VKORC1 and the vitamin K cycle.

Vitamin K epoxide, a product of gamma-carboxylation, must be rapidly recycled to its reduced form before it can be reused. The set of sequential reactions that guarantees vitamin K recycling is known as the vitamin K cycle. This review is focused on biochemical and genetic aspects of a recently characterized key enzyme of the cycle named vitamin K epoxide reductase complex subunit 1 (VKORC1). This 163-amino acid long protein (18 kDa) is responsible for vitamin K reduction. Recent studies also demonstrated the existence of a VKOR complex in which protein disulfide isomerase (PDI) and VKORC1 appear to be tightly associated. PDI is a thioredoxin-like oxidoreductase and chaperone that is present at high concentrations in the endoplasmic reticulum (ER) and that provides electrons for reduction of the CXXC center in VKORC1. Genetic studies have shown that the VKORC1 gene extends over 5126 base pairs on human chromosome 16 and comprises three exons. Mutations in the VKORC1 gene causes generalized defective vitamin K-dependent clotting factors (VKCFD2) and warfarin resistance (WR). More detailed pharmacogenetic studies have demonstrated a strong association between single nucleotide polymorphisms (SNPs) in the VKORC1 gene and the requirement of warfarin dosage. Screening for VKORC1 polymorphisms that affect warfarin dosage could be helpful to tailor dosage at the onset of oral anticoagulant treatment in order to lower thrombosis and bleeding risks.