Nature Communications (Jul 2024)

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,
  • Shunji Takahashi

DOI
https://doi.org/10.1038/s41467-024-50142-1
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 13

Abstract

Read online

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.