Vitamin K Epoxide Reductase Complex and Vascular Calcification

Vitamin K is a cofactor in the -glutamyl carboxylation pathway, a posttranslational conversion of specific glutamate residues into -carboxyglutamic acid (Gla) residues, catalyzed by the endoplasmic reticulum enzyme -glutamyl carboxylase. The substrates of carboxylase are the so-called vitamin K–dependent proteins, which are involved in diverse physiological processes such as blood coagulation, bone and soft tissue mineralization, and cellular proliferation. The coagulation factors II (prothrombin), VII, IX, and X have procoagulant activity, whereas proteins C and S inhibit blood coagulation (see reviews by Dahlback1 and Stafford2). Protein Z is involved in the fixation of thrombin by binding to a phospholipid surface. Matrix Gla protein (MGP) and osteocalcin (or bone Gla protein) are regulators of tissue mineralization, whereas Gas6 is involved in the regulation of cell growth. The mRNA sequences of 4 new putative vitamin K–dependent proteins were recently reported, but their functions remain elusive: 2 proline-rich Gla proteins, PRGP1 and PRGP2, and 2 transmembrane Gla proteins, TMG3 and TMG4. For each of these proteins, the presence of Gla residues is a prerequisite for Ca binding and/or Ca dependent interaction with negatively charged surfaces. Four key components are involved in the proper biosynthesis of the vitamin K–dependent proteins: the enzymes -glutamyl carboxylase and vitamin K epoxide reductase complex (VKORC1), vitamin K, and a precursor protein. Not the form in which it occurs in food (vitamin K quinone) but the reduced form, vitamin K hydroquinone (KH2), is the active cofactor used by the enzyme -glutamyl carboxylase (Figure). KH2 is converted into vitamin K epoxide (KO), and KO is subsequently reduced to vitamin K and vitamin KH2 in 2 reactions by the action of VKORC1. This recycling mechanism is called the vitamin K cycle and explains why the daily requirement for vitamin K is low and why vitamin K deficiency is rarely seen in healthy subjects. Except for the dithiol-dependent pathway, vitamin K (and not KO) may also be reduced by DT diaphorase, an NAD(P)H-dependent dehydrogenase. Although DT diaphorase is highly expressed in the liver, the dithiol-dependent pathway is the most active one for KH2 generation3 (Figure).