VKORC1: a warfarin-sensitive enzyme in vitamin K metabolism and biosynthesis of vitamin K-dependent blood coagulation factors.
The recently discovered enzyme VKORC1 of the vitamin K cycle, which is the target for the anticoagulant drug warfarin, has opened new opportunities to understand warfarin resistance and biosynthesis of vitamin K-dependent blood coagulation factors and other members of this protein family. Furthermore, it has opened new opportunities to study the vitamin K-dependent posttranslational gamma-carboxylational system in the endoplasmic reticulum in greater detail and its molecular operation in vivo. Other accomplishments resulting from this discovery are: (1) the finding that VKORC1 is the rate-limiting step in biosynthesis of functional vitamin K-dependent proteins, and (2) engineering of recombinant intracellular gamma-carboxylation systems in cell lines producing recombinant coagulation factor used clinically to treat bleeding disorders. The engineered cells significantly enhance production of the fraction of fully functional gamma-carboxylated proteins compared to cell lines only overexpressing the specific coagulation factor. The first described inhibitor of the gamma-carboxylation system has been identified as calumenin, a resident chaperone in the endoplasmic reticulum (ER). Together, the new information gained about the vitamin K-dependent gamma-carboxylation system will stimulate new research which will benefit medicine and our understanding of the molecular mechanisms involved in this protein modification reaction.
Wallin
Reidar
R
Departments of Internal Medicine and Biochemistry, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157.
Wajih
Nadeem
N
Hutson
Susan M
SM
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001779:Blood Coagulation Factors / Q000096:biosynthesis*; D002135:Calcium-Binding Proteins; D001728:Dicumarol; D004351:Drug Resistance / Q000235:genetics; D006801:Humans; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D011994:Recombinant Proteins; D014812:Vitamin K / Q000378:metabolism*; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000494:pharmacology*
D000925:Anticoagulants; D001779:Blood Coagulation Factors; C510527:CALU protein, human; D002135:Calcium-Binding Proteins; D011994:Recombinant Proteins; D014812:Vitamin K; D014859:Warfarin; D001728:Dicumarol; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases