Structural Modeling Insights into Human VKORC1 Phenotypes

Nutrients. 2015 Aug 14;7(8):6837-51. doi: 10.3390/nu7085313.

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.

Keywords: VKCFD2; VKORC1; molecular modeling; vitamin K; vitamin K 2,3-epoxide; vitamin K antagonists; vitamin K epoxide reductase (VKOR); warfarin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 4-Hydroxycoumarins / pharmacology
  • Amino Acid Sequence
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Resistance
  • Genetic Variation
  • Homozygote
  • Humans
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation
  • Phenotype*
  • Synechococcus / enzymology
  • Thromboembolism / drug therapy
  • Vitamin K / antagonists & inhibitors
  • Vitamin K / chemistry*
  • Vitamin K Epoxide Reductases / chemistry
  • Vitamin K Epoxide Reductases / genetics*
  • Warfarin / pharmacology

Substances

  • 4-Hydroxycoumarins
  • Vitamin K
  • Warfarin
  • VKORC1 protein, human
  • Vitamin K Epoxide Reductases
  • 4-hydroxycoumarin