Vitamin K-dependent carboxylation of glutamate residues to gamma-carboxyglutamate (Gla) is required for functional coagulation factors II, VII, IX, and X, as well as proteins C and S. Which enzyme is specifically inhibited by warfarin to block this carboxylation cycle?

• A Gamma-glutamyl carboxylase
• B Prothrombin activator complex directly
• C Carboxypeptidase that cleaves Gla residues from prothrombin
• D Vitamin K epoxide reductase (VKOR), preventing recycling of vitamin K epoxide to reduced vitamin K ✓

Explanation

Gamma-glutamyl carboxylase uses reduced vitamin K (vitamin KH2) as a cofactor and converts it to vitamin K epoxide during carboxylation of Gla residues. Vitamin K epoxide is then reduced back to active vitamin KH2 by vitamin K epoxide reductase complex (VKORC1). Warfarin is a competitive inhibitor of VKORC1, trapping vitamin K in the inactive epoxide form and depleting reduced vitamin K needed for carboxylation. Genetic variants in VKORC1 are the primary determinant of individual warfarin dose requirements; the VKORC1 1639G>A polymorphism reduces enzyme expression and requires lower warfarin doses.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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