2006-Protein Structure and Function

Amino Acid and Protein
1
Proteins Structure and
Function
SPECIFIC LEARNING OBJECTIVE
At the end of the session the student should be able to
explain:
Structures of amino acids
Peptides and proteins
Classification of protein
Denaturation of protein
Prion protein
2
3
I .AMINO ACID
Amino acids are fundamental units of proteins.
4
continued
5
Structure of the -Amino Acids
All proteins are polymers, and the monomers
combine are -Amino Acids.
A representative -Amino Acids, e.g.. valine
is shown in figure:
6
7
A. Composition
< The amino group are attached to the -carbon,
the carbon next to the carboxyl group, hence
the name -amino acids.
< To the -carbon of every amino acid are also
attached a hydrogen atom and side chains (R).
< Their different side chains distinguish different
-amino acids.
< We can write the general structure for an -
amino acid in next figure:
8
< The complete structures of these amino acids
are shown in next slide (slide no.9).
< Only 20 -amino acids used by cells when they
synthesize protein.
< Hydroxyproline, present mainly in collagen, is
synthesized from proline, and cystine, present in
most proteins, is synthesized from cysteine.
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10
B. Amphoteric properties
< Amino acids are amphoteric molecules ; that is,
they have both basic and acidic groups
< Monoamino-monocarboxylic acids exist in solution
neutral pH are predominantly dipolar ions (or
zwitter ion). In dipolar form of an amino acid, the
amino group is protonated and positively charged
(-NH
3
+
) and the carboxyl group is dissociated and
negatively charged (-COO
-
)
< At low pH, the carboxyl group accepts a proton
and becomes uncharged, so that the overall
charge on the molecule is positive
< At high pH, the amino group loses its proton and
becomes uncharged; thus, the overall charge on
the molecule is negative
11
C. Stereochemistry of the -amino acids
- The -carbon of amino acids are formed an
asymmetric molecule, the -carbon is said to
be chiral or stereocenter or also called an
asymmetric carbon.
- The important fact that all of the amino acids
incorporated by organisms into proteins are
of the L-form, with the exception of glycine
- D-isomers of amino acids exist in nature, and
some play important biochemical roles but
they are never found in proteins.
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13
D. Properties of amino acid side chains
+ Some amino acids have side chains that
contain dissociating groups.
+ Side chains: aspartate and glutamate are
acidic: Histidine, lysine and arginine are basic
+ Side chains : cystein and tyrosine, have a
negative charge on the side chain when
dissociated
+ Dissociating groups. For example, glutamate
has three dissociable protons with pK
a
2.1,
3.9.and 9.8. As the pH increases above each of
these pK
a
values, proton dissociate and the
charge changes as shown: overall charge 1+,
0, +1 and 2+ respectively
14
E. Classes of -amino acids.
1. Amino Acids with Aliphatic Side Chain
Glycine, alanine, valine, leucine, and
isoleucine have aliphatic, or alkane, side chain.
The R group becomes more extended and more
hydrophobic.
Isoleucine, for example the more hydrophobic
amino acids are usually found within a protein
molecule, where they are shielded from water.
Proline, note that proline is cyclic amino acids
although it is cyclic amino acid; its side chain has a
primarily aliphatic character. However the rigidity of
the ring often makes the folding proline residues
into protein structure difficult.
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2. Amino acids with Hydroxyl or Sulfur-
Containing Side Chains
In this category are serine, cysteine, threonine,
and methionine, because of their weakly polar side
chains, are generally more hydrophilic than
aliphatic chains,
Although methionine is fairly hydrophobic.
17
Cystein.
First, the side chain can ionize at
moderately high pH;
18
Second, oxidation can occur between pairs of
cysteine side chains to form a disulfide bond. The
product of this oxidation is given the name cystine.
The presence of such disulfide bonds between
cysteine residues in proteins often plays an
important structural role
19
The primary structure of bovine insulin
20
3. Aromatic Amino Acids
g Three amino acids, phenylalanine, tyrosine,
tryptophan, carry aromatic side chains

g Phenylalanine, together with the aliphatic
amino acids valine, leucine and isoleusine, is
one of the hydrophobic amino acids.

