Structural Modeling Insights into Human VKORC1 Phenotypes

Nutrients

Katrin J. Czogalla¹  Matthias Watzka¹ 

[1] Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany; E-Mails:

关键词: vitamin K epoxide reductase (VKOR);    VKORC1;    vitamin K;    vitamin K 2;    3-epoxide;    warfarin;    VKCFD2;    molecular modeling;    vitamin K antagonists;   

DOI  :  10.3390/nu7085313

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.