Amino acids, peptides and proteins - Essentials of Organic Chemistry - page 521

provides a charge-relay network , in which a charge, here a proton, is effectively passed from one molecule to
another. In due course, the groups can be restored to their original nature by a reverse of the sequence. We shall
see this feature again with chymotrypsin below.

aspartate − histidine − serine charge relay network

H

O O O O

N H N

H

N N

O

O

H

Asp Asp

Ser

Ser

His His

aspartate facilitates removal
of proton from serine via
charge-relay network

later in the sequence,
the original residues
can be regenerated

Acetylcholinesterase is a remarkably efficient enzyme; turnover has been estimated as over 10 000 molecules
per second at a single active site. This also makes it a key target for drug action, and acetylcholinesterase inhibitors
are of considerable importance. Some natural and synthetic toxins also function by inhibiting this enzyme (see
Box 7.26).

Box 13.5
Chymotrypsin and other serine proteases
The serine proteases cleave amide (peptide) bonds in peptides and have a wide variety of functions, including
food digestion, blood clotting, and hormone production. They feature as one of the best-understood groups of
enzymes as far as mechanism of action is concerned. We are able to ascribe a function to many of the amino acid
residues in the active site, and we also understand how they determine the specificity of the various enzymes in
the group.
For example, chymotrypsin cleaves peptides on the C -terminal side of aromatic amino acid residues
phenylalanine, tyrosine, and tryptophan, and to a lesser extent some other residues with bulky side-chains, e.g.
Leu, Met, Asn, Gln. On the other hand, trypsin cleaves peptides on the C -terminal side of the basic residues
arginine and lysine. Elastase usually catalyses hydrolysis of peptide bonds on the C -terminal side of neutral
aliphatic amino acids, especially glycine or alanine. These three pancreatic enzymes are about 40% identical in
their amino acid sequences, and their catalytic mechanisms are nearly identical.

cleavage sites for serine proteases

chymotrypsin chymotrypsin

Enzyme Cleavage site
trypsin C -terminal Lys, Arg
chymotrypsin C -terminal Tyr, Phe, Trp

carboxyl
terminus

amino
terminus

− Gly − Arg − Ser − Phe − Ala − Lys − Ala − Trp − Val −

trypsin trypsin

hydrolysis with trypsin − Gly − Arg Ser − Phe − Ala − Lys Ala − Trp − Val −

hydrolysis with chymotrypsin − Gly − Arg − Ser − Phe Ala − Lys − Ala − Trp Val −

Because of their known specificity, these enzymes, especially trypsin and chymotrypsin, have been widely
utilized in helping to determine the amino acid sequences of peptides (see Section 13.7). Hydrolysis using these