Inhibition of the vitamin K cycle by warfarin. KH₂ is converted to KO during the carboxylation of Glu to Gla residues by γ-glutamyl carboxylase. Under normal physiologic conditions in the liver, VKORC1 efficiently recycles KO back to KH₂ in a 2-step reaction, generating K as an intermediate product (left side). The uncoupling of the 2 VKORC1-mediated reactions (KO→K and K→KH₂) in the presence of warfarin, as described by Rishavy et al, causes a loss in efficiency of VKORC1 for the full recycling of KO to KH₂ and a loss in carboxylation. However, because warfarin uncouples the reaction rather than directly inhibits the reaction, VKORC1 can still generate considerable amounts of the K intermediary. The completion of the final step (K→KH₂) then becomes dependent on the extent to which the second warfarin-resistant vitamin K quinone reductase (2nd VKR) is present and active. Thus, although VKORC1 is responsible for the full recycling of KO to KH₂ in the absence of warfarin, the recycling pathway changes in the presence of warfarin and requires cooperation of VKORC1 and the 2nd VKR.³  The degree of carboxylation in the presence of warfarin is therefore dependent on the expression and activity of 2nd VKR (indicated by the dotted arrows), the identity of which remains unknown to date.