Chemistry Reference
In-Depth Information
the participation of the histidine group, with the basicity of the histidine nitrogen also being increased because of
the proximity of a neighbouring aspartate residue - a
charge-relay network
, as seen with acetylcholinesterase
(see Box 13.4). This allows nucleophilic attack on to the peptide carbonyl, giving an initial tetrahedral transition
state. We also know that specific amino acid residues are positioned so that they help to stabilize this anionic tran-
sition state. Reformation of the carbonyl group is followed by cleavage of the peptide bond. The proton required
to form the amino group is acquired from the imidazole. The product is now an acyl - enzyme intermediate, actu-
ally an ester involving the serine hydroxyl. This ester is hydrolysed by a water nucleophile, and deprotonation is
achieved via the aspartate - histidine system once again. This generates another tetrahedral transition state, which
collapses and allows release of the carboxylic acid and regeneration of the serine hydroxyl by protonation from
the imidazole system.
Note that
penicillins
and structurally related antibiotics are frequently deactivated by the action of bacterial
β-lactamase
enzymes. These enzymes also contain a serine residue in the active site, and this is the nucleophile
that attacks and cleaves the
β
-lactam ring (see Box 7.20). The
β
-lactam (amide) linkage is hydrolysed, and then the
inactivated penicillin derivative is released from the enzyme by further hydrolysis of the ester linkage, restoring
the functional enzyme. The mode of action of these enzymes thus closely resembles that of the serine proteases;
there is further discussion in Box 7.20.
Whilst chymotrypsin and trypsin are especially useful in peptide sequence analysis, they also have medicinal
applications. Their ability to hydrolyse proteins makes them valuable for wound and ulcer cleansing (trypsin) or
during cataract removal (chymotrypsin).
13.4.2 Enolization and enolate anion
biochemistry
of acid - base catalysis. We saw that the chemical
process for enolization could be either acid- or
base-catalysed (see Section 10.1), and the following
scheme should remind us of the mechanism for base-
catalysed enolization of acetone.
Let us now look at an example of how nature
exploits the equivalent of enol and enolate anion
chemistry.
Enolization
provides another application
base-catalysed enolization
HOH
O
OH
O
OH
sl
ow
f
ast
H
H
3
C
CH
2
H
3
C
CH
2
H
3
C
CH
2
OH
abstraction of
proton
resonance
O
H
3
C
CH
2
conjugate base
enolate anion
enzyme-catalysed enolization
The enzymic processes appear exactly equivalent,
except that protons are removed and supplied through
the involvement of peptide side-chains. It is unlikely
that a distinct enolate anion is formed; instead, we
should consider the process as concerted with a
smooth flow of electrons. Thus, as a basic group
removes a proton from one part of the molecule, an
acidic group supplies a proton at another.
The
AH
A
H
B
HB
O
O
H
H
3
C
CH
2
H
3
C
CH
2
forward reaction
reverse reaction
example
of
triose
phosphate
isomerase
in
A and B are part of enzyme
Box 13.6
provides
us
with
an
easily
understood
analogy.
