Peptides
G. The peptide bond and its characteristics
Proteins are macromolecules with a backbone formed by polymerization of amino acids in a
polyamide structure. These amide bonds in protein, known as peptide bonds formed by linkage
of α - carboxyl group of one amino acid with α- amino groups of the next amino acid by amide
bonds.
During the formation of a peptide bond, a molecule of water is eliminated as shown below:-
A peptide chain consisting of two amino acid residues is called a dipeptide, three amino acids
tripeptide (e. g Glutathione) etc.
E.g. A tripeptide formed from Cysteine, Glycine and Alanine.
By convention, peptide structures are written with amino terminal residues on the left and with
the carboxyl terminal residue at the right.
In peptides, the amino acids are joined covalently through peptide bonds, and are formed on
partial hydrolysis of much longer polypeptides. Note that the C=O and the NH – bonds are
nearly parallel and that the C, O, N, and H are usually co-planar. The C - N single bond in the
peptide linkage has ~ 40% double bond character and C = O double bond has ~ 40% single
bond character. This has two important consequences.
1. The imino group (-NH-) of the peptide linkage has no significant tendency to ionize or
protonate in the pH range 0 – 14
2. The C - N of a peptide linkage is relatively rigid and cannot rotate freely, a property of
supreme importance with respect to the three dimensional conformation of polypeptide
chains.
In amide linkage of the peptide bond due to the substantial double bond character there exists
little twisting. As a result the group of atoms in the peptide bond exist in the cis or trans nature of
the peptide bond. It was found out that the trans configuration is usually favored in order to
minimize the steric interaction between bulky R groups on adjacent -carbon atoms. One
exception is bonds in the sequence X – Pro, which X is any amino acid followed by Proline. In
this case Cis configuration may be favored.
In fact, the peptide bond can be considered a resonance hybrid of the forms
Peptides of Physiological Significance
Glutathione
Glutathione is a tripeptide formed from amino acids glutamate, cysteine and Glycine, linked
together in that order. The glutamate is linked to cysteine through the γ- carboxyl group and α -
amino group of cysteine.
Here, the carboxyl group is first activated by ATP to form an acyl-phosphate derivative which is
then attacked by cysteine amino group then undergoes condensation with glycine.
Fig 5.11: Glutathione Synthesis
The role of GSH as a reductant is extremely important particularly in the highly oxidizing
environment of the erythrocyte. The sulfhydryl of GSH can be used to reduce peroxides formed
during oxygen transport. The resulting oxidized form of GSH consists of two molecules disulfide
bonded together (abbreviated GSSG). The enzyme glutathione reductase utilizes NADPH as
a cofactor to reduce GSSG back to two moles of GSH. Hence, the pentose phosphate pathway
is an extremely important pathway of erythrocytes for the continuing production of the NADPH
needed by glutathione reductase. In fact as much as 10% of glucose consumption, by
erythrocytes, may be mediated by the pentose phosphate pathway.
Fig5. 12. Structure of GSSG (Glutathione disulphide).
Glutathione is virtually present in all cells often at high levels and can be thought as a kind of
redox buffer, which probably helps to maintain.
1) Sulfhydryl groups of proteins in the reduced state
2) Keeps the iron of heme in the ferrious (Fe2+) state
3) Serves as a reducing agent for glutaredoxin.
With its redox function it can also be used to remove toxic peroxides that are formed in the
course of growth and metabolism under aerobic condition.
2GSH + R – O – O – H →GSSG + H2O + R – OH
Glutathione peroxidase is a remarkable enzyme that contain a covalently bound selenium (Se)
atom in the form of selenocysteine.
Conjugation of drugs by glutathione is often a preliminary reaction catalyzed by cytochrome
P450, rendering substances to be more polar and assist their excretion as shown in the figure
5.13.
b) Scavenging of peroxides by glutathione peroxidase.
Fig 5.14: Role of Glutathione in scavenging Peroxides or
(2 GSH + H2O2 ↔ GSSG + 2H2O).
* Other peptides having physiological role include:
- Enkephalin (penta peptide)
- Bradykinin (nano peptide)
- Antidiuretic hormone (ADH) (nano peptide), etc.