A cinnamyl alcohol dehydrogenase-like scaffold organizes monoterpenoid indole alkaloid biosynthesis

• 成果类型: Article
• 署名作者: Gao, Di; Mann, Scott Galeung Alexander; Chen, Binbin; Gou, Yuanwei; Chen, Cong; Qiao, Chong; Garza-Garcia, Jorge Jonathan Oswaldo; Shahsavarani, Mohammadamin; Jiang, Xiaojing; Tran, Hannah Caroline; Bao, Jingfei; Richardson, Mathew Bailey; Li, Jianing; Perley, Jacob Owen; Hwang, Jaewook; Dong, Feng; Dong, Chang; Huang, Lei; De Luca, Vincenzo; Wang, Yajie; Qu, Yang; Lian, Jiazhang
• 署名单位: Zhejiang University; Zhejiang University; Zhejiang University; University of New Brunswick; Westlake University; Westlake University; Brock University; Beijing Life Science Academy; Zhejiang University; Zhejiang University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aeb0357
• 发表日期: 2026-08-20
• 页码: 788-794
• 关键词: molecular-cloning; ANTICANCER; PATHWAY; lignin; genes

摘要

Biosynthesis of similar to 3000 monoterpenoid indole alkaloids (MIAs), including the anticancer drug vinblastine, involves the highly unstable intermediate strictosidine aglycone. Its formation by strictosidine beta-glucosidase (SGD) and subsequent conversion by geissoschizine synthase (GS) occur in spatially separated compartments, representing a major biosynthesis bottleneck. In this study, we discover VinBLAST, a cinnamyl alcohol dehydrogenase-like protein repurposed as a scaffold for efficient processing of this labile intermediate. VinBLAST physically mediates the interaction of SGD and GS in the nucleus and allosterically enhances the catalytic efficiency of GS. VinBLAST homologs from diverse plant families enhance the biosynthesis of several representative MIAs, with the production of catharanthine increased to similar to 160 milligrams per liter in yeast, nearly 1000-fold higher than shown in previous studies. Our discovery provides a missing link in organizing MIA biosynthesis and enables scalable bioproduction of geissoschizine-derived therapeutics.