Identification of Key Functional Residues in the Active Site of Vitamin K Epoxide Reductase-like Protein

The vitamin K epoxide reductase (VKOR) activity has been described since the early 70s’. This VKOR activity allows the reduction of vitamin K epoxide in order to regenerate vitamin K quinone. This activity is a key step of the vitamin cycle and is the target of vitamin K antagonist (VKA).

The VKORC1 gene has only been identified in 2004. This gene encodes for a 163 amino acid protein with, probably, four transmembrane domains and a luminal loop. This protein contains also a C132XXC135 redox motif, as previously hypothesized by Silverman. This motif is located in the fourth transmembrane domain.

VKA actively inhibit VKORC1 in the liver and thus limit the gamma-carboxylation of hepatic VKD proteins resulting in an intense anticoagulant effect. VKA are extensively used worldwide for prevention and treatment of thromboembolic disorders. Many missenses mutations have been detected in VKORC1 gene in humans and rats and are sometimes associated to a VKA resistance phenotype

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