VKORC1: molecular target of coumarins.
The genetic diagnosis of a single family with combined vitamin K-dependent clotting factor deficiency (VKCFD2, OMIM #607473) finally led to the identification and molecular characterization of vitamin K epoxide reductase (VKORC1). VKORC1 is the key enzyme of the vitamin K cycle and the molecular target of coumarins, which represent the most commonly prescribed drugs for therapy and prevention of thromboembolic conditions. However, coumarins are known to have a narrow therapeutic window and a considerable risk of bleeding complications caused by a broad variation of intra- and inter-individual drug requirement. Now, 3 years after its identification, VKORC1 has greatly improved our understanding of the vitamin K cycle and has led to the translation of basic research into clinical practise in at least three directions: (i) Mutations within VKORC1 have been shown to cause a coumarin-resistant phenotype and a single SNP (rs9923231) within the VKORC1 promoter region has been identified as the major pharmacodynamic determinant of coumarin dose. Together with the previously described CYP2C9 variants and other dose-influencing factors, such as age, gender and weight, individualized dosing algorithms have become available. (ii) Preliminary studies indicate that concomitant application of low-dose vitamin K (80-100 microg day(-1)) and warfarin significantly improves INR stability and time of INR within the therapeutic range. (iii) Co-expression studies of FIX and FX with VKORC1 have shown that VKOR activity is the rate-limiting step in the synthesis of biologically active vitamin K-dependent factors. Thus, co-expression of VKORC1 leads to a more efficient production of recombinant vitamin K-dependent coagulation factors such as FIX and FVII. This could improve production of recombinant factor concentrates in the future.
Oldenburg
J
J
Institute for Experimental Haematology and Transfusion Medicine, University Clinic Bonn, Bonn, Germany. johannes.oldenburg@ukb.uni-bonn.de
Watzka
M
M
Rost
S
S
Müller
C R
CR
D000595:Amino Acid Sequence; D003374:Coumarins / Q000493:pharmacokinetics / Q000494:pharmacology*; D006239:Haplotypes; D006801:Humans; D006899:Mixed Function Oxygenases / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D064417:Vitamin K Epoxide Reductases
D003374:Coumarins; D006899:Mixed Function Oxygenases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases