Ancient gene clusters govern the initiation of monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion
The inversion of C3 stereochemistry in monoterpenoid indole alkaloids (MIAs), derived from the central precursor strictosidine (3S), is essential for producing pharmacologically important 3 R MIAs and spirooxindoles such as reserpine. While early MIA biosynthesis preserves the 3S configuration, the mechanism underlying C3 inversion has remained unresolved. Here, we identify and biochemically characterize a conserved oxidase-reductase pair in Gentianales: heteroyohimbine/yohimbine/corynanthe C3-oxidase (HYC3O) and C3-reductase (HYC3R), which together invert the 3S stereochemistry to 3 R across diverse substrates. HYC3O and HYC3R are encoded within biosynthetic gene clusters in Rauvolfia tetraphylla and Catharanthus roseus, homologous to a geissoschizine synthase (GS) cluster also uncovered. Comparative genomics indicate that the GS cluster originated at the base of Gentianales (~135 Mya), coinciding with the evolution of the strictosidine synthase cluster, whereas the reserpine cluster arose later. These findings uncover the genomic and biochemical basis of key events driving MIA diversification beyond canonical vinblastine and ajmaline pathways.
Authors
- Mohammadamin Shahsavarani (ORCID: https://orcid.org/0000-0002-7011-2775)
- Zhan Mai (ORCID: https://orcid.org/0000-0002-4575-7141)
- Ghislain Deslongchamps (ORCID: https://orcid.org/0000-0002-3184-3807)
- Steven J. Fleck (ORCID: https://orcid.org/0000-0001-5370-2258)
- Jiazhang Lian (ORCID: https://orcid.org/0000-0001-9784-9876)
- Barry A. Blight (ORCID: https://orcid.org/0000-0003-1166-6206)
- Larry A. Calhoun (ORCID: https://orcid.org/0009-0001-1792-2373)
- Yang Qu (ORCID: https://orcid.org/0000-0002-0847-7212)
- Victor A. Albert (ORCID: https://orcid.org/0000-0002-0262-826X)
- Di Gao (ORCID: https://orcid.org/0000-0001-7619-1964)
- Sarah A. Englehart
- Jun Guo (ORCID: https://orcid.org/0000-0002-4681-6983)
- J. Y. Hwang
- Jacob Owen Perley
- S. G. MANN
- Daniel André Ramey Deschênes
- Matthew Bailey Richardson
- Jorge Jonathan Oswaldo Garza‐García
- Jonathan Kirshner (ORCID: https://orcid.org/0009-0008-5521-0351)
- Alyssa Dawn Seveck
- Savannah Sadie Doiron
- Stephen Nelson Silliphant
Institutions
- University of New Brunswick (CA)
- Zhejiang University of Science and Technology (CN)
- Buffalo VA Medical Center (US)
- University at Buffalo, State University of New York (US)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-25
- DOI
- https://doi.org/10.1038/s41467-025-65543-z
- Citations
- 3
- Primary Topic
- Alkaloids: synthesis and pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 4.67
Funders
- National Science Foundation
- New Brunswick Innovation Foundation
- Ministry of Education, India
- Alliance de recherche numérique du Canada
- Natural Sciences and Engineering Research Council of Canada