Structural Modeling Insights into Human VKORC1 Phenotypes.

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.

• Authors: Katrin J Czogalla, Matthias Watzka, Johannes Oldenburg
• Journal: Nutrients (Nutrients) Vol. 7 Issue 8 Pg. 6837-51 (Aug 14 2015) ISSN: 2072-6643 [Electronic] Switzerland
• PMID: 26287237 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

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

Topics

• 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, chemistry)
• Vitamin K Epoxide Reductases (chemistry, genetics)
• Warfarin (pharmacology)