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Ancient gene clusters govern the initiation of monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion

Author

Listed:
  • Jaewook Hwang

    (University of New Brunswick, Department of Chemistry)

  • Jonathan Kirshner

    (University at Buffalo, Department of Biological Sciences)

  • Daniel André Ramey Deschênes

    (University of New Brunswick, Department of Chemistry)

  • Matthew Bailey Richardson

    (University of New Brunswick, Department of Chemistry)

  • Steven J. Fleck

    (University at Buffalo, Department of Biological Sciences)

  • Scott Galeung Alexander Mann

    (University of New Brunswick, Department of Chemistry)

  • Jun Guo

    (University of New Brunswick, Department of Chemistry)

  • Jacob Owen Perley

    (University of New Brunswick, Department of Chemistry)

  • Mohammadamin Shahsavarani

    (University of New Brunswick, Department of Chemistry)

  • Jorge Jonathan Oswaldo Garza-Garcia

    (University of New Brunswick, Department of Chemistry)

  • Alyssa Dawn Seveck

    (University of New Brunswick, Department of Chemistry)

  • Savannah Sadie Doiron

    (University of New Brunswick, Department of Chemistry)

  • Zhan Mai

    (University of New Brunswick, Department of Chemistry)

  • Stephen Nelson Silliphant

    (University of New Brunswick, Department of Chemistry)

  • Sarah Anne Englehart

    (University of New Brunswick, Department of Chemistry)

  • Barry A. Blight

    (University of New Brunswick, Department of Chemistry)

  • Larry Calhoun

    (University of New Brunswick, Department of Chemistry)

  • Di Gao

    (Zhejiang University, Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering)

  • Jiazhang Lian

    (Zhejiang University, Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering
    Zhejiang University, ZJU-Hangzhou Global Scientific and Technological Innovation Center
    Zhejiang University, Zhejiang Key Laboratory of Smart Biomaterials)

  • Ghislain Deslongchamps

    (University of New Brunswick, Department of Chemistry)

  • Victor A. Albert

    (University at Buffalo, Department of Biological Sciences)

  • Yang Qu

    (University of New Brunswick, Department of Chemistry)

Abstract

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.

Suggested Citation

  • Jaewook Hwang & Jonathan Kirshner & Daniel André Ramey Deschênes & Matthew Bailey Richardson & Steven J. Fleck & Scott Galeung Alexander Mann & Jun Guo & Jacob Owen Perley & Mohammadamin Shahsavarani , 2025. "Ancient gene clusters govern the initiation of monoterpenoid indole alkaloid biosynthesis and C3 stereochemistry inversion," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65543-z
    DOI: 10.1038/s41467-025-65543-z
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