, and ion channels. Other assemblies referred to
instead as multiprotein complexes also possess quaternary
Tertiary structure is considered to be largely determined structure. Examples include nucleosomes and micro-
by the proteins primary structure - the sequence of amino tubules.
acids of which it is composed. Eorts to predict tertiary Changes in quartary structure can occur through confor-
structure from the primary structure are known generally mational changes within individual subunits or through
as protein structure prediction. However, the environ- reorientation of the subunits relative to each other. It is
ment in which a protein is synthesized and allowed to fold through such changes, which underlie cooperativity and
are signicant determinants of its nal shape and are usu- allostery in multimeric enzymes, that many proteins un-
ally not directly taken into account by current prediction dergo regulation and perform their physiological func-
methods. In globular proteins, tertiary interactions are tion. The above denition follows a classical approach
frequently stabilized by the sequestration of hydrophobic to biochemistry, established at times when the distinc-
amino acid residues in the protein core, from which water tion between a protein and a functional, proteinaceous
is excluded, and by the consequent enrichment of charged unit was dicult to elucidate. More recently, people re-
or hydrophilic residues on the proteins water-exposed fer to protein-protein interaction when discussing quar-
surface. In secreted proteins that do not spend time in the tary structure of proteins and consider all assemblies of
cytoplasm, disulde bonds between cysteine residues help proteins as protein complexes.
to maintain the proteins tertiary structure. A variety of
common and stable tertiary structures appear in a large
number of proteins that are unrelated in both function
and evolution - for example, many proteins are shaped 3 Types of protein
like a TIM barrel, named for the enzyme triosephos-
phateisomerase. Another common structure is a highly 3.1 Conjugated protein
stable dimeric coiled coil structure composed of 2-7 al-
pha helices. The majority of protein structures known to
A conjugated protein is a protein that functions in inter-
date have been solved with the experimental technique
action with other chemical groups attached by covalent
of X-ray crystallography, which typically provides data
bonds or by weak interactions. Many proteins contain
of high resolution but provides no time-dependent in-
only amino acids and no other chemical groups, and they
formation on the proteins conformational exibility. A
are called simple proteins. However, other kind of pro-
second common way of solving protein structures uses
teins yield, on hydrolysis, some other chemical compo-
NMR, which provides somewhat lower-resolution data
nent in addition to amino acids and they are called conju-
in general and is limited to relatively small proteins, but
gated proteins. The nonamino part of a conjugated pro-
can provide time-dependent information about the mo-
tein is usually called its prosthetic group. Most prosthetic
tion of a protein in solution. Dual polarisation inter-
groups are formed from vitamins. Conjugated proteins
ferometry is a time resolved analytical method for de-
are classied on the basis of the chemical nature of their
termining the overall conformation and conformational
prosthetic groups. Some examples of conjugated proteins
changes in surface captured proteins providing comple-
are
mentary information to these high resolution methods.
More is known about the tertiary structural features of
soluble globular proteins than about membrane proteins 3.1.1 Lipoproteins
because the latter class is extremely dicult to study us-
ing these methodshttp://en.wikipedia.org/w/index.php?
A lipoprotein is a biochemical assembly that contains
title=Protein_tertiary_structure&oldid=422486540.
both proteins and lipids water-bound to the proteins.
Many enzymes, transporters, structural proteins, anti-
gens, adhesins and toxins are lipoproteins. Examples
2.4 Quartary structure of proteins include the high density (HDL) and low density (LDL)
lipoproteins which enable fats to be carried in the blood
Several proteins are actually assemblies of more than one stream, the transmembrane proteins of the mitochon-
polypeptide chain, which in the context of the larger drion and the chloroplast, and bacterial lipoproteins.
assemblage are known as protein subunits. In addition
to the tertiary structure of the subunits, multiple-subunit
proteins possess a quartary structure, which is the ar- 3.1.2 Glycoproteins
rangement into which the subunits assemble. Enzymes
composed of subunits with diverse functions are some- Glycoproteins are proteins that contain oligosaccharide
times called holoenzymes, in which some parts may be chains (glycans) covalently attached to polypeptide side-
known as regulatory subunits and the functional core is chains. The carbohydrate is attached to the protein in
