Warfarin alters vitamin K metabolism: a surprising mechanism of VKORC1 uncoupling necessitates an additional reductase
| Autor: | Kevin W. Hallgren, Savita Singh, Kurt W. Runge, Kathleen L. Berkner, Lee Wilson, Mark A. Rishavy |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Vitamin medicine.medical_specialty Immunology 030204 cardiovascular system & hematology Reductase Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Oxidoreductase Internal medicine medicine Warfarin resistance Factor IX chemistry.chemical_classification Warfarin Cell Biology Hematology 030104 developmental biology Endocrinology chemistry Carboxylation VKORC1 medicine.symptom medicine.drug |
| Zdroj: | Blood. 131:2826-2835 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2017-09-804666 |
| Popis: | 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 K concentrations that result from inhibition of KO to K. Carboxylation that required only K to KH2 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|