Chemistry Reference
In-Depth Information
Enzyme inhibitors
are chemicals that may serve
as a natural means of controlling metabolic activ-
ity by reducing the number of enzyme molecules
available for catalysis. In many cases, natural or syn-
thetic inhibitors have allowed us to unravel the path-
ways and mechanisms of intermediary metabolism.
Enzyme inhibitors may also be used as pesticides or
drugs. Such materials are designed so that they inhibit
a specific enzyme that is peculiar to an organism or
a disease state. For example, a good antibiotic may
inhibit a bacterial enzyme, but it should have no effect
on the host person or animal.
We may consider enzyme inhibitors as either
irreversible or reversible inhibitors. Some inhibitors
become covalently linked to the enzyme and are
bound so strongly that they cannot be removed. As a
result, the enzyme activity decreases and eventually
becomes zero.
The enzyme becomes inactivated, and a toxic level
of acetylcholine builds up. Organophosphorus com-
pounds provide a range of insecticides and nerve
gases.
Reversible inhibitors
are potentially less damag-
ing. In the presence of a reversible inhibitor, the
enzyme activity decreases, but to a constant level as
equilibrium is reached. The enzyme activity reflects
the lower level of enzyme available for cataly-
sis. We can subdivide the reversible inhibition into
three types, i.e. competitive, non-competitive, and
allosteric inhibition.
Competitive inhibitors
bind to specific groups in
the enzyme active site to form an enzyme - inhibitor
complex. The inhibitor and substrate compete for
the same site, so that the substrate is prevented
from binding. This is usually because the substrate
and inhibitor share considerable structural similarity.
Catalysis is diminished because a lower proportion
of molecules have a bound substrate. Inhibition
can be relieved by increasing the concentration of
substrate. Some simple examples are shown below.
Thus, sulfanilamide is an inhibitor of the enzyme
that incorporates
p
-aminobenzoic acid into folic acid,
and has antibacterial properties by restricting folic
acid biosynthesis in the bacterium (see Box 11.13).
Some phenylethylamine derivatives, e.g. phenelzine,
provide useful antidepressant drugs by inhibiting the
enzyme monoamine oxidase. The
cis
-isomer maleic
acid is a powerful inhibitor of the enzyme that utilizes
the
trans
-isomer fumaric acid in the Krebs cycle.
E+ I
EI
irreversible inhibitor:
reversible inhibitor:
E+ I
EI
Irreversible inhibition
in an organism usually
results in a toxic effect. Examples of this type of
inhibitor are the organophosphorus compounds that
interfere with acetylcholinesterase (see Box 7.26).
The organophosphorus derivative reacts with the
enzyme in the normal way, but the phosphory-
lated intermediate produced is resistant to normal
hydrolysis and is not released from the enzyme.
competitive
inhibitor
competitive
inhibitor
competitive
inhibitor
substrate
substrate
substrate
NHNH
2
NH
2
NH
2
CO
2
H
CO
2
H
CO
2
H
O
S
O
HO
2
C
CO
2
H
fumaric acid
Krebs cycle
intermediate
maleic acid
Krebs cycle
inhibitor
NH
2
NH
2
phenylethylamine
phenelzine
p
-aminobenzoic acid
sulfanilamide
substrate for
monamine oxidases
antidepressant
substrate for folic
acid biosynthesis
antibacterial
Non-competitive inhibitors
do not bind to the
active site, but bind at another site on the enzyme and
distort the shape of the protein, resulting in a lowering
of activity. Both inhibitor and substrate can bind
simultaneously to the enzyme. A non-competitive
inhibitor decreases the activity of the enzyme rather
