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首页> 外文期刊>Journal of Molecular Biology >Atomic-Resolution Structures of Discrete Stages on the Reaction Coordinate of the [Fe4S4] Enzyme IspG (GcpE)
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Atomic-Resolution Structures of Discrete Stages on the Reaction Coordinate of the [Fe4S4] Enzyme IspG (GcpE)

机译：[Fe4S4]酶IspG（GcpE）反应坐标上离散阶段的原子分辨结构。

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摘要

IspG is the penultimate enzyme in non-mevalonate biosynthesis of the universal terpene building blocks isopentenyl diphosphate and dimethylallyl diphosphate. Its mechanism of action has been the subject of numerous studies but remained unresolved due to difficulties in identifying distinct reaction intermediates. Using a moderate reducing agent and an epoxide substrate analogue, we were now able to trap and crystallographically characterize various stages in the IspG-catalyzed conversion of 2-C-methyl-D-erythritol-2,4-cyclo-diphosphate into (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate. In addition, the enzyme's structure was determined in complex with several inhibitors. These results, combined with recent electron paramagnetic resonance data, allowed us to deduce a detailed and complete IspG catalytic mechanism, which describes all stages from initial ring opening to formation of (E)-1-hydroxy-2-methylbut-2-enyl-4-diphosphate via discrete radical and carbanion intermediates. The data presented in this article provide a guide for the design of selective drugs against many prokaryotic and eukaryotic pathogens to which the non-mevalonate pathway is essential for survival and virulence. (C) 2015 Elsevier Ltd. All rights reserved.
机译：IspG是通用萜烯结构单元异戊烯基二磷酸和二甲基烯丙基二磷酸的非甲羟戊酸生物合成中的倒数第二个酶。它的作用机理已成为众多研究的主题，但由于难以确定不同的反应中间体而仍未解决。使用中度还原剂和环氧底物类似物，我们现在能够捕获和结晶表征IspG催化的2-C-甲基-D-赤藓糖醇-2,4-环二磷酸酯转化为（E）的各个阶段-1-羟基-2-甲基丁-2-烯基-4-二磷酸酯。另外，与几种抑制剂复合测定了酶的结构。这些结果与最新的电子顺磁共振数据相结合，使我们能够推断出详细而完整的IspG催化机理，该机理描述了从初始开环到形成（E）-1-羟基-2-甲基丁-2-烯基-的所有阶段。通过离散的自由基和碳负离子中间体产生的4-二磷酸酯。本文中提供的数据为设计针对许多原核和真核病原体的选择性药物提供了指南，非甲羟戊酸途径对于这些原核和真核生物病原体的存活和毒性至关重要。 （C）2015 Elsevier Ltd.保留所有权利。

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