known as the catalytic subunit. Examples of proteins a cotranslational or posttranslational modication. This
with quartary structure include hemoglobin, DNA poly- process is known as glycosylation. In proteins that have
3.1 Conjugated protein
segments extending extracellularly, the extracellular seg-
ments are often glycosylated. Glycoproteins are often
important integral membrane proteins, where they play
a role in cell-cell interactions. Glycoproteins also oc-
cur in the cytosol, but their functions and the pathways
producing these modications in this compartment are
less well-understood.Glycoproteins are generally the
largest and most abundant group of conjugated pro-
teins. They range from glycoproteins in cell surface
membranes that constitute the glycocalyx, to important
antibodies produced by leukocytes.
3.1.3 phosphoproteins
Phosphoproteins are proteins which are chemically
bonded to a substance containing phosphoric acid (see
phosphorylation for more). The category of organic
molecules that includes Fc receptors, Ulks, Calcineurins,
K chips, and urocortins.
3.1.4 Metalloprotein
A protein that contains a metal ion cofactor known as
Metalloprotein. Metalloproteins have many dierent
functions in cells, such as enzymes, transport and storage
proteins, and signal transduction proteins. Indeed, about
one quarter to one third of all proteins require metals to
carry out their functions. The metal ion is usually co-
ordinated by nitrogen, oxygen or sulfur atoms belonging
to amino acids in the polypeptide chain and/or a macro-
cyclic ligand incorporated into the protein. The presence
of the metal ion allows metalloenzymes to perform func-
tions such as redox reactions that cannot easily be per-
formed by the limited set of functional groups found in
amino acids.
Computer-generated 3-D representation of the zinc nger motif
of proteins, consisting of an helix and an antiparallel sheet.
The zinc ion (green) is coordinated by two histidine residues and
two cysteine residues.
11
3.1.5 hemoproteins
A hemeprotein (or hemoprotein or haemoprotein), or
heme protein, is a metalloprotein containing a heme pros-
thetic group, either covalently or noncovalently bound to
the protein itself. The iron in the heme is capable of
undergoing oxidation and reduction (usually to +2 and
+3, though stabilized Fe+4 and even Fe+5 species are
well known in the peroxidases). Hemoproteins probably
evolved from a primordial strategy allowing to incorpo-
rate the iron (Fe) atom contained within the protopor-
phyrin IX ring of heme into proteins. This strategy has
been maintained throughout evolution as it makes hemo-
proteins responsive to molecules that can bind divalent
iron (Fe). These molecules included, but are probably
not restricted to, gaseous molecules, such as oxygen (O2)
nitric oxide (NO), carbon monoxide (CO) and hydrogen
sulde (H2S). Once bound to the prosthetic heme groups
of hemoproteins these gaseous molecules can modulate
the activity/function of those hemoproteins in a way that
is said to aord signal transduction. Therefore, when pro-
duced in biologic systems (cells), these gaseous molecules
are referred to as gasotransmitters.Haemoglobin con-
tains the prosthetic group containing iron, which is
the haem. It is with in the haem group that carries
the oxygen molecule through the binding of the oxy-
gen molecule to the iron ion (Fe2+) found in the haem
group[27] .
Hemoglobin Hemoglobin (also spelled haemoglobin and
abbreviated Hb or Hgb) is the iron-containing oxygen-
transport metalloprotein in the red blood cells of all ver-
tebrates (except the sh family Channichthyidae ) and the
tissues of some invertebrates. Hemoglobin in the blood is
what transports oxygen from the lungs or gills to the rest
of the body (i.e. the tissues) where it releases the oxygen
for cell use, and collects carbon dioxide to bring it back
to the lungs. In mammals the protein makes up about
97% of the red blood cells dry content, and around 35%
of the total content (including water). Hemoglobin has
an oxygen binding capacity of 1.34 ml O2 per gram of
hemoglobin, which increases the total blood oxygen ca-
pacity seventyfold. Hemoglobin is involved in the trans-
port of other gases: it carries some of the bodys respi-
ratory carbon dioxide (about 10% of the total) as car-
baminohemoglobin, in which CO2 is bound to the globin
protein. The molecule also carries the important regu-
latory molecule nitric oxide bound to a globin protein
thiol group, releasing it at the same time as oxygen.
Hemoglobin is also found outside red blood cells and their
progenitor lines. Other cells that contain hemoglobin
include the A9 dopaminergic neurons in the substantia
nigra, macrophages, alveolar cells, and mesangial cells
in the kidney. In these tissues, hemoglobin has a non-
oxygen-carrying function as an antioxidant and a regula-
tor of iron metabolism. Hemoglobin and hemoglobin-like
molecules are also found in many invertebrates, fungi,
and plants. In these organisms, hemoglobins may carry
oxygen, or they may act to transport and regulate other
12 3 TYPES OF PROTEIN

