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Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like1

Abstract Human vitamin K epoxide reductase (hVKOR) is a small integral membrane protein involved in recycling vitamin K. hVKOR produces vitamin K hydroquinone, a crucial cofactor for γ-glutamyl carboxylation of vitamin K dependent proteins, which are necessary for blood coagulation. Because of this, hVKOR is the target of a common anticoagulant, warfarin. Spurred by the identification of the hVKOR gene less than a decade ago, there have been a number of new insights related to this protein. Nonetheless, there are a number of key issues that have not been resolved; such as where warfarin binds hVKOR, or if human VKOR shares the topology of the structurally characterized but distantly related prokaryotic VKOR. The pharmacogenetics and single nucleotide polymorphisms of hVKOR used in personalized medicine strategies for warfarin dosing should be carefully considered to inform the debate. The biochemical and cell biological evidence suggests that hVKOR has a distinct fold from its ancestral protein, though the controversy will likely remain until structural studies of hVKOR are accomplished. Resolving these issues should impact development of new anticoagulants. The paralogous human protein, VKOR-like1 (VKORL1) was recently shown to also participate in vitamin K recycling. VKORL1 was also recently characterized and assigned a functional role as a housekeeping protein involved in redox homeostasis and oxidative stress with a potential role in cancer regulation. As the physiological interplay between these two human paralogs emerge, the impacts could be significant in a number of diverse fields from coagulation to cancer.