g Tyrosine and tryptophan have some
hydrophobic character as well.
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22
4. Basic Amino Acids
; Histidine, lysine, and arginine carry basic
groups in their side chains. They are
represented in Figure 5.3 in the form that
exists at pH values near neutrality.
; Histidine is the least basic of the three.
; Lysine and arginine are more basic amino
acids, their side chains are always positively
charged
; The basic amino acids are strongly polar, they
are usually found on the exterior surfaces of
proteins (hydrophilic), where the surrounding
aqueous environment can hydrate them.
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24
5. Acidic Amino Acids and Their Amides
* Aspartic acids and glutamic acid are the only
amino acids that carry negative charges at pH
7: they are represented in the anionic forms in
Figure 5.3.
* Companion to aspartic acid and glutamic acids
are their amides, asparagines and glutamine.
Asparagine and glutamine have uncharged side
chains, although they are decidedly polar. Like
the basic and acidic amino acids, they are
definitely hydrophilic and tend to be on the
surface of a protein molecule, in contact with
surrounding water.
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26
MODIFIED AMINO ACIDS
+ Representation of several such modified amino
acids follows, with the modifying group shown in
red : Figure phosphoserine, 4-hydroxyproline,
hydroxylysine - Carboxyglutamic acid
+ Phosphoserine, source many protein e.g enzymes
etc
+ 4-hydroxyproline, source collagen and gelatine
+ hydroxylysine, source collagen and gelatine
+ - Carboxyglutamic acid, source Prothrombin
and bone protein
+ And many other amino acids play important roles
in metabolism is given in Table 5.2.
27
28
29
continued
30
PEPTIDES AND THE PEPTIDE BOND
Amino acids can be covalently linked together
by formation of an amide bond between the -
carboxyl group of one amino acid and the -
amino group on another.
This bond is referred to as peptide bond,
and the products formed are called peptides.
The peptide bond is nearly planar, and the
trans form is favored. The process is highly
endergonic (i.e. energy-requiring) and requires
the concomitant hydrolysis of high-energy
phosphate bonds
31
32
33
The formation of a peptide bond between
glycine and alanine is shown in Figure 5.8. The
product is called dipeptide, the reaction can
be eliminated a water molecule. Chains
containing four amino acid residues are referred
tetrapeptide shown in Figure 5.9.
E G A K
34
35
The portion of each amino acids remaining in
the chain is called an amino acid residue
Chains containing a few amino acid residues
are collectively referred to as oligopeptides.
If the chain is very long, it is called a
polypeptide. Oligopeptides and polypeptides
are formed by polymerization of amino acids
via peptide bonds
In writing the sequence of an oligopeptide or
polypeptide that the convention is to always
write the N-terminal amino acid (the residue
has a free -amino group) to the left, and the
C-terminal to the right. (the residue has a free
-carboxyl group)
36
Large peptide chain. Protein polypeptide
chain are typically more than 100 amino acid
residue. All proteins are polypeptides. This is
why understanding the nature of polypeptides
and the peptide bond is so important a part of
biochemistry.
Small peptide chains are common and often
have important biologic roles. For example the
hormone glucagon has 29 residues,
vasopressin has 9 residue and thyrotropin-
releasing hormone has 3 residue
37
CONFORMATION OF PROTEINS
Every protein in its native state has a
unique three-dimentional structure, which
referred to as its conformation.
The function of a protein arises from its
conformation.
Protein structures can be classified into
four levels of organization : primary,
secondary, tertiary, and quartenary.
38
39
The primary structure is the covalent
backbone of the polypeptide formed
by the specific sequence. This sequence
is coded for by DNA and determines
the final three dimensional from
adopted by the protein in its native
state
40
The secondary structure is the spatial
relationships of neighboring amino acid residue.
1. Secondary structure is dictated by
primary structure. The secondary structure
arises from interactions of neighboring amino
acids. Because DNA coded primary sequence
dictated which amino acids are near each
other, secondary structure often form as the
peptide chain comes off the ribosome.
41
2. Hydrogen bonds, these formation very
important characteristic of secondary
structure, (H-bond) between the CO- group
of one peptide bond and the NH group of
another nearby peptide bond.
(a). If the H-bonds form between peptide bonds in
the same chain, either helical structure such as
the -helix develop or turn such as -turns are
formed.
(b). If the H-bonds form between peptide bonds in
different chains, extended structures form, such
as the -pleated sheet.
42
3. The -helix is rod like structure with the
peptide bond coiled tightly inside and the side
chain of the residue protruding outward.
(a). Characteristics
(1.) Each CO is hydrogen-bonded to the NH of
a peptide bond that is four residues away
from it along the same chain
2.) There are 3.6 amino acid residue per turn of
the helix, and the helix is right-handed (turn
in a clockwise around the axis)
(b). Helical structures in proteins were predicted
by Linus Pauling from his studies of fibrous proteins.
However, the -helix can also be important in the
structure globular proteins, although those chains are
much shorter than the chains in fibrous proteins
43
-Helix
-Sheet
44
Tertiary structure refers to the spatial
relationships of more distant residues
1. Folding. The secondary ordered polypeptide
chains of soluble proteins tend to fold into globular
structure with the hydrophobic side chain in the
interior of the structure away from the water and
the hydrophilic side chains on the outside in contact
with water. This folding is due to associations
between segments -helix, extended -chains, or
other secondary structures and represent a state of
lowest energy (greatest stability)
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2. The conformation result from:
a. Hydrogen bonding within a chain or between
chains
b. The flexibility of the chain at points of
instability, allowing water to obtain maximum
entropy and thus govern the structure to
some extent
c. The formation of other non covalent bonds
between side chain groups, such as salt
linkages, or -electron interaction of aromatic
rings
d. The sites and numbers of disulfide bridges
between Cys residues within the chain
46
47
Quartenary structure refers to the spatial
relationships between individual polypeptide
chains in a multi chain protein; that is, the
characteristic noncovalent interaction between
the chains that form the native conformation of
the protein as well as occasional disulfide bonds
between the chains
1. Many proteins larger than 50 kdal have more than
one chain and are said to contain multiple subunits,
with individual chains known as protomers.
2. Many multisubunit proteins are composed of different
kinds of functional subunits.
48
Denaturation
Denaturation is the organization of the
overall molecular shape of a protein. It
can occur as an unfolding of uncoiling
of helices, or as separation of subunits.
Denaturation is usually is accompanied
by a major loss in solubility.
Several reagents or physical force like
heat, UV radiation, shaking, ethanol,
heavy metals, and strong acids and
bases that cause denaturation.
49
denaturation
renaturation
50
The gene-encoded primary structure of
polypeptide is the sequence of its amino
acids. Primary structure are stabilized
by covalent peptide bonds.
Its secondary structure results from
folding of polypeptide into hydrogen-
bonded motifs can form supersecondary
motifs. Secondary structure (higher
orders) are stabilized by weak force-
multiple hydrogen bond, electrostatic
bond (salt bond), and association of
hydrophobic R groups.
Tertiary structure concern the
relationships between secondary
structure domains.
Quartenary structure of proteins with
two or more polypeptides (oligometric
proteins) is a feature based on the
spatial relationships between various
types of polypeptide
51
Protein can be classified according to solubility,
shape or the presence of nonprotein groups, etc.
For example:
1. Solubility, two major families are the globular and
fibrous protein. The globular proteins are compact, are
roughly spherical or ovoid in shape, and have axial
ratios of not over 3 (the ratio of their shortes to
longest dimention).
2. Composition. For example: glycoproteins, lipoproteins,
metaloproteins (that incorporate a metal ion such as
many enzyme do) etc.
3. Biologycal functions: enzymes, hormones,
neurotransmitters, toxin, contractile muscle (myosin
and actin), storage protein (casein, ovalbumin and
ferritin), transfort protein (hemoglobin), structural
proteins (collagen, elastine, and protein cell
membranes) and protective proteins.
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Globular Proteins
Myoglobin, a monomeric protein of red
muscle, stores oxygen.
Hemoglobin, a tetramic (
2
2
) protein of
eritrocytes, transport O
2
to the tissue and
return CO
2
and rptons to the lung. Despite
different primary structures, the secondary-
tertiary structure of subunits of hemoglobin
(Hb S), Val replaces the 6 Glu of Hb A. The
genetic defect has known as thalassemia
result from theh partial or total absence of
one or more