things such as carbon dioxide, nitric oxide, hydrogen sul-

de and sulde. A variant of the molecule, called leghe-
moglobin, is used to scavenge oxygen, to keep it from poi-
soning anaerobic systems, such as nitrogen-xing nodules
of leguminous plants[28] . phytochromes,
Cytochromes

Cytochrome c with heme c.

Cytochromes are, in general, membrane-bound hemo- 3-dimensional structure of bovine rhodopsin. The seven
proteins that contain heme groups and carry out electron transmembrane domains are shown in varying colors. The
transport. They are found either as monomeric proteins chromophore is shown in red.
(e.g., cytochrome c) or as subunits of bigger enzymatic
complexes that catalyze redox reactions. They are found
synthesis, DNA repair, and apoptosis. The spectroscopic
in the mitochondrial inner membrane and endoplasmic
properties of the avin cofactor make it a natural reporter
reticulum of eukaryotes, in the chloroplasts of plants, in
for changes occurring within the active site; this makes
photosynthetic microorganisms, and in bacteria.
avoproteins one of the most-studied enzyme families.

3.1.6 Opsins
3.2 Simple proteins
Opsins are a group of light-sensitive 35-55 kDa
The proteins which upon hydrolysis yield only amino
membrane-bound G protein-coupled receptors of the
acids are known as simple proteins.
retinylidene protein family found in photoreceptor cells
of the retina. Five classical groups of opsins are involved
in vision, mediating the conversion of a photon of light 3.2.1 Albumin
into an electrochemical signal, the rst step in the vi-
sual transduction cascade. Another opsin found in the Albumin (Latin: albus, white) refers generally to any pro-
mammalian retina, melanopsin, is involved in circadian tein that is water soluble, which is moderately soluble in
rhythms and pupillary reex but not in image-forming. concentrated salt solutions, and experiences heat denatu-
ration. They are commonly found in blood plasma, and
are unique to other plasma proteins in that they are not
3.1.7 Flavoproteins glycosylated. Substances containing albumin, such as egg
white, are called albuminoids.
Flavoproteins are proteins that contain a nucleic acid
derivative of riboavin: the avin adenine dinucleotide
(FAD) or avin mononucleotide (FMN). Flavoproteins 3.2.2 Globulin
are involved in a wide array of biological processes, in-
cluding, but by no means limited to, bioluminescence, re- Globulin is one of the three types of serum proteins, the
moval of radicals contributing to oxidative stress, photo- others being albumin and brinogen. Some globulins are
4.2 Protein as cell signalling molecule
produced in the liver, while others are made by the im-
mune system. The term globulin encompasses a hetero-
geneous group of proteins with typical high molecular
weight, and both solubility and electrophoretic migration
rates lower than for albumin.
3.2.3 Histones
In biology, histones are highly alkaline proteins found in
all eukaryotic cell nuclei and some archaea, which pack-
age and order the DNA into structural units called nucle-
osomes. They are the chief protein components of chro-
matin, acting as spools around which DNA winds, and
play a role in gene regulation.
3.3 Derived protein
3.3.1 Peptones
Peptones are derived from animal milk or meat digested
by proteolytic digestion. In addition to containing small
peptides, the resulting spray-dried material includes fats,
metals, salts, vitamins and many other biological com-
pounds. Peptone is used in nutrient media for growing
bacteria and fungi
3.3.2 Proteases
Proteases occur naturally in all organisms. These en-
zymes are involved in a multitude of physiological reac-
tions from simple digestion of food proteins to highly-
regulated cascades (e.g., the blood-clotting cascade, the
complement system, apoptosis pathways, and the inver-
tebrate prophenoloxidase-activating cascade). Proteases
can either break specic peptide bonds (limited proteol-
ysis), depending on the amino acid sequence of a pro-
tein, or break down a complete peptide to amino acids
(unlimited proteolysis). The activity can be a destruc-
tive change, abolishing a proteins function or digesting it
to its principal components; it can be an activation of a
function, or it can be a signal in a signaling pathway.
4 Functions of protein
4.1 Protein as an Enzyme
The best-known role of proteins in the cell is as enzymes,
which catalyze chemical reactions. Enzymes are usually
highly specic and accelerate only one or a few chemi-
cal 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 post-
translational modication. About 4,000 reactions are
13
known to be catalyzed by enzymes. The rate acceleration
conferred by enzymatic catalysis is often enormousas
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 en-
zyme). 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 fractionthree to four residues on
averagethat are directly involved in catalysis. The re-
gion of the enzyme that binds the substrate and contains
the catalytic residues is known as the active site[29] .
4.2 Protein as cell signalling molecule
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 recep-
tors whose main function is to bind a signaling molecule
and induce a biochemical response in the cell. Many re-
ceptors have a binding site exposed on the cell surface and
an eector domain within the cell, which may have en-
zymatic activity or may undergo a conformational change
detected by other proteins within the cell. Antibodies are
protein components of adaptive immune system whose
main function is to bind antigens, or foreign substances
in the body, and target them for destruction. Antibod-
ies 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 anity for their substrates by the necessity of
conducting their reaction, antibodies have no such con-
straints. An antibodys binding anity to its target is ex-
traordinarily high. 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 anity when their lig-
and is present in high concentrations, but must also re-
lease 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 verte-
brates and has close homologs in every biological king-
dom. Lectins are sugar-binding proteins which are highly
specic for their sugar moieties. Lectins typically play a
role in biological recognition phenomena involving cells
and proteins. Receptors and hormones are highly spe-
cic binding proteins. Transmembrane proteins can also
serve as ligand transport proteins that alter the perme-
ability of the cell membrane to small molecules and ions.
The membrane alone has a hydrophobic core through
which polar or charged molecules cannot diuse. Mem-
brane proteins contain internal channels that allow such
molecules to enter and exit the cell. Many ion channel
14 5 PROTEIN STRUCTURE DETERMINATION

