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

Abstract

In contrast to other fat-soluble vitamins, dietary vitamin K is rapidly lost to the body resulting in comparatively low tissue stores. Deficiency is kept at bay by the ubiquity of vitamin K in the diet, synthesis by gut microflora in some species, and relatively low vitamin K cofactor requirements for γ-glutamyl carboxylation. However, as shown by fatal neonatal bleeding in mice that lack vitamin K epoxide reductase (VKOR), the low requirements are dependent on the ability of animals to regenerate vitamin K from its epoxide metabolite via the vitamin K cycle. The identification of the genes encoding VKOR and its paralog VKOR-like 1 (VKORL1) has accelerated understanding of the enzymology of this salvage pathway. In parallel, a novel human enzyme that participates in the cellular conversion of phylloquinone to menaquinone (MK)-4 was identified as UbiA prenyltransferase-containing domain 1 (UBIAD1). Recent studies suggest that side-chain cleavage of oral phylloquinone occurs in the intestine, and that menadione is a circulating precursor of tissue MK-4. The mechanisms and functions of vitamin K recycling and MK-4 synthesis have dominated advances made in vitamin K biochemistry over the last five years and, after a brief overview of general metabolism, are the main focuses of this review.

Keywords: UbiA prenyltransferase-containing domain 1; anticoagulants; menaquinones; phylloquinone; vitamin K antagonists; vitamin K dehydrogenase; vitamin K epoxide; vitamin K epoxide reductase; warfarin; warfarin resistance; γ-carboxyglutamate proteins.

Fig. 1.

Chemical structures of vitamin K compounds.

Fig. 2.

Metabolism of vitamin K via the vitamin K-epoxide cycle in the absence (A) and presence (B) of warfarin. A: In the absence of warfarin, peptide-bound glutamic acid (Glu) residues are transformed to γ-carboxy glutamic acid (Gla) residues by the enzyme γ-glutamyl carboxylase (GGCX) shown as enzyme activity (1). The active cofactor form of vitamin K required by the GGCX is the reduced form vitamin K quinol (KH₂). During γ-glutamyl carboxylation, the carboxylated substrates (Gla proteins) are secreted into the circulation and KH₂ becomes oxidized to vitamin K epoxide (K>O). This epoxide metabolite is reduced to vitamin K quinone by the enzyme VKOR, shown as enzyme activity (2). Vitamin K quinone is then reduced to KH₂ by a vitamin K reductase activity to complete the cycle. The reduction of vitamin K quinone to KH₂ may be achieved by VKOR or by a NAD(P)H-dependent activity shown as enzyme activity (3). There are several candidate quinone dehydrogenases for activity (3). B: In the presence of a VKA such as warfarin, the activity of the VKOR (2) is inhibited leading to an accumulation of K>O in the cell, and release into the circulation. As a consequence of VKOR inhibition there is a reduced capacity of the cell to generate sufficient active KH₂ cofactor to enable the GGCX to carboxylate VKD peptide substrates. This results in the cellular synthesis of inactive species of undercarboxylated proteins called proteins induced by vitamin K absence or antagonism (PIVKAs), which for coagulation and bone proteins are secreted into the circulation. Given a sufficient supply of vitamin K (e.g., from the diet) the alternative quinone reductase activity (3) can bypass the warfarin inhibition of the VKOR to provide the KH₂ substrate for the GGCX and hence overcome the inhibitory action of warfarin, even under extreme blockade.

Fig. 3.

Scheme showing the putative catabolism of K₁ to menadione (MD) in the intestine, its uptake into the blood via the mesenteric lymphatic system and delivery to target tissues for local synthesis of MK-4 by UBIAD1. Taken from (122) with permission of authors.