Structural Modeling Insights into Human VKORC1 Phenotypes.

Katrin J Czogalla, Matthias Watzka, Johannes Oldenburg

Journal: Nutrients 2016;7(8):6837-51

PMID: 26287237

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.

Address: Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. [email protected].; Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. [email protected].; Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn 53127, Germany. [email protected].; Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. [email protected].; Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn 53127, Germany. [email protected].

DOI: 10.3390/nu7085313

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MeSH Terms: 4-Hydroxycoumarins, Amino Acid Sequence, Cell Line, Dose-Response Relationship, Drug, Drug Resistance, Genetic Variation, Homozygote, Humans, Models, Molecular, Molecular Sequence Data, Mutation, Phenotype, Synechococcus, Thromboembolism, Vitamin K, Vitamin K Epoxide Reductases, Warfarin