Catalytic cycle that regenerates active vitamin K hydroquinone (KH2) after each γ-carboxylation event. γ-Carboxylase uses KH2 + O2 + CO2 to add a γ-carboxyl group to glutamate residues on vitamin-K-dependent proteins (factors II, VII, IX, X + proteins C, S, Z; also osteocalcin and MGP). KH2 is oxidized to vitamin K epoxide in the reaction. VKORC1 reduces the epoxide back to vitamin K, completing the cycle. WARFARIN inhibits VKORC1 → epoxide accumulates → KH2 depletes → γ-carboxylation halts → undercarboxylated coagulation factors are functionally inactive.
Organ Systems
cardiovascular
immune-hematologic
Pathway Steps
phylloquinone → vitamin-k-hydroquinone — via vitamin K reductase. Vitamin K is reduced to its active hydroquinone to serve as the γ-carboxylase cofactor. Dietary K1 (phylloquinone, leafy greens) and bacterial/animal K2 (menaquinones) both feed this cycle.
vitamin-k-hydroquinone → vitamin-k-epoxide — via γ-carboxylase (consumes O2 + CO2; carboxylates Glu → Gla on factors II/VII/IX/X). γ-glutamyl carboxylase uses the hydroquinone (plus O2/CO2) to carboxylate glutamates to Gla on factors II/VII/IX/X and proteins C/S — and on osteocalcin/MGP (bone, vascular) — the modification that lets these proteins bind Ca²⁺ and membranes.
vitamin-k-epoxide → phylloquinone — via VKORC1 — WARFARIN TARGET. VKOR (VKORC1) recycles the spent epoxide back to vitamin K — the warfarin target. Warfarin depletes reduced vitamin K, yielding under-carboxylated, nonfunctional factors; VKORC1/CYP2C9 variants explain much of warfarin’s dosing variability, and dietary vitamin K antagonizes it.
Known Modulators
warfarin (inhibitor) — VKORC1. Both R- and S-enantiomers inhibit VKORC1; S-warfarin is 2.7-3.8× more potent than R.