SECTION 6.4
Inhibition
95
Guanosine 5'-
triphosphate "
6-HydroxymethyIdi hydropterin
diphosphate
^-H,N
/
\
COOH
p-Aminobenzoic acid (PABA)
H.N
n^
h
ch, _ k^
A
COOH + PPi
7,8-Dihydropteroic acid
L-ATP
Glutamic acid
^ A D P + Pj
NADPH + H+ >
NADP+~-y
Dihydrofolate
reductase
H,N-
H
I
«
_____ .
O
COOH
I '
II
l / H
f ^
\
II
H
I
N5
4
A.
s ?C— CH— NH—
V
XV -C — N— C—
I
9
10
: f i
C— CKCKCOOH
H
OH
H
5,6,7,8-Tetrahydrofolate
FIGURE 6-7
Folate biosynthetic pathways in bacteria. The incorporation of p-aminobenzoic acid into 7,8-dihydropteroic acid is
competitively inhibited by sulfanilamide.
slow, thereby affecting the overall catalytic process. Thus,
in this type of inhibition, an inhibitor bearing a particu-
lar structural similarity to the substrate binds to the ac-
tive site of the enzyme and, through the catalytic action
of the enzyme, is converted to a reactive compound that
can form a covalent (or coordinate covalent) bond with
a functional group at the active site. This type of inhi-
bition, known as
mechanism-based enzyme inactivation,
depends on both the structural similarity of the inhibitor to
the substrate and the mechanism of action of the target en-
zyme. The substrate analogue is called a
suicide substrate
because the enzyme is inactivated in one of the steps of the
catalytic cycle. The suicide substrate, by virtue of its high
selectivity, provides possibilities for many
in vivo
applica-
tions (e.g., development of rational drug design). Suicide
substrates with potential clinical applications for several
enzymes (e.g., penicillinase, prostaglandin cyclooxyge-
nase) have been synthesized. Examples of suicide sub-
strates harmful to the body are given in Chapter 27.
Allopurinol, which affects both the penultimate and
ultimate steps in the production of uric acid, is used to
lower plasma uric acid levels in conditions associated
with excessive urate production (e.g., gout, hematologic
disorders, and antineoplastic therapy). Sodium urate has a
