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

Di Gao; Scott Galeung Alexander Mann; Binbin Chen; Yuanwei Gou; Cong Chen; Chong Qiao; Jorge Jonathan Oswaldo Garza‐García; Mohammadamin Shahsavarani; Xiaojing Jiang; Hannah Caroline Tran; Jingfei Bao; Mathew Bailey Richardson; Li J; Jacob Owen Perley; Jaewook Hwang; Feng Dong; Chang Dong; Lei Huang; Vincenzo De Luca; Yajie Wang; Yang Qu; Jiazhang Lian

doi:10.1126/science.aeb0357

Synthetic BiologyScienceJul 16, 2026

Peer-reviewed journal article

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

Di Gao iD, Scott Galeung Alexander Mann iD, Binbin Chen iD, Yuanwei Gou iD, Cong Chen iD, Chong Qiao iD, Jorge Jonathan Oswaldo Garza‐García iD, Mohammadamin Shahsavarani iD, Xiaojing Jiang, Hannah Caroline Tran iD, Jingfei Bao, Mathew Bailey Richardson iD, Li J iD, Jacob Owen Perley iD, Jaewook Hwang, Feng Dong iD, Chang Dong iD, Lei Huang iD, Vincenzo De Luca iD, Yajie Wang iD, Yang Qu iD, Jiazhang Lian iD

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 {beta}-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 homologues 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.

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