Vitamin K Epoxide Reductase Complex Subunit 1 (VKORC1): The Key Protein of the Vitamin K Cycle

Abstract

Vitamin K epoxide, a by-product of the carboxylation of blood coagulation factors, is reduced to vitamin K by an enzymatic system possessing vitamin K epoxide reductase (VKOR) activity. This system is the target of coumarin-derived drugs widely used in thrombosis therapy and prophylaxis. Recently, the key protein of the VKOR system has been identified. The human VKORC1 gene maps to chromosome 16 and consists of 3 exons encoding a 163-amino acid integral ER membrane protein with three or four predicted transmembrane alpha- helices. Expression of human VKORC1 in Spodoptera frugiperda (Sf9) cells and in Pichia pastoris results in enhanced VKOR activity over low endogenous constitutive levels. Sequence based search methods reveal that human VKORC1 belongs to a large family of homologous genes found in vertebrates, insects, plants, protists, archea, and bacteria. All orthologs share five completely conserved amino acids, including two cysteines found in a tetrapeptide motif presumably required for redox function. The recent discovery of the VKORC1 gene has initiated renewed interest in understanding VKOR activity. Analysis of VKORC1 protein structure and function will be crucial in understanding the VKOR catalytic mechanism, how anticoagulant drugs modulate VKOR activity, and the role of VKORC1 in downstream physiological and pathological pathways.

Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

“…As a consequence, purifi ed recombinant VKOR requires an intact membrane for its function ( 65 ). Recombinant VKOR alone is suffi cient to catalyze the conversion of both K>O to K and humans ( 97 ), tyrosine139 has also been proposed as being important for the binding site of VKAs to VKOR. At the time of these studies, the lack of apparent activity of many other VKOR mutations was diffi cult to explain.…”

The Arg98Trp mutation in human VKORC1 causing VKCFD2 disrupts a di-arginine–based ER retention motif

“…During g-carboxylation, KH 2 is oxidized to vitamin K 2,3-epoxide to complete the vitamin K cycle. 3,4 Defects in the vitamin K cycle can cause combined deficiency of VKD clotting factors (VKCFD), resulting in reduced activity levels for VKCFD FII, FVII, FIX, and FX, as well as for other VKD proteins. This deficiency can be caused either by various mutations in g-glutamyl carboxylase leading to VKCFD type 1 or by a single VKORC1 missense mutation that results in VKCFD type 2 (VKCFD2) 1,5 The VKCFD2 phenotype was first presented by Pauli et al, 6 followed by a more detailed description of 7 patients from 2 independent families by Oldenburg et al 7 The latter 2 families enabled a homozygosity mapping study locating the affected gene for this phenotype to chromosome 16.…”

Human Herpesvirus 8 Viral Interleukin-6 Interacts with Splice Variant 2 of Vitamin K Epoxide Reductase Complex Subunit 1

“…While VKORC1 (variant 1) is a well-characterized protein involved in the vitamin K cycle and the target of the anticoagulant warfarin (18), VKORC1 variant 2 (VKORC1v2) shares only N-terminal sequences with its well-known counterpart. This region encompasses the first of three predicted transmembrane (TM) domains and part of the TM1-to-TM2 sequence of variant 1, followed by variant 2-specific "soluble" (non-TM) residues.…”