proteins are specialized to select for only a particular ion; 3D density distribution of electrons in the protein (in
for example, potassium and sodium channels often dis- the crystallized state) and thereby infer the 3D coordi-
criminate for only one of the two ions[30] . nates of all the atoms to be determined to a certain res-
olution. Roughly 9% of the known protein structures
have been obtained by Nuclear Magnetic Resonance tech-
4.3 Other functions niques. The secondary structure composition can be de-
termined via circular dichroism or dual polarisation in-
Structural proteins confer stiness and rigidity to terferometry. Cryo-electron microscopy has recently be-
otherwise-uid biological components. Most structural come a means of determining protein structures to high
proteins are brous proteins; for example, actin and tubu- resolution (less than 5 angstroms or 0.5 nanometer) and
lin are globular and soluble as monomers, but polymerize is anticipated to increase in power as a tool for high res-
to form long, sti bers that comprise the cytoskeleton, olution work in the next decade. This technique is still a
which allows the cell to maintain its shape and size. Col- valuable resource for researchers working with very large
lagen and elastin are critical components of connective protein complexes such as virus coat proteins and amyloid
tissue such as cartilage, and keratin is found in hard or l- bers.
amentous structures such as hair, nails, feathers, hooves,
and some animal shells. Other proteins that serve struc-
tural functions are motor proteins such as myosin, ki-
nesin, and dynein, which are capable of generating me-
chanical forces. These proteins are crucial for cellu-
lar motility of single celled organisms and the sperm
5.1 X-ray crystallography
of many multicellular organisms which reproduce sexu-
ally. They also generate the forces exerted by contracting
muscles[31] . X-ray crystallography of biological molecules took o
with Dorothy Crowfoot Hodgkin, who solved the struc-
tures of cholesterol (1937), vitamin B12 (1945) and
5 Protein structure determination penicillin (1954), for which she was awarded the Nobel
Prize in Chemistry in 1964. In 1969, she succeeded in
solving the structure of insulin, on which she worked for
over thirty years.[32]
X-ray crystallography is a method of determining the ar-
rangement of atoms within a crystal, in which a beam
of X-rays strikes a crystal and diracts into many spe-
cic directions. Crystal structures of proteins (which
are irregular and hundreds of times larger than choles-
terol) began to be solved in the late 1950s, beginning
with the structure of sperm whale myoglobin by Max
Perutz and Sir John Cowdery Kendrew, for which they
were awarded the Nobel Prize in Chemistry in 1962.[33]
Since that success, over 61840 X-ray crystal structures
of proteins, nucleic acids and other biological molecules
have been determined.[34] For comparison, the nearest
competing method in terms of structures analyzed is
nuclear magnetic resonance (NMR) spectroscopy, which
has resolved 8759 chemical structures.[35] Moreover,
crystallography can solve structures of arbitrarily large
molecules, whereas solution-state NMR is restricted to
Ribbon diagram of the structure of myoglobin, showing colored relatively small ones (less than 70 kDa). X-ray crystal-
alpha helices. Such proteins are long, linear molecules with thou- lography is now used routinely by scientists to determine
sands of atoms; yet the relative position of each atom has been how a pharmaceutical drug interacts with its protein tar-
determined with sub-atomic resolution by X-ray crystallography. get and what changes might improve it.[36] However, in-
Since it is dicult to visualize all the atoms at once, the ribbon trinsic membrane proteins remain challenging to crystal-
shows the rough path of the protein polymer from its N-terminus lize because they require detergents or other means to sol-
(blue) to its C-terminus (red). ubilize them in isolation, and such detergents often inter-
fere with crystallization. Such membrane proteins are a
Around 90% of the protein structures available in the large component of the genome and include many pro-
Protein Data Bank have been determined by X-ray crys- teins of great physiological importance, such as ion chan-
tallography. This method allows one to measure the nels and receptors.[37][38]
 15

