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.