or chains of hemoglobin.
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MYOGLOBIN STRUCTURE
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Fibrous Proteins
Collagen is the most abundant of the fibrous
proteins that constitute more than 25% of the
protein mass in the human body. These
proteins in bone, teeth, tendons, skin, and soft
connective tissue. Collagen forms a unique
triple helix. Every third amino acid residue in
collagen is a glycine residue. Collagen is also
rich in proline and hydroxyproline, yielding a
repetitive Gly-X-Y pattern in which Y generally
is proline or hydroxyproline (Gly-X-Y-Gly-X-Y-
Gly-X-Y-). Disease of collagen maturation
include the vitamin C deficiency disease scurvy
and Ehlers-Danlos syndrome.
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Prions-Protein
Human prionrelated protein, PrP, a glycoprotein
encoded on the short arm of chromosome 20,
normally is monomeric and rich helix.
Pathologic prion proteins, known as PrPc, is rich
in sheet with many hydrophobic aminoacyl
side chains. Prion disease are protein
conformation diseases transmitted by altering
the conformation, fatal neurogenerative
diseases characterized by spongiform changes.
For example: Creutzfeld-Jacob disease in
humans, scrapie in sheep, and bovine
spongiform encephalopathy (mad cow disease)
in cattle.
58
References:
Mathews, C.K., etc. 2000,
Biochemistry, 3
rd
Edition, Addison
Wesley Longman, Inc., California.

Murray, R.K., etc., 2003, Harpers
Illustrated Biochemistry, 26
th
Ed.,
McGraw-Hill, California.

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Amino Acid and Protein

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