5.2 Nuclear magnetic resonance spec- quences of amino acids. These sequences are linear, in
troscopy or NMR the manner of letters in a written sentence or beads on
a string. In all proteins, it is the variation in the type
Protein nuclear magnetic resonance spectroscopy (usually of amino acids in the protein sequence of amino acids,
abbreviated protein NMR) is a eld of structural biology which determine the proteins chemical properties and
in which NMR spectroscopy is used to obtain information function. This is true of hemoglobin, where the sequence
about the structure and dynamics of proteins. The eld of amino acids may aect crucial functions such as the
was pioneered by Richard R. Ernst and Kurt Wthrich[1], proteins anity for oxygen.
among others. Protein NMR techniques are continu- There is more than one hemoglobin gene. The amino
ally being used and improved in both academia and the acid sequences of the globin proteins in hemoglobins usu-
biotech industry. Structure determination by NMR spec- ally dier between species, although the dierences grow
troscopy usually consists of several following phases, each with the evolutionary distance between species. For ex-
using a separate set of highly specialized techniques. The ample, the most common hemoglobin sequences in hu-
sample is prepared, resonances are assigned, restraints mans and chimpanzees are nearly identical, diering by
are generated and a structure is calculated and validated only one amino acid in both the alpha and the beta globin
protein chains. These dierences grow larger between
less closely related species. Even within a species, dier-
6 Hemoglobin and its structure ent variants of hemoglobin always exist, although one se-
quence is usually a most common one in each species.
Mutations in the genes for the hemoglobin protein in a
The oxygen-carrying protein hemoglobin was discovered species result in hemoglobin variants. Many of these mu-
by Hnefeld in 1840. In 1851, Otto Funke published a se- tant forms of hemoglobin cause no disease. Some of these
ries of articles in which he described growing hemoglobin mutant forms of hemoglobin, however, cause a group
crystals by successively diluting red blood cells with a sol- of hereditary diseases termed the hemoglobinopathies.
vent such as pure water, alcohol or ether, followed by The best known hemoglobinopathy is sickle-cell disease,
slow evaporation of the solvent from the resulting pro- which was the rst human disease whose mechanism was
tein solution. Hemoglobins reversible oxygenation was understood at the molecular level. A (mostly) separate
described a few years later by Felix Hoppe-Seyler. In set of diseases called thalassemias involves underproduc-
1959 Max Perutz determined the molecular structure of tion of normal and sometimes abnormal hemoglobins,
hemoglobin by X-ray crystallography. This work resulted through problems and mutations in globin gene regula-
in his sharing with John Kendrew the 1962 Nobel Prize tion. All these diseases produce anemia[40] .
in Chemistry. The role of hemoglobin in the blood was
elucidated by physiologist Claude Bernard. The name Hemoglobin variants are a part of the normal embryonic
hemoglobin is derived from the words heme and globin, and fetal development, but may also be pathologic mutant
reecting the fact that each subunit of hemoglobin is forms of hemoglobin in a population, caused by varia-
a globular protein with an embedded heme (or haem) tions in genetics. Some well-known hemoglobin variants
group. Each heme group contains one iron atom, that such as sickle-cell anemia are responsible for diseases,
can bind one oxygen molecule through ion-induced dipole and are considered hemoglobinopathies. Other variants
forces. The most common type of hemoglobin in mam- cause no detectable pathology, and are thus considered
mals contains four such subunits. Hemoglobin (also non-pathological variants[41] .
spelled haemoglobin and abbreviated Hb or Hgb) is the In the embryo: Gower 1 (22) Gower 2 (22)
iron-containing oxygen-transport metalloprotein in the (PDB 1A9W) Hemoglobin Portland (22) In the fetus:
red blood cells of all vertebrates[1] (except the sh family Hemoglobin F (22) (PDB 1FDH)
Channichthyidae ) and the tissues of some invertebrates.
In adults: Hemoglobin A (22) (PDB 1BZ0) - The most
Hemoglobin in the blood is what transports oxygen from
common with a normal amount over 95% Hemoglobin
the lungs or gills to the rest of the body (i.e. the tissues)
A2 (22) - chain synthesis begins late in the third
where it releases the oxygen for cell use, and collects car-
trimester and in adults, it has a normal range of 1.5-3.5%
bon dioxide to bring it back to the lungs. In mammals
Hemoglobin F (22) - In adults Hemoglobin F is re-
the protein makes up about 97% of the red blood cells
stricted to a limited population of red cells called F-cells.
dry content, and around 35% of the total content (includ-
However, the level of Hb F can be elevated in persons
ing water). Hemoglobin has an oxygen binding capac-
with sickle-cell disease and beta-thalassemia.
ity of 1.34 ml O2 per gram of hemoglobin, which in-
creases the total blood oxygen capacity seventyfold com- Variant forms that cause disease: Hemoglobin H (4)
pared to dissolved oxygen in blood. The mammalian - A variant form of hemoglobin, formed by a tetramer
hemoglobin molecule can bind (carry) up to four oxygen of chains, which may be present in variants of tha-
molecules[39] . lassemia. Hemoglobin Barts (4) - A variant form of
hemoglobin, formed by a tetramer of chains, which may
Hemoglobin consists mostly of protein (the globin
be present in variants of thalassemia. Hemoglobin S
chains), and these proteins, in turn, are composed of se-
16 6 HEMOGLOBIN AND ITS STRUCTURE

(2S2) - A variant form of hemoglobin found in people

with sickle cell disease. There is a variation in the -chain
gene, causing a change in the properties of hemoglobin,
which results in sickling of red blood cells. Hemoglobin
C (2C2) - Another variant due to a variation in the -
chain gene. This variant causes a mild chronic hemolytic
anemia. Hemoglobin E (2E2) - Another variant due to
a variation in the -chain gene. This variant causes a mild
chronic hemolytic anemia. Hemoglobin AS - A heterozy-
gous form causing Sickle cell trait with one adult gene and
one sickle cell disease gene Hemoglobin SC disease - An-
other heterozygous form with one sickle gene and another
encoding Hemoglobin C.
Distribution of the sickle-cell trait shown in pink and purple
Variations in hemoglobin amino acid sequences, as with
other proteins, may be adaptive. For example, recent
studies have suggested genetic variants in deer mice that
help explain how deer mice that live in the mountains are
able to survive in the thin air that accompanies high al-
titudes. A researcher from the University of Nebraska-
Lincoln found mutations in four dierent genes that can
account for dierences between deer mice that live in
lowland prairies versus the mountains. After examining
wild mice captured from both highlands and lowlands,
it was found that: the genes of the two breeds are vir-
tually identicalexcept for those that govern the oxygen-
carrying capacity of their hemoglobin. The genetic dif-
ference enables highland mice to make more ecient use
of their oxygen, since less is available at higher altitudes,
Historical distribution of malaria (no longer endemic in Europe)
such as those in the mountains. Mammoth hemoglobin shown in green
featured mutations that allowed for oxygen delivery at
lower temperatures, thus enabling mammoths to migrate
to higher latitudes during the Pleistocene.

