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Nutrients 2015, 7(8), 6837-6851; doi:10.3390/nu7085313

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
*
Author to whom correspondence should be addressed.
Received: 20 May 2015 / Revised: 3 August 2015 / Accepted: 6 August 2015 / Published: 14 August 2015
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Abstract

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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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