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

Yu Zheng, Katsuyuki Sakai, Kohei Watanabe, Hiroshi Takagi, Yumi Sato-Shiozaki, Yuko Misumi, Yohei Miyanoiri, Genji Kurisu, Toshihiko Nogawa, Ryo Takita and Shunji Takahashi ()
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Yu Zheng: RIKEN Center for Sustainable Resource Science
Katsuyuki Sakai: RIKEN Center for Sustainable Resource Science
Kohei Watanabe: The University of Tokyo
Hiroshi Takagi: RIKEN Center for Sustainable Resource Science
Yumi Sato-Shiozaki: RIKEN Center for Sustainable Resource Science
Yuko Misumi: Osaka University
Yohei Miyanoiri: Osaka University
Genji Kurisu: Osaka University
Toshihiko Nogawa: RIKEN Center for Sustainable Resource Science
Ryo Takita: The University of Tokyo
Shunji Takahashi: RIKEN Center for Sustainable Resource Science

Nature Communications, 2024, vol. 15, issue 1, 1-13

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50142-1

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