A cinnamyl alcohol dehydrogenase–like scaffold organizes monoterpenoid indole alkaloid biosynthesis
Biosynthesis of ~3,000 monoterpenoid indole alkaloids (MIAs), including the anticancer drug vinblastine, involves the highly unstable intermediate strictosidine aglycone. Its formation by strictosidine β-glucosidase (SGD) and subsequent conversion by geissoschizine synthase (GS) occur in spatially separated compartments, representing a major biosynthesis bottleneck. Here we discover VinBLAST, a cinnamyl alcohol dehydrogenase–like protein repurposed as a scaffold for efficient processing of this labile intermediate. VinBLAST physically mediates SGD and GS interaction in the nucleus and allosterically enhances GS catalytic efficiency. VinBLAST homologs from diverse plant families enhance biosynthesis of several representative MIAs, with the production of catharanthine increased to ~160 mg L −1 in yeast, nearly 1,000-fold higher than previous studies. Our discovery provides a missing link in organizing MIA biosynthesis and enables scalable bioproduction of geissoschizine-derived therapeutics.
Authors
- Vincenzo De Luca (ORCID: https://orcid.org/0000-0001-8925-9382)
- Mohammadamin Shahsavarani (ORCID: https://orcid.org/0000-0002-7011-2775)
- Yuanwei Gou (ORCID: https://orcid.org/0000-0003-4472-1822)
- Jiazhang Lian (ORCID: https://orcid.org/0000-0001-9784-9876)
- Yang Qu (ORCID: https://orcid.org/0000-0002-0847-7212)
- Jorge Jonathan Oswaldo Garza-García (ORCID: https://orcid.org/0000-0001-6307-6908)
- Cong Chen (ORCID: https://orcid.org/0000-0002-9842-9141)
- Li J (ORCID: https://orcid.org/0000-0002-6679-5227)
- Yajie Wang (ORCID: https://orcid.org/0000-0002-6216-791X)
- Binbin Chen (ORCID: https://orcid.org/0000-0002-3910-0426)
- Chang Dong
- Lei Huang (ORCID: https://orcid.org/0000-0003-2838-2680)
- Jacob Owen Perley
- S. G. MANN
- Jingfei Bao
- Di Gao
- Mathew Bailey Richardson
- Hannah Caroline Tran
- Jaewook Hwang
- Feng Dong (ORCID: https://orcid.org/0009-0001-1311-9209)
- Chong Qiao (ORCID: https://orcid.org/0009-0008-9332-5811)
- Xiaojing Jiang
Institutions
- University of New Brunswick (CA)
- Ministry of Education (NZ)
- Brock University (CA)
- Westlake University (CN)
- Zhejiang Lab (CN)
- Beijing Academy of Science and Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Science
- Published
- 2026-07-16
- DOI
- https://doi.org/10.1126/science.aeb0357
- Primary Topic
- Alkaloids: synthesis and pharmacology
- Type
- article
- Field-Weighted Citation Impact
- 0.00