Any substance that can decrease the velocity of an enzyme-catalyzed reaction is called an inhibitor. Inhibitors can be reversible or irreversible. Irreversible inhibitors bind to enzymes through covalent bonds.
INHIBITION OF ENZYME ACTIVITY
Any substance that can
decrease the velocity of an enzyme-catalyzed reaction is called an inhibitor.
Inhibitors can be reversible or irreversible. Irreversible inhibitors bind to
enzymes through covalent bonds. Lead, for example, forms covalent bonds with
the sulfhydryl side chain of cysteine in proteins. Ferrochelatase, an enzyme
involved in heme synthesis, is irreversibly inhibited by lead. [Note: An important
group of irreversible inhibitors are the mechanism-based inhibitors that are
converted by the enzyme itself to a form that covalently links to the enzyme,
thereby inhibiting it. They also are referred to as “suicide” inhibitors.]
Reversible inhibitors bind to enzymes through noncovalent bonds and, thus,
dilution of the enzyme–inhibitor complex results in dissociation of the
reversibly bound inhibitor and recovery of enzyme activity. The two most
commonly encountered types of reversible inhibition are competitive and
noncompetitive.
This type of inhibition
occurs when the inhibitor binds reversibly to the same site that the substrate
would normally occupy and, therefore, competes with the substrate for that
site.
1. Effect on Vmax: The effect of a competitive
inhibitor is reversed by increasing [S]. At a sufficiently high substrate
concentration, the reaction velocity reaches the Vmax observed in
the absence of inhibitor (Figure 5.12).
2. Effect on Km: A competitive inhibitor increases
the apparent Km for a given substrate. This means that, in the
presence of a competitive inhibitor, more substrate is needed to achieve 1⁄2Vmax.
3. Effect on the Lineweaver-Burk plot: Competitive inhibition shows a
characteristic Lineweaver-Burk plot in which the plots of the inhibited and
uninhibited reactions intersect on the y axis at 1/Vmax (Vmax is unchanged).
The inhibited and uninhibited reactions show different x-axis intercepts,
indicating that the apparent Km is increased in the presence of the competitive
inhibitor because - 1/Km moves closer to zero from a negative value (see Figure
5.12). [Note: An important group of competitive inhibitors are the transition
state analogs, stable molecules that approximate the structure of the transition
state and, therefore, bind the enzyme with a higher affinity than the
substrate.]
Figure 5.12 A. Effect of a
competitive inhibitor on the reaction velocity versus substrate ([S]) plot. B.
Lineweaver-Burk plot of competitive inhibition of an enzyme.
4. Statin drugs as examples of competitive
inhibitors: This
group of antihyperlipidemic agents competitively inhibits the rate-limiting
(slowest) step in cholesterol biosynthesis. This reaction is catalyzed by
hydroxymethylglutaryl–CoA reductase (HMG-CoA reductase). Statins, such as
atorvastatin (Lipitor) and pravastatin (Pravachol), are structural analogs of
the natural substrate for this enzyme and compete effectively to inhibit
HMG-CoA reductase. By doing so, they inhibit de novo cholesterol synthesis,
thereby lowering plasma cholesterol levels (Figure 5.13).
Figure 5.13 Pravastatin
competes with HMGCoA for the active site of HMGCoA reductase. HMG-CoA =
hydroxymethylglutaryl-coenzyme A.
This type of inhibition
is recognized by its characteristic effect on Vmax (Figure 5.14).
Noncompetitive inhibition occurs when the inhibitor and substrate bind at
different sites on the enzyme. The noncompetitive inhibitor can bind either
free enzyme or the enzyme-substrate complex, thereby preventing the reaction
from occurring (Figure 5.15).
Figure 5.14 A. Effect of a noncompetitive inhibitor on the reaction velocity versus substrate ([S]) plot. B. Lineweaver-Burk plot of noncompetitive inhibition of an enzyme.
Figure 5.15 A noncompetitive inhibitor binding to both free enzyme and enzyme-substrate (ES) complex.
1. Effect on Vmax: Noncompetitive inhibition cannot
be overcome by increasing the concentration of substrate. Therefore,
noncompetitive inhibitors decrease the apparent Vmax of the
reaction.
2. Effect on Km: Noncompetitive inhibitors do not interfere with the binding of substrate to enzyme. Therefore, the enzyme shows the same Km in the presence or absence of the noncompetitive inhibitor.
3. Effect on Lineweaver-Burk plot: Noncompetitive inhibition is readily differentiated from competitive inhibition by plotting 1/vo versus 1/[S] and noting that the apparent Vmax decreases in the presence of a noncompetitive inhibitor, whereas Km is unchanged (see Figure 5.14). [Note: Oxypurinol, a metabolite of the drug allopurinol, is a noncompetitive inhibitor of xanthine oxidase, an enzyme of purine degradation.]
At least half of the
ten most commonly prescribed drugs in the United States act as enzyme
inhibitors. For example, the widely prescribed β-lactam antibiotics, such as
penicillin and amoxicillin, act by inhibiting enzymes involved in bacterial
cell wall synthesis. Drugs may also act by inhibiting extracellular reactions.
This is illustrated by angiotensin-converting enzyme (ACE) inhibitors. They lower
blood pressure by blocking the enzyme that cleaves angiotensin I to form the
potent vasoconstrictor, angiotensin II. These drugs, which include captopril,
enalapril, and lisinopril, cause vasodilation and, therefore, a reduction in
blood pressure. Aspirin, a nonprescription drug, irreversibly inhibits
prostaglandin and thromboxane synthesis.
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