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1、2；.3；.4；.5；.6；.7；.8；.Identification of the gene for vitaminK epoxide reductaseTao Li1, Chun-Yun Chang1, Da-Yun Jin1, Pen-Jen Lin1,Anastasia Khvorova2 & Darrel W. Stafford11Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill,North Carolina 27599, USA2Dharmacon, Inc., 1

2、376 Miners Drive 101, Lafayette, Colorado 80026, USA Vitamin K epoxide reductase (VKOR) is the target of warfarin,the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes perinduced bleeding episode1, warfarin is under-used because of the di

3、fficulty of controlling dosage and the fear of inducing bleeding. Although identified in 1974 (ref. 2), the enzyme has yet to be purified or its gene identified. A positional cloning approach has become possible after the mapping of warfarin resistance to rat chromosome 1 (ref. 3) and of vitamin K d

4、ependent protein deficiencies to the syntenic region of human chromosome 16 (ref. 4). Localization of VKOR to 190 genes within human chromosome 16p12-q21 narrowed the search to 13genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes

5、 totest their ability to inhibit VKOR activity in human cells. Here,we report the identification of the gene for VKOR based on specific inhibition of VKOR activity by a single siRNA pool. We confirmed that MGC11276 messenger RNA encodes VKOR through its expression in insect cells and sensitivity to warfarin.The expressed enzyme is 163 amino acids long, with at least one transmembrane domain. Identification of the VKOR gene extends our understanding of blood clotting, and should facilitate development of new anticoagulant drugs.9；.10；.11；.12；.13；.14；.15；.16；.17；.18；.19；.20；.21；.22；.23