Iron-sulphur protein catalysed [4+2] cycloadditions in natural product biosynthesis.

Autor: Zheng Y; Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan., Sakai K; Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan., Watanabe K; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan., Takagi H; Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan., Sato-Shiozaki Y; Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan., Misumi Y; Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan., Miyanoiri Y; Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan., Kurisu G; Institute for Protein Research, Osaka University, Osaka, 565-0871, Japan., Nogawa T; Molecular Structure Characterization Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan., Takita R; Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, 113-0033, Japan.; Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan., Takahashi S; Natural Product Biosynthesis Research Unit, RIKEN Center for Sustainable Resource Science, Saitama, 351-0198, Japan. shunjitaka@riken.jp.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Jul 10; Vol. 15 (1), pp. 5779. Date of Electronic Publication: 2024 Jul 10.
DOI: 10.1038/s41467-024-50142-1
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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