Vinigrol Tricyclic Scaffold Biosynthesis Employs an Atypical Terpene Cyclase and a Multipotent Cyclization Cascade
Vinigrol (<b>1</b>) is a fungal diterpenoid consisting of a decahydro-1,5-butanonaphthalene ring system with no analogs in nature. Despite immense efforts in synthetic studies, the vinigrol biosynthesis pathway remains largely unknown. Herein, we identified a biosynthetic gene cluster for <b>1</b> and fully elucidated the biosynthetic pathway. By employing an AlphaFold-generated model structure, we identified the possible catalytic residues of the noncanonical terpene cyclase and analyzed their function by site-directed mutagenesis. We found that the G340A mutation opened a cryptic pathway for an unprecedented tetracyclic diterpene, defined here as virgarene. Retro-biosynthetic theoretical analysis provided a solid foundation for the complex cyclization pathway for the vinigrol scaffold, its chemical transformation to a structurally distinct bonnadiene, and redirection of the enzymatic cyclization cascade to virgarene. Close inspection of the terpene cyclization pathway via integrated experimental and theoretical approaches would allow efficient exploration of novel terpenoid chemistries.
Authors
- Sho Furumura
- Taro Ozaki (ORCID: https://orcid.org/0000-0002-4673-4478)
- Makoto Fujita (ORCID: https://orcid.org/0000-0001-6105-7340)
- Tohru Taniguchi (ORCID: https://orcid.org/0000-0002-4965-7383)
- Akihiro Sugawara (ORCID: https://orcid.org/0000-0003-1266-7497)
- Tomohisa Kuzuyama (ORCID: https://orcid.org/0000-0002-7221-5858)
- Tetsuro Shinada (ORCID: https://orcid.org/0000-0001-9145-1533)
- Yuto Homma
- Taro Matsuyama (ORCID: https://orcid.org/0009-0002-4138-7988)
- Takaaki Mitsuhashi (ORCID: https://orcid.org/0000-0001-7728-6869)
- Yohei Morishita (ORCID: https://orcid.org/0000-0001-8442-8642)
- Marie Kubota (ORCID: https://orcid.org/0000-0002-5059-9387)
- R. NAGATA (ORCID: https://orcid.org/0000-0002-2288-7111)
- Ryo Matsuda
- Masanobu Uchiyama (ORCID: https://orcid.org/0000-0001-6385-5944)
- Kento Tsukada
- Teigo Asai (ORCID: https://orcid.org/0000-0002-8903-392X)
- Yoko Yasuno (ORCID: https://orcid.org/0000-0001-6725-8610)
- Hitoshi Sekiya (ORCID: https://orcid.org/0000-0002-7387-7474)
- Fumito Sato (ORCID: https://orcid.org/0009-0009-5912-2532)
Institutions
- Nagano University (JP)
- Shinshu University (JP)
- Tohoku University (JP)
- Hokkaido University (JP)
- Institute for Advanced Study (DE)
- Institute for Molecular Science (JP)
- Ōtani University (JP)
- Osaka Metropolitan University (JP)
- The University of Tokyo (JP)
- Kumamoto University (JP)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2025-11-27
- DOI
- https://doi.org/10.1021/jacs.5c14400
- Citations
- 1
- Primary Topic
- Plant biochemistry and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.81