Unaected Unaected
"Carrier" "Carrier"
Father Mother
Modern distribution of malaria

R r R r
anaemia (or anemia; SCA) or drepanocyto-
sisis an autosomal recessive genetic blood dis-
R R R r R r r r
order, with overdominance, characterized by
red blood cells that assume an abnormal, rigid,
sickle shape. Sickling decreases the cells ex-
ibility and results in a risk of various com-
plications. The sickling occurs because of a
mutation in the haemoglobin gene. Life ex-
pectancy is shortened, with studies reporting
an average life expectancy of 42 in males and
48 in females.Sickle-cell anaemia is caused
Unaected Unaected "Carrier" Aected
1 in 4 chance 2 in 4 chance 1 in 4 chance by a point mutation in the -globin chain of
haemoglobin, causing the hydrophilic amino
Sickle-cell disease is inherited in the autosomal recessive pattern. acid glutamic acid to be replaced with the hy-
drophobic amino acid valine at the sixth posi-
Sickle-cell disease (SCD) or sickle-cell tion. The -globin gene is found on the short

arm of chromosome 11. The association of
two wild-type -globin subunits with two mu-
tant -globin subunits forms haemoglobin S
(HbS). Under low-oxygen conditions (being at
high altitude, for example), the absence of a
polar amino acid at position six of the -globin
chain promotes the non-covalent polymerisa-
tion (aggregation) of haemoglobin, which dis-
torts red blood cells into a sickle shape and de-
creases their elasticity.
The loss of red blood cell elasticity is cen-
tral to the pathophysiology of sickle-cell dis-
ease. Normal red blood cells are quite elas-
tic, which allows the cells to deform to pass
through capillaries. In sickle-cell disease, low-
oxygen tension promotes red blood cell sick-
ling and repeated episodes of sickling damage
the cell membrane and decrease the cells elas-
ticity. These cells fail to return to normal shape
when normal oxygen tension is restored. As a
consequence, these rigid blood cells are unable
to deform as they pass through narrow capillar-
ies, leading to vessel occlusion and ischaemia.
The actual anaemia of the illness is caused by
haemolysis, the destruction of the red cells in-
side the spleen, because of their misshape. Al-
though the bone marrow attempts to compen-
sate by creating new red cells, it does not match
the rate of destruction. Healthy red blood cells
typically live 90120 days, but sickle cells only
survive 1020 days. Normally, humans have
Haemoglobin A, which consists of two alpha
and two beta chains, Haemoglobin A2, which
consists of two alpha and two delta chains and
Haemoglobin F, consisting of two alpha and
two gamma chains in their bodies. Of these,
Haemoglobin A makes up around 96-97% of
the normal haemoglobin in humans.
Sickle-cell gene mutation probably arose
spontaneously in dierent geographic areas, as
suggested by restriction endonuclease analysis.
These variants are known as Cameroon, Sene-
gal, Benin, Bantu and Saudi-Asian. Their clin-
ical importance springs from the fact that some
of them are associated with higher HbF lev-
els, e.g., Senegal and Saudi-Asian variants, and
tend to have milder disease.[42]
In people heterozygous for HgbS (carri-
ers of sickling haemoglobin), the polymeri-
sation problems are minor, because the nor-
mal allele is able to produce over 50% of
the haemoglobin. In people homozygous for
HgbS, the presence of long-chain polymers of
HbS distort the shape of the red blood cell from
a smooth doughnut-like shape to ragged and
full of spikes, making it fragile and susceptible
to breaking within capillaries. Carriers have
symptoms only if they are deprived of oxygen
17
(for example, while climbing a mountain) or
while severely dehydrated. Under normal cir-
cumstances, these painful crises occur about
0.8 times per year per patient. The sickle-cell
disease occurs when the seventh amino acid
(if the initial methionine is counted), glutamic
acid, is replaced by valine to change its struc-
ture and function.
The gene defect is a known mutation of a
single nucleotide ( single-nucleotide polymor-
phism - SNP) (A to T) of the -globin gene,
which results in glutamic acid being substituted
by valine at position 6. Haemoglobin S with
this mutation are referred to as HbS, as op-
posed to the normal adult HbA. The genetic
disorder is due to the mutation of a single nu-
cleotide, from a GAG to GTG codon mutation,
becoming a GUG codon by transcription. This
is normally a benign mutation, causing no ap-
parent eects on the secondary, tertiary, or
quaternary structure of haemoglobin in condi-
tions of normal oxygen concentration. What it
does allow for, under conditions of low oxygen
concentration, is the polymerization of the HbS
itself. The deoxy form of haemoglobin ex-
poses a hydrophobic patch on the protein be-
tween the E and F helices. The hydrophobic
residues of the valine at position 6 of the beta
chain in haemoglobin are able to associate with
the hydrophobic patch, causing haemoglobin S
molecules to aggregate and form brous pre-
cipitates.
The allele responsible for sickle-cell
anaemia is autosomal recessive and can be
found on the short arm of chromosome 11. A
person that receives the defective gene from
both father and mother develops the disease;
a person that receives one defective and one
healthy allele remains healthy, but can pass on
the disease and is known as a carrier. If two
parents who are carriers have a child, there
is a 1-in-4 chance of their child developing
the disease and a 1-in-2 chance of their
childs being just a carrier. Since the gene is
incompletely recessive, carriers can produce
a few sickled red blood cells, not enough to
cause symptoms, but enough to give resistance
to malaria. Because of this, heterozygotes
have a higher
tness than either of the homozygotes.
This is known as heterozygote advantage. Due
to the adaptive advantage of the heterozygote,
the disease is still prevalent, especially among
people with recent ancestry in malaria-stricken
areas, such as Africa, the Mediterranean, India
and the Middle East.[43] Malaria was histori-
cally endemic to southern Europe, but it was
declared eradicated in the mid-20th century,
18 6 HEMOGLOBIN AND ITS STRUCTURE

with the exception of rare sporadic cases.[44]

