Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis
Structural basis for bisphosphonate-mediated inhibition of isoprenoid biosynthesis
复制标题
DOI：
10.1074/jbc.c300511200
复制
发表时间：
2004-03-05
影响因子：
4.8
通讯作者：
Finn, J
中科院分区：
文献类型：
--
作者：
Hosfield, DJ;Zhang, YM;Finn, J
法呢基焦磷酸合成酶（FPPS）通过焦磷酸异戊酯与焦磷酸二甲基烯丙酯和焦磷酸香叶酯的连续缩合合成法呢基焦磷酸。用于治疗破骨细胞介导的骨吸收和肿瘤诱导的高钙血症的含氮双膦酸盐药物是该酶的有效抑制剂。在这里，我们提出的底物和双膦酸盐复合物的FPPS的晶体结构。结构揭示了酶的构象变化如何组织保守的活性位点残基，利用金属诱导的电离和底物定位催化。这些结构进一步证明了含氮双膦酸盐如何模拟碳阳离子中间体来抑制酶。总之，这些FPPS复合物为设计新型抑制剂提供了结构模板，这些新型抑制剂可能被证明可用于治疗骨质疏松症和其他临床适应症，包括癌症。
Farnesyl pyrophosphate synthetase (FPPS) synthesizes farnesyl pyrophosphate through successive condensations of isopentyl pyrophosphate with dimethylallyl pyrophosphate and geranyl pyrophosphate. Nitrogen-containing bisphosphonate drugs used to treat osteoclast-mediated bone resorption and tumor-induced hypercalcemia are potent inhibitors of the enzyme. Here we present crystal structures of substrate and bisphosphonate complexes of FPPS. The structures reveal how enzyme conformational changes organize conserved active site residues to exploit metal-induced ionization and substrate positioning for catalysis. The structures further demonstrate how nitrogen-containing bisphosphonates mimic a carbocation intermediate to inhibit the enzyme. Together, these FPPS complexes provide a structural template for the design of novel inhibitors that may prove useful for the treatment of osteoporosis and other clinical indications including cancer.