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The presence of a competitive inhibitor causes the inhibited and uninhibited reactions to have different x-axis intercepts. This indicates that the apparent Km is increased because -1/Km moves closer to zero from a negative value. Competitive inhibitors that are transition state analogs bind the enzyme more tightly than the substrate due to their similar structure. Statin drugs, such as Lipitor and Pravachol, are examples of competitive inhibitors that effectively inhibit the rate-limiting step in cholesterol biosynthesis by competitively inhibiting HMG CoA reductase, the enzyme responsible for this reaction.

Noncompetitive inhibition occurs when the inhibitor and substrate bind to different sites on the enzyme. It is characterized by its effect on Vmax, which decreases in the presence of a noncompetitive inhibitor. Increasing the concentration of substrate cannot overcome noncompetitive inhibition. However, the binding of substrate to the enzyme is not affected, so the Km remains unchanged. Noncompetitive inhibition can be distinguished from competitive inhibition by plotting 1/vo versus 1/[S] on a Lineweaver-Burk plot. The apparent Vmax decreases in the presence of a noncompetitive inhibitor, while the Km remains the same. Oxypurinol, a metabolite of allopurinol, is an example of a noncompetitive inhibitor that inhibits xanthine oxidase, an enzyme involved in purine degradation.

Enzyme inhibitors are commonly used as drugs, with at least half of the top ten prescribed drugs in the United States acting as enzyme inhibitors. For instance, β-lactam antibiotics like penicillin and amoxicillin inhibit enzymes involved in bacterial cell wall synthesis. ACE inhibitors, such as captopril, enalapril, and lisinopril, lower blood pressure by blocking plasma ACE, which cleaves angiotensin I to form angiotensin II, a potent vasoconstrictor. Aspirin irreversibly inhibits the synthesis of prostaglandins and thromboxanes by inhibiting cyclooxygenase.

VIII. ENZYME REGULATION

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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 Fig. 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 more tightly than does the substrate.] 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 coenzyme A reductase (HMG CoA reductase; see p. 221). 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 (Fig. 5.13).
B. Noncompetitive inhibition
This type of inhibition is recognized by its characteristic effect on Vmax (Fig. 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 (Fig. 5.15).
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, that is, Km is unchanged.
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 Fig. 5.14). [Note: Oxypurinol, a metabolite of the prodrug allopurinol, is a noncompetitive inhibitor of xanthine oxidase, an enzyme of purine degradation (see p. 301).]
C. Enzyme inhibitors as drugs
At least half of the ten most commonly prescribed drugs in the United States act as enzyme inhibitors. For example, the widely prescribed βlactam 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 angiotensinconverting enzyme (ACE) inhibitors. They lower blood pressure by blocking plasma ACE 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 by inhibiting cyclooxygenase (see p. 214).
VIII. ENZYME REGULATION