Assembly of the Warfarin-sensitive Vitamin K 2,3-Epoxide Reductase Enzyme Complex in the Endoplasmic Reticulum Membrane

Cain, Dean; Hutson, Susan M.; Wallin, Reidar

doi:10.1074/jbc.272.46.29068

Cited by 98 publications

(86 citation statements)

References 39 publications

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“…The protein resides in the endoplasmic reticulum, and may be complexed with microsomal epoxide hydrolase (encoded by EPHX1), to produce a multiprotein complex that is responsible for vitamin K epoxide reduction. 86,87 Microsomal epoxide hydrolase by itself does not possess vitamin K epoxide reductase activity. 88 Interestingly, a recent study in an Israeli population has shown an association between high doses of warfarin and a coding EPHX1 polymorphism (rs1051740) in CYP2C9 extensive metabolizers.…”

Section: Wadelius and M Pirmohamedmentioning

confidence: 99%

Pharmacogenetics of warfarin: current status and future challenges

2006

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Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P 450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

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Section: Wadelius and M Pirmohamedmentioning

confidence: 99%

Pharmacogenetics of warfarin: current status and future challenges

2006

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“…43 Since malondialdehyde is the final product of phospholipid peroxidation induced by oxidative stress, the organization of cell membranes in PXE would be different from controls (unpublished data). This, in turn, may affect the activity of enzymes localized on membranes of the endoplasmic reticulum, such as the enzyme g-carboxylase, 44,45 whose activity is necessary for MGP g-carboxylation. Therefore, disturbance of the g-carboxylase system, however induced, might lead to deficient expression of active MGP.…”

Section: Mgp and Elastic Fiber Calcification In Pxe D Gheduzzi Et Almentioning

confidence: 99%

Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients

Gheduzzi

Boraldi

Annovi

et al. 2007

Laboratory Investigation

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Mature MGP (Matrix g-carboxyglutamic acid protein) is known to inhibit soft connective tissues calcification. We investigated its possible involvement in pseudoxanthoma elasticum (PXE), a genetic disorder whose clinical manifestations are due to mineralization of elastic fibers. PXE patients have lower serum concentration of total MGP compared to controls (Po0.001). Antibodies specific for the noncarboxylated (Glu-MGP) and for the g-carboxylated (Gla-MGP) forms of MGP were assayed on ultrathin sections of dermis from controls and PXE patients. Normal elastic fibers in controls and patients were slightly positive for both forms of MGP, whereas Gla-MGP was more abundant within control's than within patient's elastic fibers (Po0.001). In patients' calcified elastic fibers, Glu-MGP intensively colocalized with mineral precipitates, whereas Gla-MGP precisely localized at the mineralization front. Data suggest that MGP is present within elastic fibers and is associated with calcification of dermal elastic fibers in PXE. To investigate whether local cells produce MGP, dermal fibroblasts were cultured in vitro and MGP was assayed at mRNA and protein levels. In spite of very similar MGP mRNA expression, cells from PXE patients produced 30% less of Gla-MGP compared to controls. Data were confirmed by immunocytochemistry on ultrathin sections. Normal fibroblasts in vitro were positive for both forms of MGP. PXE fibroblasts were positive for Glu-MGP and only barely positive for Gla-MGP (Po0.001). In conclusion, MGP is involved in elastic fiber calcification in PXE. The lower ratio of Gla-MGP over Glu-MGP in pathological fibroblasts compared to controls suggests these cells may play an important role in the ectopic calcification in PXE.

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“…Because of our limited knowledge of the vitamin K-dependent ␥-carboxylation system, the mechanism of inhibition is not fully understood (11). However, the recent identification of VKORC1 (12), an 18-kDa ER membrane protein believed to be a subunit of VKOR (13), has provided new opportunities to understand the system. When expressed in various cell lines, VKORC1 increases reduced vitamin K cofactor production (14,15).…”

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confidence: 99%

Increased Production of Functional Recombinant Human Clotting Factor IX by Baby Hamster Kidney Cells Engineered to Overexpress VKORC1, the Vitamin K 2,3-Epoxide-reducing Enzyme of the Vitamin K Cycle

Wajih

Hutson

Owen

et al. 2005

Journal of Biological Chemistry

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Some recombinant vitamin K-dependent blood coagulation factors (factors VII, IX, and protein C) have become valuable pharmaceuticals in the treatment of bleeding complications and sepsis. Because of their vitamin K-dependent post-translational modification, their synthesis by eukaryotic cells is essential. The eukaryotic cell harbors a vitamin K-dependent ␥-carboxylation system that converts the proteins to ␥-carboxyglutamic acid-containing proteins. However, the system in eukaryotic cells has limited capacity, and cell lines overexpressing vitamin K-dependent clotting factors produce only a fraction of the recombinant proteins as fully ␥-carboxylated, physiologically competent proteins. In this work we have used recombinant human factor IX (r-hFIX)-producing baby hamster kidney (BHK) cells, engineered to stably overexpress various components of the ␥-carboxylation system of the cell, to determine whether increased production of functional r-hFIX can be accomplished. All BHK cell lines secreted r-hFIX into serum-free medium. Overexpression of ␥-carboxylase is shown to inhibit production of functional r-hFIX. On the other hand, cells overexpressing VKORC1, the reduced vitamin K cofactor-producing enzyme of the vitamin Kdependent ␥-carboxylation system, produced 2.9-fold more functional r-hFIX than control BHK cells. The data are consistent with the notion that VKORC1 is the ratelimiting step in the system and is a key regulatory protein in synthesis of active vitamin K-dependent proteins. The data suggest that overexpression of VKORC1 can be utilized for increased cellular production of recombinant vitamin K-dependent proteins.

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Assembly of the Warfarin-sensitive Vitamin K 2,3-Epoxide Reductase Enzyme Complex in the Endoplasmic Reticulum Membrane

Cited by 98 publications

References 39 publications

Pharmacogenetics of warfarin: current status and future challenges

Pharmacogenetics of warfarin: current status and future challenges

Matrix Gla protein is involved in elastic fiber calcification in the dermis of pseudoxanthoma elasticum patients

Increased Production of Functional Recombinant Human Clotting Factor IX by Baby Hamster Kidney Cells Engineered to Overexpress VKORC1, the Vitamin K 2,3-Epoxide-reducing Enzyme of the Vitamin K Cycle

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