COOH COOHOOHO
ONHCOCHNHCO NHCOCHNHCO NHCOCHNHCO
CH 2
OHCH (^2) CH
2
COOH
O
C
O
CH 3
O
COOH
O C− CH
3
- O
COOH
O
C
O
CH 3
O H +H+
Prostaglandin
synthase / O 2
Arachidonic acid PGG
2
Various
prostaglandins
−
:
Figure 7.4 The biosynthesis of prostaglandins
first used clinically at the end of the 19th century as an antipyretic, is now
believed to irreversibly inhibit prostaglandin synthase (cyclooxygenase), the
enzyme that catalyses the conversion of arachidonic acid to PGG 2 (Appen-
dix 8), which acts as a source for a number of other prostaglandins (Figure 7.4).
Experimental evidence suggests that aspirin acts by acetylating serine
hydroxy groups at the enzyme’s active site, probably by a transesterification
mechanism.
Suicide inhibitors, alternatively known asKcat or irreversible mechanism
based inhibitors (IMBIs), are irreversible inhibitors that are often analogues
of the normal substrate of the enzyme. The inhibitor binds to the active
site, where it is modified by the enzyme to produce a reactive group, which
reacts irreversibly to form a stable inhibitor–enzyme complex. This subse-
quent reaction may or may not involve functional groups at the active site.
This means that suicide inhibitors are likely to be specific in their action, since
they can only be activated by a particular enzyme. This specificity means
that drugs designed as suicide inhibitors could exhibit a lower degree of tox-
icity.
A wide variety of structures have been found to act as sources of the electro-
philic groups of suicide inhibitors (Figure 7.5). These structures will only give
rise to an electrophilic group if the compound containing the structure can act as
a substrate for the enzyme. They often take the form of a,b unsaturated
carbonyl compounds and imines formed by the reverse of a Michael addition
at the active site of the enzyme.
L LXXH B+Enz+ Enz− BH+DRUGS THAT TARGET ENZYMES 141