Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan.
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.
Nat Commun. 2024 Jul 10;15(1):5779. doi: 10.1038/s41467-024-50142-1.
To the best of our knowledge, enzymes that catalyse intramolecular Diels-Alder ([4+2] cycloaddition) reactions are frequently reported in natural product biosynthesis; however, no native enzymes utilising Lewis acid catalysis have been reported. Verticilactam is a representative member of polycyclic macrolactams, presumably produced by spontaneous cycloaddition. We report that the intramolecular [4+2] cycloadditions can be significantly accelerated by ferredoxins (Fds), a class of small iron-sulphur (Fe-S) proteins. Through iron atom substitution by Lewis acidic gallium (Ga) iron and computational calculations, we confirm that the ubiquitous Fe-S cluster efficiently functions as Lewis acid to accelerate the tandem [4+2] cycloaddition and Michael addition reactions by lowering free energy barriers. Our work highlights Nature's ingenious strategy to generate complex molecule structures using the ubiquitous Fe-S protein. Furthermore, our study sheds light on the future design of Fd as a versatile Lewis acid catalyst for [4+2] cycloaddition reactions.
据我们所知，在天然产物生物合成中，催化分子内 Diels-Alder([4+2]环加成)反应的酶经常被报道；然而，尚未有报道称利用路易斯酸催化的天然酶。Verticilactam 是多环大环内酯类的代表成员，推测是通过自发环加成产生的。我们报告称，铁氧还蛋白（Fds），一类小型铁硫（Fe-S）蛋白，可显著加速分子内[4+2]环加成反应。通过路易斯酸镓（Ga）铁取代铁原子和计算计算，我们证实普遍存在的 Fe-S 簇有效地充当路易斯酸，通过降低自由能垒来加速串联[4+2]环加成和迈克尔加成反应。我们的工作强调了自然界利用普遍存在的 Fe-S 蛋白生成复杂分子结构的巧妙策略。此外，我们的研究为 Fd 作为[4+2]环加成反应的多功能路易斯酸催化剂的未来设计提供了思路。
