Suicide (mechanism-based) inhibition occurs when an enzyme activates an inhibitor to form a reactive intermediate that covalently inactivates the enzyme. Which drug-enzyme pair exemplifies mechanism-based irreversible inhibition?

• A Methotrexate inhibiting dihydrofolate reductase (competitive reversible)
• B Aspirin irreversibly acetylating COX-1 Ser529
• C Allopurinol converted to oxipurinol by xanthine oxidase, which then forms a covalent complex with reduced molybdenum cofactor of xanthine oxidase ✓
• D PMSF irreversibly inhibiting serine proteases by sulfonylation

Explanation

Mechanism-based (suicide) inhibition requires the enzyme to catalytically convert the inhibitor prodrug to an active species that then inactivates that same enzyme. Allopurinol is oxidised by xanthine oxidase to oxipurinol (alloxanthine), which forms a tight inhibitory complex with the reduced molybdenum-Fe/S centre of xanthine oxidase, preventing its reoxidation and causing pseudo-irreversible inhibition. Methotrexate is a tight-binding competitive inhibitor of DHFR, not mechanism-based. Aspirin is an irreversible inhibitor but it is a direct acetylating agent, not a prodrug requiring enzyme conversion. PMSF is a chemical modifying agent, not a mechanism-based inhibitor.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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