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Structural Modeling Insights into Human VKORC1 Phenotypes

1
Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany
2
Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn 53127, Germany
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Author to whom correspondence should be addressed.
Nutrients 2015, 7(8), 6837-6851; https://doi.org/10.3390/nu7085313
Received: 20 May 2015 / Revised: 3 August 2015 / Accepted: 6 August 2015 / Published: 14 August 2015
Vitamin K 2,3-epoxide reductase complex subunit 1 (VKORC1) catalyses the reduction of vitamin K and its 2,3-epoxide essential to sustain γ-carboxylation of vitamin K-dependent proteins. Two different phenotypes are associated with mutations in human VKORC1. The majority of mutations cause resistance to 4-hydroxycoumarin- and indandione-based vitamin K antagonists (VKA) used in the prevention and therapy of thromboembolism. Patients with these mutations require greater doses of VKA for stable anticoagulation than patients without mutations. The second phenotype, a very rare autosomal-recessive bleeding disorder caused by combined deficiency of vitamin K dependent clotting factors type 2 (VKCFD2) arises from a homozygous Arg98Trp mutation. The bleeding phenotype can be corrected by vitamin K administration. Here, we summarize published experimental data and in silico modeling results in order to rationalize the mechanisms of VKA resistance and VKCFD2. View Full-Text
Keywords: vitamin K epoxide reductase (VKOR); VKORC1; vitamin K; vitamin K 2,3-epoxide; warfarin; VKCFD2; molecular modeling; vitamin K antagonists vitamin K epoxide reductase (VKOR); VKORC1; vitamin K; vitamin K 2,3-epoxide; warfarin; VKCFD2; molecular modeling; vitamin K antagonists
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Czogalla, K.J.; Watzka, M.; Oldenburg, J. Structural Modeling Insights into Human VKORC1 Phenotypes. Nutrients 2015, 7, 6837-6851.

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