![]() In contrast, 293 cells expressing factor IX and this reductase activity showed much less inhibition of carboxylation. Uncoupling was revealed because a second activity, a warfarin-resistant quinone reductase, was not present. The results indicate that warfarin uncouples the 2 reactions that fully reduce KO. Carboxylation that required only K to KH 2 reduction was inhibited much less than observed with the KO substrate that requires full VKORC1 reduction (eg, 2.5-fold vs 70-fold, respectively, in cells expressing wild-type VKORC1 and factor IX). ![]() The K to KH 2 reaction was analyzed using low K concentrations that result from inhibition of KO to K. Carboxylation was much more strongly inhibited (∼400-fold) than KO reduction (two- to threefold). 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. Our dissection of full reduction vs the individual reactions revealed a surprising mechanism of warfarin inhibition. ![]() VKORC1 produces KH 2 in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH 2. The anticoagulant warfarin inhibits the vitamin K oxidoreductase (VKORC1), which generates vitamin K hydroquinone (KH 2) required for the carboxylation and consequent activation of vitamin K–dependent (VKD) proteins. ![]()
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