Structure and function of vitamin K epoxide reductase.
Jian-Ke Tie1, Darrel W Stafford
1Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3280, USA.
Vitamins and Hormones
|April 1, 2008
Summary
Vitamin K epoxide reductase (VKOR) is crucial for blood clotting. Warfarin inhibits VKOR, impacting vitamin K activity and protein carboxylation. Identifying VKOR's physiological reductant remains key.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Vitamin K epoxide reductase (VKOR) is an integral membrane protein essential for the vitamin K cycle.
- VKOR catalyzes the reduction of vitamin K 2,3-epoxide to vitamin K hydroquinone, a cofactor for gamma-glutamyl carboxylation.
- Warfarin, a common oral anticoagulant, inhibits VKOR, reducing vitamin K-dependent carboxylation and leading to inactive proteins.
Purpose of the Study:
- To elucidate the structure-function relationship of VKOR at a molecular level.
- To investigate the catalytic mechanism and warfarin inhibition of VKOR.
- To identify the physiological reductant of VKOR.
Main Methods:
- Gene identification and expression of VKOR in insect cells.
- Purification of VKOR for biochemical and structural studies.
- Membrane topology modeling to determine protein orientation.
Main Results:
- A membrane topology model indicates VKOR spans the endoplasmic reticulum membrane three times.
- The active site (Cys132, Cys135) and warfarin binding site (Tyr139) are located in the third transmembrane helix.
- VKOR can be highly expressed and purified, facilitating structural and mechanistic studies.
Conclusions:
- The identification and purification of VKOR enable detailed molecular investigations.
- Understanding VKOR's structure and mechanism is crucial for anticoagulant drug development.
- The physiological reductant of VKOR remains an important area for future research.
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