Enzyme activities of the vitamin K (VK) cycle in the (A) absence and (B) presence of warfarin. (A) The enzyme γ-glutamyl carboxylase (GGCX) (activity 1) with the cofactor vitamin K hydroquinone (VKH₂) facilitates the transformation of peptide-bound glutamate (Glu) to γ-carboxyglutamate (Gla) residues and the subsequent synthesis and secretion of carboxylated VK-dependent proteins. The γ-carboxylation reaction results in the generation of VK epoxide (VK>O), which is reduced to VK quinone by the enzyme VK epoxide reductase (VKOR) (activity 2). VK quinone is then reduced to the VKH₂ cofactor by 1 or more unidentified NAD(P)H-dependent reductases (activity 3), or possibly by VKOR itself (activity 2), to complete the cycle. (B) In the presence of a vitamin K antagonist (VKA) such as warfarin, VKOR (activity 2) is inhibited, resulting in the synthesis and secretion of inactive species of undercarboxylated proteins called proteins induced by vitamin K absence or antagonism (PIVKAs). Given sufficient input of vitamin K into the cycle, an alternative quinone reductase pathway (activity 3) can bypass the VKOR to provide the VKH₂ substrate for GGCX and hence overcome the inhibitory action of warfarin, even under extreme blockade. Reproduced with permission from Shearer and Okano.³