Bioorganic Chemistry
17
distinction being whether or not a covalent
chemical bond forms between enzyme
and inhibitor. These classiFcations may
be further divided into categories on the
basis of kinetic and mechanistic criteria.
Major subclasses include transition-state
analogs, multisubstrate analogs, afFnity
labels, and mechanism-based inhibitors.
Noncovalent enzyme inhibitors rely on
having two important features: (1) enough
structural similarity to the actual enzyme’s
substrate to allow recognition and tight
binding to the enzyme that is to be in-
hibited and (2) differences in the chemical
structure that prevents the normal chem-
istry from taking place. An example of this
type of compound is the drug Enalapril.
It is the prodrug of Enalaprilat, which is
an inhibitor of the protease angiotensin-
converting enzyme (ACE). This enzyme
cleaves the 10-residue peptide angiotensin
I into the 8-residue peptide angiotensin
II. These peptides are part of a pathway
that controls blood pressure, and it has
been found that preventing the conver-
sion of angiotensin I to angiotensin II can
be effective in reducing certain types of
blood pressure (±ig. 13). This Fgure also
shows schematically the interactions be-
tween enzyme and substrate that have
been deduced to be crucial for binding
afFnity. Of note are a hydrogen bond
to a carbonyl group, a salt bridge from
the carboxyl terminus to a cationic site
on the protein, and a putative hydropho-
bic pocket that binds the phenyl ring of
the phenylalanine residue that is adja-
cent to the scissile (or cleavable) peptide
bond. Also indicated schematically is an
enzyme-bound zinc ion that is crucial
for catalysis. It is shown to be interact-
ing with the carbonyl of the peptide bond
that is to be cleaved. It is believed that
the zinc polarizes the carbonyl group,
pulling electron density from the oxygen
and therefore, indirectly, from the carbonyl
H
2
N-D-R-V-Y-I-H-P-F-H-L-COOH
ACE
H
2
N-D-R-V-Y-I-H-P-F-COOH
Angiotensin I
Angiotensin II
(a)
(c)
H
X
N
O
O
H
R
O
N
O
O
Zn
2
+
Catalytic
cationic zinc
Structural mimic
enalaprilat
Hydrophobic
site
Hydrogen
bond
donating
site
Cationic
site
(b)
N
H
N
O
O
N
O
R
H
O
R
H
H
X
Zn
2
+
Catalytic
cationic zinc
Natural
substrate
Hydrophobic
site
Hydrogen
bond
donating
site
Cationic
site
+
+
Fig. 13
(a) The reaction catalyzed by angiotensin-converting enzyme (ACE). (b) Schematic
representation of the interaction of ACE with both substrate and (c) Enalaprilat, an inhibitor.
previous page 691 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 693 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off