Page 105 - Color Atlas of Biochemistry
P. 105
96 Metabolism
Inhibitors “Suicide substrates” (5)are substrateana-
logs that also contain a reactive group. Ini-
Many substances can affect metabolic pro- tially, they bind reversibly, and then they
cesses by influencing the activity of form a covalent bond with the active center
enzymes. Enzyme inhibitors are particularly of the enzyme. Their effect is therefore also
important here. A large proportion of non-competitive. A well-known example of
medicines act as enzyme inhibitors. Enzyme- this is the antibiotic penicillin (see p. 254).
kinetic experiments are therefore an impor- Allosteric inhibitors bind to a separate
tant aspect of drug development and testing binding site outside the active center (6).
procedures. Natural metabolites are also in- This results in a conformational change in
volved in regulatory processes as inhibitors the enzyme protein that indirectly reduces
(see p.114). its activity (see p.116). Allosteric effects prac-
tically only occur in oligomeric enzymes. The
kinetics of this type of system can no longer
A. Types of inhibitor
be described using the simple Micha-
Most enzyme inhibitors act reversibly—i. e., elis–Menten model.
they do not cause any permanent changes in
the enzyme. However, there are also irrever-
sible inhibitors that permanently modify the B. Inhibition kinetics
target enzyme. The mechanism of action of an In addition to the Lineweaver–Burk plot (see
inhibitor—its inhibition type—can be deter- p. 92), the Eadie–Hofstee plot is also com-
mined by comparing the kinetics (see p. 92) monly used. In this case, the velocity v is
of the inhibited and uninhibited reactions (B). plotted against v /[A]. In this type of plot,
This makes it possible to distinguish compet- V max corresponds to the intersection of the
itive inhibitors (left) from noncompetitive approximation lines with the v axis, while
inhibitors (right), for example. Allosteric K m is derived from the gradient of the lines.
inhibition is particularly important for meta- Competitive and non-competitive inhibitors
bolic regulation (see below). are also easily distinguishable in the Eadie—
Substrate analogs (2) have properties sim- Hofstee plot. As mentioned earlier, competi-
ilar to those of one of the substrates of the tive inhibitors only influence K m , and not
target enzyme. They are bound by the en- V max . The lines obtained in the absence and
zyme, but cannot be converted further and presence of an inhibitor therefore intersect on
therefore reversibly block some of the enzyme the ordinate. Non-competitive inhibitors pro-
molecules present. A higher substrate concen- duce lines that have the same slope (K m un-
tration is therefore needed to achieve a half- changed) but intersect with the ordinate at a
lower level. Another type of inhibitor, not
maximum rate; the Michaelis constant K m
increases (B). High concentrations of the sub- shown here, in which V max and K m are re-
strate displace the inhibitor again. The max- duced by the same factor, is referred to as
imum rate V max is therefore not influenced by uncompetitive. Inhibitors with purely uncom-
this type of inhibition. Because the substrate petitive effects are rare. A possible explana-
and the inhibitor compete with one another tion for this type of inhibition is selective
for the same binding site on the enzyme, this binding of the inhibitor to the EA complex.
type of inhibition is referred to as compe- Allosteric enzymes shift the target en-
titive. Analogs of the transition state (3)usu- zyme’s saturation curve to the left (see
ally also act competitively. p. 92). In Eadie–Hofstee and Lineweaver–Burk
When an inhibitor interacts with a group plots (see p. 92), allosteric enzymes are recog-
that is important for enzyme activity, but does nizable because they produce curved lines
not affect binding of the substrate, the inhi- (not shown).
bition is non-competitive (right). In this case,
K m remains unchanged, but the concentration
of functional enzyme [E] t ,and thus V max ,de-
crease. Non-competitive inhibitors generally
act irreversibly, by modifying functional
groups of the target enzyme (4).
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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