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 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.
Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. katrin.czogalla@ukb.uni-bonn.de.
Katrin J
KJ
Czogalla
Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. matthias.watzka@ukb.uni-bonn.de.|Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn 53127, Germany. matthias.watzka@ukb.uni-bonn.de.
Matthias
M
Watzka
Institute of Experimental Hematology and Transfusion Medicine, University Clinic Bonn, Bonn 53105, Germany. johannes.oldenburg@ukb.uni-bonn.de.|Center for Rare Diseases Bonn (ZSEB), University Clinic Bonn, Bonn 53127, Germany. johannes.oldenburg@ukb.uni-bonn.de.
Johannes
J
Oldenburg
D015110:4-Hydroxycoumarins / Q000494:pharmacology; D000595:Amino Acid Sequence; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D014644:Genetic Variation; D006720:Homozygote; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D046940:Synechococcus / Q000201:enzymology; D013923:Thromboembolism / Q000188:drug therapy; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000737:chemistry*; D064417:Vitamin K Epoxide Reductases / Q000737:chemistry / Q000235:genetics*; D014859:Warfarin / Q000494:pharmacology
D015110:4-Hydroxycoumarins; D014812:Vitamin K; D014859:Warfarin; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases; C068805:4-hydroxycoumarin
VKCFD2; VKORC1; molecular modeling; vitamin K; vitamin K 2,3-epoxide; vitamin K antagonists; vitamin K epoxide reductase (VKOR); warfarin