Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase.

ABSTRACT: The anticoagulant warfarin inhibits the vitamin K oxidoreductase (VKORC1), which generates vitamin K hydroquinone (KH₂) required for the carboxylation and consequent activation of vitamin K-dependent (VKD) proteins. VKORC1 produces KH₂ in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH₂ Our dissection of full reduction vs the individual reactions revealed a surprising mechanism of warfarin inhibition. Warfarin inhibition of KO to K reduction and carboxylation that requires full reduction were compared in wild-type VKORC1 or mutants (Y139H, Y139F) that cause warfarin resistance. Carboxylation was much more strongly inhibited (∼400-fold) than KO reduction (two- to threefold). The K to KH₂ reaction was analyzed using low

SUBMITTER: Rishavy MA 

PROVIDER: S-EPMC6014353 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature