Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase.
In: Blood, Jg. 131 (2018-06-21), Heft 25, S. 2826
academicJournal
Zugriff:
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. VKORC1 produces KH 2 in 2 reactions: reduction of vitamin K epoxide (KO) to quinone (K), and then KH 2 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 KH 2 reaction was analyzed using low K concentrations that result from inhibition of KO to K. 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 results indicate that warfarin uncouples the 2 reactions that fully reduce KO. Uncoupling was revealed because a second activity, a warfarin-resistant quinone reductase, was not present. In contrast, 293 cells expressing factor IX and this reductase activity showed much less inhibition of carboxylation. This activity therefore appears to cooperate with VKORC1 to accomplish full KO reduction. Cooperation during warfarin therapy would have significant consequences, as VKD proteins function in numerous physiologies in many tissues, but may be poorly carboxylated and dysfunctional if the second activity is not ubiquitously expressed similar to VKORC1.
(© 2018 by The American Society of Hematology.)
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Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase.
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Autor/in / Beteiligte Person: | Rishavy, MA ; Hallgren, KW ; Wilson, L ; Singh, S ; Runge, KW ; Berkner, KL |
Zeitschrift: | Blood, Jg. 131 (2018-06-21), Heft 25, S. 2826 |
Veröffentlichung: | 2021- : [New York] : Elsevier ; <i>Original Publication</i>: New York, Grune & Stratton [etc.], 2018 |
Medientyp: | academicJournal |
ISSN: | 1528-0020 (electronic) |
DOI: | 10.1182/blood-2017-09-804666 |
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