Structural Modeling Insights into Human VKORC1 Phenotypes

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...

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Bibliographic Details
Published in:Nutrients 2015-08, Vol.7 (8), p.6837-6851
Main Authors: Czogalla, Katrin J, Watzka, Matthias, Oldenburg, Johannes
Format: Article
Language:English
Subjects:
4-Hydroxycoumarins - pharmacology
Amino Acid Sequence
Cell Line
Dose-Response Relationship, Drug
Drug Resistance
Genetic Variation
Homozygote
Humans
Models, Molecular
molecular modeling
Molecular Sequence Data
Mutation
Phenotype
Review
Synechococcus - enzymology
Thromboembolism - drug therapy
vitamin K
Vitamin K - antagonists & inhibitors
Vitamin K - chemistry
vitamin K 2,3-epoxide
vitamin K antagonists
vitamin K epoxide reductase (VKOR)
Vitamin K Epoxide Reductases - chemistry
Vitamin K Epoxide Reductases - genetics
VKCFD2
VKORC1
warfarin
Warfarin - pharmacology
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Summary: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.
ISSN:2072-6643
2072-6643
DOI:10.3390/nu7085313