Reaction Kinetics, Catalytic Mechanisms, Conformational Changes, and Inhibitor Design for Prenyltransferases
Reaction Kinetics, Catalytic Mechanisms, Conformational Changes, and Inhibitor Design for Prenyltransferases
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DOI：
10.1021/bi900371p
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发表时间：
2009-07-21
期刊：
影响因子：
2.9
通讯作者：
Liang, Po-Huang
中科院分区：
文献类型：
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作者：
Liang, Po-Huang
类异戊二烯包括一个超过55000种天然产物的家族，其具有很大的结构多样性，衍生自五碳异戊烯基二磷酸（IPP）及其异构体二甲基烯丙基二磷酸（DMAPP）。由DMAPP和IPP合成的烯丙基二磷酸酯如法尼基二磷酸酯（FPP）是各种产物的出口点。根据IPP缩合形成的双键的立体化学性质，一类异戊二烯基转移酶催化FPP通过与特定数目的IPP的连续缩合反应而延伸到指定长度。完整的动力学的多步IPP缩合反应由这两种类型的酶已被确定使用稳态和预稳态的方法。由于它们的晶体结构是结合生物化学研究确定的，因此最近对其催化机制、蛋白质构象变化和产物链长确定机制有了更深入的了解。由于这些异戊烯基转移酶发挥重要作用，有效的抑制剂已被确定，其共晶结构已被确定用于药物开发。在这篇综述中，这些异戊二烯基转移酶合成异戊二烯基低聚物或聚合物的当前知识进行了总结。
Isoprenoids comprise a family of more than 55000 natural products with great structural variety derived from five-carbon isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP). Allylic diphosphates such as farnesyl diphosphate (FPP) synthesized from DMAPP and IPP serve as outlet points for a great variety of products, A group of prenyltransferases catalyzing chain elongation of FPP to designated lengths by consecutive condensation reactions with specific numbers of IPP are classified as cis and trans types according to the stereochemistry of the double bonds formed by I PP condensation. The complete kinetics of the multistep IPP condensation reactions by both types of enzymes has been determined using steady-state and pre-steady-state approaches. Because their crystal structures were determined in conjunction with biochemical studies, a more thorough understanding of their catalytic mechanisms, protein conformational changes, and product chain-length determination mechanisms has been gained recently. Since these prenyltransferases play important roles, potent inhibitors have been identified and their cocrystal structures have been determined for drug development. In this review, the current knowledge of these prenyltransferases that synthesize prenyl oligomers or polymers is summarized.