Center for Integrated Protein Science Munich (CIPSM) at the Department Chemie, Technische Universität München , Lichtenbergstraße 4, 85748 Garching, Germany.
Chem Rev. 2017 Apr 26;117(8):5675-5703. doi: 10.1021/acs.chemrev.6b00537. Epub 2016 Dec 20.
Isoprenoids constitute one of the most diverse classes of natural products. As a compound class, they are essential to basic metabolic processes including cell-wall biosynthesis, post-translational protein modifications, and signaling. In addition, isoprenoid secondary metabolites are highly valuable natural products with a wide range of biotechnological applications. The biosynthesis of their two universal building blocks, isopentenyl diphosphate and dimethylallyl diphosphate, was thought to proceed exclusively by way of mevalonate as a key intermediate until a novel pathway involving methylerithritol phosphate (MEP) was discovered in the early 1990s. In this review, we describe the seven enzymes of the MEP pathway, along with their discoveries, three-dimensional structures, and mechanisms. The latter include examples of remarkable enzyme catalysis including an unusual cytidilation reaction and the use of iron-sulfur cluster cofactors in reductive ring opening and hydroxy-group elimination. Furthermore, isoprenoid biosynthesis shows a characteristic species distribution. A brief overview highlights the MEP pathway's potential as a selective drug target, which is absent in humans but essential to the survival of many important bacterial and apicomplexan pathogens.
异戊二烯类化合物构成了最多样化的天然产物类别之一。作为一类化合物，它们是包括细胞壁生物合成、翻译后蛋白质修饰和信号转导在内的基本代谢过程所必需的。此外，异戊二烯类次生代谢物是具有广泛生物技术应用价值的高度有价值的天然产物。其两个通用构建块，异戊烯二磷酸和二甲基烯丙基二磷酸的生物合成，直到 20 世纪 90 年代初发现了一种涉及甲基赤藓醇磷酸 (MEP) 的新途径，才被认为仅通过甲羟戊酸作为关键中间体进行。在这篇综述中，我们描述了 MEP 途径的七种酶，以及它们的发现、三维结构和机制。后者包括一些显著的酶催化实例，包括一种不寻常的胞嘧啶化反应以及在还原环开裂和羟基消除中使用铁硫簇辅因子。此外，异戊二烯生物合成表现出特征性的物种分布。简要概述强调了 MEP 途径作为选择性药物靶点的潜力，该靶点在人类中不存在，但对许多重要细菌和顶复体病原体的生存至关重要。