The malaria parasite has a complex life cy-
cle and spends part of it in red blood cells.
In a carrier, the presence of the malaria par-
asite causes the red blood cells with defective
haemoglobin to rupture prematurely, making
the plasmodium unable to reproduce. Fur-
ther, the polymerization of Hb aects the abil-
ity of the parasite to digest Hb in the rst
place. Therefore, in areas where malaria is a
problem, peoples chances of survival actually
increase if they carry sickle-cell trait (selec-
tion for the heterozygote). In the USA, where
there is no endemic malaria, the prevalence
of sickle-cell anaemia among blacks is lower
(about 0.25%) than in West Africa (about
4.0%) and is falling. Without endemic malaria
from Africa, the sickle cell mutation is purely
disadvantageous and will tend to be selected
out of the aected population. Another factor
limiting the spread of sickle-cell genes in North Heme b group
America is the absence of cultural proclivities
to polygamy.[45] Inheritance Sickle-cell con-
ditions are inherited from parents in much the
molecules cyclically linked together (by methene bridges)
same way as blood type, hair colour and tex-
with the iron ion bound in the center. The iron ion, which
ture, eye colour, and other physical traits. The
is the site of oxygen binding, coordinates with the four ni-
types of haemoglobin a person makes in the red
trogens in the center of the ring, which all lie in one plane.
blood cells depend on what haemoglobin genes
The iron is bound strongly (covalently) to the globular
are inherited from his parents. If one parent
protein via the imidazole ring of the F8 histidine residue
has sickle-cell anaemia (SS) and the other has
(also known as the proximal histidine) below the por-
sickle-cell trait (AS), there is a 50% chance
phyrin ring. A sixth position can reversibly bind oxygen
of a childs having sickle-cell disease (SS) and
by a coordinate covalent bond,[24] completing the octa-
a 50% chance of a childs having sickle-cell
hedral group of six ligands. Oxygen binds in an end-on
trait (AS). When both parents have sickle-cell
bent geometry where one oxygen atom binds Fe and the
trait (AS),a child has a 25% chance (1 of 4)
other protrudes at an angle. When oxygen is not bound,
of sickle-cell disease (SS), as shown in the di-
a very weakly bonded water molecule lls the site, form-
agram above.
ing a distorted octahedron. Even though carbon dioxide
is carried by hemoglobin, it does not compete with oxy-
Hemoglobin has a quaternary structure characteristic of gen for the iron-binding positions, but is actually bound
many multi-subunit globular proteins. Most of the amino to the protein chains of the structure. The iron ion may
acids in hemoglobin form alpha helices, connected by be either in the Fe2+ or in the Fe3+ state, but ferrihe-
short non-helical segments. Hydrogen bonds stabilize moglobin (methemoglobin) (Fe3+) cannot bind oxygen.
the helical sections inside this protein, causing attractions In binding, oxygen temporarily and reversibly oxidizes
within the molecule, folding each polypeptide chain into a (Fe2+) to (Fe3+) while oxygen temporally turns into su-
specic shape. Hemoglobins quaternary structure comes peroxide, thus iron must exist in the +2 oxidation state
from its four subunits in roughly a tetrahedral arrange- to bind oxygen. If superoxide ion associated to Fe3+
ment. In most vertebrates, the hemoglobin molecule is is protonated the hemoglobin iron will remain oxidized
an assembly of four globular protein subunits. Each sub- and incapable to bind oxygen. In such cases, the en-
unit is composed of a protein chain tightly associated zyme methemoglobin reductase will be able to eventu-
with a non-protein heme group. Each protein chain ar- ally reactivate methemoglobin by reducing the iron cen-
ranges into a set of alpha-helix structural segments con- ter. In adult humans, the most common hemoglobin type
nected together in a globin fold arrangement, so called is a tetramer (which contains 4 subunit proteins) called
because this arrangement is the same folding motif used hemoglobin A, consisting of two and two subunits
in other heme/globin proteins such as myoglobin. This non-covalently bound, each made of 141 and 146 amino
folding pattern contains a pocket that strongly binds the acid residues, respectively. This is denoted as 22. The
heme group. A heme group consists of an iron (Fe) ion subunits are structurally similar and about the same size.
(charged atom) held in a heterocyclic ring, known as a Each subunit has a molecular weight of about 17,000
porphyrin. This porphyrin ring consists of four pyrrole daltons, for a total molecular weight of the tetramer of
 19

about 68,000 daltons (64,458 g/mol).[26] Thus, 1 g/dL = [2] http://en.wikipedia.org/w/index.php?title=Protein&

