A cinnamyl alcohol dehydrogenase–like scaffold organizes monoterpenoid indole alkaloid biosynthesis
Abstract
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.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (22)
Di Gao
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Scott Galeung Alexander Mann
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Binbin Chen
School of Engineering, Westlake University, Hangzhou, China.
Yuanwei Gou
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Cong Chen
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Chong Qiao
Zhejiang Key Laboratory of Intelligent Manufacturing for Functional Chemicals, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China.
Jorge Jonathan Oswaldo Garza-Garcia
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Mohammadamin Shahsavarani
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Xiaojing Jiang
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Hannah Caroline Tran
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Jingfei Bao
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Mathew Bailey Richardson
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Jianing Li
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Jacob Owen Perley
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Jaewook Hwang
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Feng Dong
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Chang Dong
Zhejiang Key Laboratory of Intelligent Manufacturing for Functional Chemicals, ZJU-Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou, China.
Lei Huang
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.
Vincenzo De Luca
Department of Biological Sciences, Brock University, St. Catharines, ON, Canada.
Yajie Wang
School of Engineering, Westlake University, Hangzhou, China.
Yang Qu
Department of Chemistry, University of New Brunswick, Fredericton, NB, Canada.
Jiazhang Lian
BLSA-ZJU Research Center and Key Laboratory of Biomass Chemical Engineering of Ministry of Education, College of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China.