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An in vivo oriented and modified model of the warfarin sensitive vitamin K‐dependent gamma‐carboxylation system
Author(s) -
Wallin Reidar
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1106.9
Subject(s) - vitamin k epoxide reductase , vkorc1 , carboxylation , chemistry , biochemistry , pyruvate carboxylase , vitamin , enzyme , cytochrome p450 , cyp2c9 , catalysis
Vitamin K in its reduced form is a cofactor for gamma‐carboxylase in post translational modification of proteins converting them to gamma‐carboxylated Glu (Gla) calcium binding proteins. The nutritional quinone form of vitamin K and the metabolite vitamin K 2,3‐epoxide (Vit.K>O) is reduced by the warfarin sensitive VKOR enzyme of the vitamin K cycle. The gamma‐carboxylation system consists of integral membrane proteins, and new knowledge of the system at the molecular level has expanded exponentially over the last years. The discovery of the VKORC1 gene and our experimental demonstration of the thioredoxin redox CxxC center in the protein opened up for new research on the molecular design of the system in the ER. We have provided strong data which indicate that VKORC1 is a subunit formed with PDI, a red/ox chaperone which reduces the CxxC redox center in VKORC1. This finding adds strong support to identification of the physiological reductant of the system. SiRNA silencing of PDI and PDI inhibitors provided the convincing data. Lately we have also challenged the existing model on warfarin inhibition of VKOR activity. We have used a highly specific disulfide reducing phosphine in experiments which provide evidence that warfarin binds both to the reduced and the oxidized CxxC redox center, which changes the current model of the system. Furthermore we have discovered calumenin as the first known in vivo inhibitor of the gamma‐carboxylation system. We have also demonstrated that VKORC1 is Ser‐phosphorylated which may be a regulatory mechanism in synthesis of vitamin K‐dependent proteins. Supported by NIH grant HL69331