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Identification of the gene for vitamin K epoxide reductase

机译：维生素K环氧还原酶基因的鉴定

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Vitamin K epoxide reductase (VKOR) is the target of warfarin, the most widely prescribed anticoagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode, warfarin is under-used because of the difficulty 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-dependent 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 13 genes encoding candidate transmembrane proteins, and we used short interfering RNA (siRNA) pools against individual genes to test 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.
机译：维生素K环氧还原酶（VKOR）是华法林的靶标，华法林是血栓栓塞性疾病中使用最广泛的抗凝剂。虽然据估计可以预防每次诱发的出血发作中风20次，但由于难以控制剂量和担心诱发出血，华法林的使用率仍很低。尽管在1974年被鉴定（参考文献2），但该酶尚未纯化或尚未鉴定其基因。在将华法林对大鼠1号染色体的抗性（图3）和维生素K依赖的蛋白质缺乏症映射到人16号染色体的同义区后，位置克隆方法已成为可能。 VKOR在人类16p12-q21染色体内的190个基因的定位将搜索范围缩小到13个编码候选跨膜蛋白的基因，我们使用针对单个基因的短干扰RNA（siRNA）库来测试其在人细胞中抑制VKOR活性的能力。在这里，我们报告基于单个siRNA库对VKOR活性的特异性抑制，从而鉴定了VKOR的基因。我们证实，MGC11276信使RNA通过其在昆虫细胞中的表达和对华法林的敏感性来编码VKOR。表达的酶长163个氨基酸，具有至少一个跨膜结构域。 VKOR基因的鉴定扩展了我们对凝血的理解，并应促进新抗凝药物的开发。

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