0.01551 mmol/L. Hemoglobin A is the most intensively oldid=422392976
studied of the hemoglobin molecules. In human infants,
[3] http://en.wikipedia.org/w/index.php?title=Amino_
the hemoglobin molecule is made up of 2 chains and 2
acid&oldid=425052968
gamma chains. The gamma chains are gradually replaced
by chains as the infant grows. The four polypeptide [4] http://en.wikipedia.org/w/index.php?title=Amino_
chains are bound to each other by salt bridges, hydrogen acid&oldid=425052968
bonds, and the hydrophobic eect. There are two kinds
of contacts between the and chains: 11 and 12. [5] Photo-leucine and photo-methionine allow identica-
tion of protein-protein interactions in living cells.Nature
Oxygen Saturation In general, hemoglobin can be satu- Methods:4,2617,2005
rated with oxygen molecules (oxyhemoglobin), or desat-
urated with oxygen molecules (deoxyhemoglobin). [6] Lovell SC et al. (2003). Structure validation by C ge-
ometry: , and C deviation. Proteins 50 (3): 437
Oxyhemoglobin Oxyhemoglobin is formed during physi- 450. doi:10.1002/prot.10286. PMID 12557186.
ological respiration when oxygen binds to the heme com-
ponent of the protein hemoglobin in red blood cells. This [7] http://en.wikipedia.org/w/index.php?title=Protein_
process occurs in the pulmonary capillaries adjacent to primary_structure&oldid=415921787
the alveoli of the lungs. The oxygen then travels through [8] http://en.wikipedia.org/w/index.php?title=Protein_
the blood stream to be dropped o at cells where it is uti- primary_structure&oldid=415921787
lized in aerobic glycolysis and in the production of ATP
by the process of oxidative phosphorylation. It does not, [9] RAMACHANDRAN GN, RAMAKRISHNAN C,
however, help to counteract a decrease in blood pH. Ven- SASISEKHARAN V (July 1963). Stereochemistry of
tilation, or breathing, may reverse this condition by re- polypeptide chain congurations. J. Mol. Biol. 7: 959
moval of carbon dioxide, thus causing a shift up in pH. [10] Pauling L, Corey RB, Branson HR (1951). The structure
Hemoglobin exists in two forms, a taut form (T) and a re- of proteins; two hydrogen-bonded helical congurations
laxed form (R). Various factors such as low pH, high CO2 of the polypeptide chain. Proc Natl Acad Sci USA 37 (4):
and high 2,3 BPG at the level of the tissues favor the taut 205211. doi:10.1073/pnas.37.4.205. PMID 14816373.
form, which has low oxygen anity and releases oxygen
in the tissues. The opposite of these aforementioned fac- [11] Chiang YS, Gelfand TI, Kister AE, Gelfand IM
(2007). New classication of supersecondary struc-
tors at the level of the lung capillaries favors the relaxed
[46] tures of sandwich-like proteins uncovers strict patterns
form which can better bind oxygen . of strand assemblage.. Proteins. 68 (4): 915921.
Deoxyhemoglobin Deoxyhemoglobin is the form of doi:10.1002/prot.21473. PMID 17557333.
hemoglobin without the bound oxygen. The absorption
[12] http://en.wikipedia.org/w/index.php?title=Protein_
spectra of oxyhemoglobin and deoxyhemoglobin dier.
secondary_structure&oldid=406816422
The oxyhemoglobin has signicantly lower absorption of
the 660 nm wavelength than deoxyhemoglobin, while at [13] http://en.wikipedia.org/w/index.php?title=Alpha_
940 nm its absorption is slightly higher. This dierence helix&oldid=423162580
is used for measurement of the amount of oxygen in pa-
tients blood by an instrument called pulse oximeter. This [14] http://en.wikipedia.org/w/index.php?title=Beta_sheet&
oldid=425195965
dierence also accounts for the presentation of cyanosis,
the blue to purplish color that tissues develop during hy- [15] Tertiary Protein Structure and Folds: section 4.3.2.1.
poxiaOxyhemoglobin is formed during physiological res- From Principles of Protein Structure, Comparative Pro-
piration when oxygen binds to the heme component of the tein Modelling, and Visualisation
protein hemoglobin in red blood cells. This process oc-
curs in the pulmonary capillaries adjacent to the alveoli [16] Hutchinson EG, Thornton JM (April 1993). The Greek
key motif: extraction, classication and analysis. Protein
of the lungs. The oxygen then travels through the blood
Eng. 6 (3): 23345. doi:10.1093/protein/6.3.233. PMID
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obic glycolysis and in the production of ATP by the pro-
cess of oxidative phosphorylation. It does not, however, [17] http://en.wikipedia.org/w/index.php?title=Beta_sheet&
help to counteract a decrease in blood pH. Ventilation, or oldid=425195965
breathing, may[47] .
[18] http://en.wikipedia.org/w/index.php?title=Beta_sheet&
oldid=425195965

[19] SCOP: Fold: WW domain-like

7 Refrences
[20] PPS '96 - Super Secondary Structure

[1] http://en.wikipedia.org/w/index.php?title=Protein& [21] http://en.wikipedia.org/w/index.php?title=Beta_sheet&

oldid=422392976 oldid=425195965
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 21

8 Text and image sources, contributors, and licenses

8.1 Text
Principles of Biochemistry/Amino acids and proteins Source: https://en.wikibooks.org/wiki/Principles_of_Biochemistry/Amino_
acids_and_proteins?oldid=3041654 Contributors: CommonsDelinker, Yikrazuul, Whoop whoop pull up, Kaushlendratripathi, Arthurvogel,
C4au, Defender, Syum90 and Anonymous: 9

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tributors: Originally from en.wikipedia; description page is/was here Original artist: The original uploader was Password at English
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key_motif.svg License: CC-BY-SA-3.0 Contributors: File:Anthrax toxin protein key motif.jpg Original artist:
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work Original artist: Yikrazuul
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cense: CC-BY-SA-3.0 Contributors: Uploaded by Habj Original artist: en:User:BerserkerBen
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22 8 TEXT AND IMAGE SOURCES, CONTRIBUTORS, AND LICENSES

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. / /U _ :A T ' 'U :A T '>T </>
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