Equipe Chimie Biologique et Applications Thérapeutiques, Institut de Chimie de Strasbourg UMR 7177, Université de Strasbourg/CNRS, 4, rue Blaise Pascal, 67070 Strasbourg, France.
Institut de Biologie Structurale, Université Grenoble Alpes/CEA/CNRS, 38000 Grenoble, France.
Molecules. 2022 Jan 21;27(3):708. doi: 10.3390/molecules27030708.
The non-mevalonate or also called MEP pathway is an essential route for the biosynthesis of isoprenoid precursors in most bacteria and in microorganisms belonging to the Apicomplexa phylum, such as the parasite responsible for malaria. The absence of this pathway in mammalians makes it an interesting target for the discovery of novel anti-infectives. As last enzyme of this pathway, IspH is an oxygen sensitive [4Fe-4S] metalloenzyme that catalyzes 2H/2e reductions and a water elimination by involving non-conventional bioinorganic and bioorganometallic intermediates. After a detailed description of the discovery of the [4Fe-4S] cluster of IspH, this review focuses on the IspH mechanism discussing the results that have been obtained in the last decades using an approach combining chemistry, enzymology, crystallography, spectroscopies, and docking calculations. Considering the interesting druggability of this enzyme, a section about the inhibitors of IspH discovered up to now is reported as well. The presented results constitute a useful and rational help to inaugurate the design and development of new potential chemotherapeutics against pathogenic organisms.
非甲羟戊酸途径或称为 MEP 途径，是大多数细菌和顶复门微生物（如引起疟疾的寄生虫）中异戊烯前体生物合成的必要途径。由于哺乳动物中不存在该途径，因此它成为发现新型抗感染药物的有趣靶点。作为该途径的最后一种酶，IspH 是一种对氧气敏感的 [4Fe-4S] 金属酶，通过涉及非传统的生物无机和生物有机金属中间体，催化 2H/2e 还原和水消除。在详细描述了 IspH 的 [4Fe-4S] 簇的发现之后，本综述重点讨论了 IspH 的机制，讨论了过去几十年使用结合化学、酶学、晶体学、光谱学和对接计算的方法获得的结果。考虑到该酶具有有趣的成药性，本文还报道了迄今为止发现的 IspH 抑制剂。所呈现的结果为设计和开发针对致病生物的新型潜在化学疗法提供了有用且合理的帮助。
