Covalent (irreversible) inhibitors permanently inactivate enzymes by forming stable covalent bonds with active site residues. Which of the following correctly illustrates an irreversible enzyme inhibitor and its target residue?

• A Ibuprofen forms a covalent bond with Arg-120 of COX-2, irreversibly blocking prostaglandin synthesis
• B Allopurinol forms a covalent bond with the molybdenum cofactor of xanthine oxidase
• C Methotrexate alkylates Glu-30 of DHFR, permanently inhibiting folate reduction
• D Aspirin (acetylsalicylate) acetylates Serine-530 of COX-1/COX-2, permanently blocking the cyclooxygenase tunnel ✓

Explanation

Aspirin irreversibly acetylates Ser-530 in the hydrophobic tunnel of prostaglandin H synthase (COX-1/COX-2), permanently blocking access of arachidonic acid to the catalytic tyrosine. This is why aspirin's antiplatelet effect lasts the lifetime of platelets (7–10 days), as anucleate platelets cannot synthesise new COX. Ibuprofen is a reversible, competitive inhibitor. Allopurinol is converted by xanthine oxidase to oxypurinol, which then non-covalently but tightly (pseudo-irreversible) binds the reduced molybdenum form — not a classic alkylation. Methotrexate binds DHFR with extremely high affinity but does not form a covalent bond.

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

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