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

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Listed:
  • 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
    University of Shizuoka)

  • Shunji Takahashi

    (RIKEN Center for Sustainable Resource Science)

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.

Suggested Citation

  • Yu Zheng & Katsuyuki Sakai & Kohei Watanabe & Hiroshi Takagi & Yumi Sato-Shiozaki & Yuko Misumi & Yohei Miyanoiri & Genji Kurisu & Toshihiko Nogawa & Ryo Takita & Shunji Takahashi, 2024. "Iron-sulphur protein catalysed [4+2] cycloadditions in natural product biosynthesis," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50142-1
    DOI: 10.1038/s41467-024-50142-1
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