Watanabe Kenji, Sato Michio, Osada Hiroyuki
Department of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.
Chemical Resource Development Research Unit, RIKEN Center for Sustainable Resource Science, Wako-shi, 351-0198, Japan.
Fungal Biol Biotechnol. 2022 Apr 29;9(1):9. doi: 10.1186/s40694-022-00139-6.
The Diels-Alder (DA) reaction refers to a [4 + 2] cycloaddition reaction that falls under the category of pericyclic reactions. It is a reaction that allows regio- and stereo-selective construction of two carbon-carbon bonds simultaneously in a concerted manner to generate a six-membered ring structure through a six-electron cyclic transition state. The DA reaction is one of the most widely applied reactions in organic synthesis, yet its role in biological systems has been debated intensely over the last four decades. A survey of secondary metabolites produced by microorganisms suggests strongly that many of the compounds possess features that are likely formed through DA reactions, and most of them are considered to be catalyzed by enzymes that are commonly referred to as Diels-Alderases (DAases). In recent years, especially over the past 10 years or so, we have seen an accumulation of a substantial body of work that substantiates the argument that DAases indeed exist and play a critical role in the biosynthesis of complex metabolites. This review will cover the DAases involved in the biosynthesis of decalin moieties, which are found in many of the medicinally important natural products, especially those produced by fungi. In particular, we will focus on a subset of secondary metabolites referred to as pyrrolidine-2-one-bearing decalin compounds and discuss the decalin ring stereochemistry and the biological activities of those compounds. We will also look into the genes and enzymes that drive the biosynthetic construction of those complex natural products, and highlight the recent progress made on the structural and mechanistic understanding of DAases, especially regarding how those enzymes exert stereochemical control over the [4 + 2] cycloaddition reactions they catalyze.
狄尔斯-阿尔德（DA）反应是指一种属于周环反应范畴的[4+2]环加成反应。它是一种能够以协同方式同时进行区域和立体选择性构建两个碳-碳键的反应，通过六电子环状过渡态生成六元环结构。DA反应是有机合成中应用最广泛的反应之一，然而在过去的四十年里，其在生物系统中的作用一直存在激烈的争论。对微生物产生的次生代谢产物的调查有力地表明，许多这类化合物具有可能通过DA反应形成的特征，并且其中大多数被认为是由通常称为狄尔斯-阿尔德酶（DAases）的酶催化的。近年来，尤其是在过去十年左右的时间里，我们看到大量的研究成果不断积累，证实了DAases确实存在并在复杂代谢产物的生物合成中发挥关键作用这一观点。本综述将涵盖参与十氢化萘部分生物合成的DAases，十氢化萘存在于许多重要的药用天然产物中，尤其是那些由真菌产生的天然产物。特别地，我们将聚焦于一类被称为含吡咯烷-2-酮的十氢化萘化合物的次生代谢产物子集，并讨论这些化合物的十氢化萘环立体化学及其生物活性。我们还将研究驱动这些复杂天然产物生物合成构建的基因和酶，并重点介绍在对DAases的结构和作用机制理解方面取得的最新进展，尤其是关于这些酶如何对它们催化的[4+2]环加成反应施加立体化学控制。
