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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3683-3684.
VKORC1: the little big proteinINSTITUTE OF EXPERIMENTAL HAEMATOLOGY AND TRANSFUSION MEDICINE
VKORC1, the recently identified protein of the vitamin K cycle, catalyzes vitamin K epoxide to vitamin K and further to vitamin K hydroquinone, thus representing the rate-limiting enzyme for the carboxylation of vitamin K–dependent proteins.
In this issue of Blood, Sun and colleagues report further key information about VKORC1. Using a HEK 293 cell line overproducing factor X, they found that the fraction of carboxylated factor X increases dramatically from 52% to 92% by coexpressing VKORC1 (see figure). The explanation for this observation is that most likely VKORC1 is responsible for both the conversion of vitamin K epoxide to vitamin K and vitamin K to vitamin K hydroquinone. Thus, although
The finding of Sun et al has important practical implications. Some vitamin K–dependent coagulation factors are of commercial interest as factor IX and rFVIIa for the treatment of hereditary or acquired bleeding disorders and as activated protein C for the treatment of sepsis. The yield of carboxylated and accordingly functional active protein in cell lines coexpressing VKORC1 will be much higher than in currently used cell lines. The role of VKORC1 as a main regulator of the carboxylation reaction has gained particular attention in view of its function as the molecular target of coumarin derivatives (eg, warfarin), the most prescribed drug for therapy of thromboembolic events. Recently, frequent VKORC1 gene variants have been reported that significantly alter the level of VKORC1 activity and consequently affect the therapeutic dose of the drug.4,5 In fact, these observations suggest VKORC1 as the principal genetic modulator of the interindividual and interethnic differences in warfarin response. Moreover, we are tempted to speculate that these naturally occurring VKORC1 gene variants may also have an important influence on downstream function of vitamin K–dependent proteins, including matrix Gla protein and osteocalcin, which have been suggested to play a role in the pathogenesis of atherosclerosis, myocardial infarction, and stroke.
The work of Sun et al demonstrates VKORC1 as a main regulator of the carboxylation reaction, which, in view of the multiple downstream pathways affected by this protein, suggests further exciting studies in the near future. References
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Related Article in Blood Online:
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| Copyright © 2005 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
-carboxylation of Gla-domain proteins such as coagulation factors II, VII, IX, and X; proteins C, S, and Z; osteocalcin; matrix Gla protein (MGP); and Gas6. This gene extended over 5126 base pairs and comprised 3 exons encoding a small protein of 163 amino acids with a calculated relative molecular mass of about 18 kDa.
