Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle

Lorenzo Caputi (1) , Jakob Franke (1) , Scott Farrow (1) , Khoa Chung (1) , Richard Payne (1) , Trinh-Don Nguyen (1) , Thu-Thuy Dang (1) , Inês Soares Teto Carqueijeiro (2) , Konstantinos Koudounas (2) , Thomas Dugé de Bernonville (2) , Belinda Ameyaw (1) , D. Marc Jones (1) , Ivo Jose Curcino Vieira (3) , Vincent Courdavault (2) , Sarah O’connor (1)

1 John Innes Centre [Norwich]
2 BBV EA 2106 - Biomolécules et biotechnologies végétales
3 UENF - Universidade Estadual do Norte Fluminense Darcy Ribeiro

Vinblastine, a potent anticancer drug, is produced by Catharanthus roseus (Madagascar periwinkle) in small quantities, and heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. However, the chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing enzymes necessary for vinblastine biosynthesis in this plant: an oxidase and a reductase that isomerize stemmadenine acetate into dihydroprecondylocarpine acetate, which is then deacetoxylated and cyclized to either catharanthine or tabersonine via two hydrolases characterized herein. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.

Domains: Life Sciences [q-bio]

Lorenzo Caputi, Jakob Franke, Scott Farrow, Khoa Chung, Richard Payne, et al.. Missing enzymes in the biosynthesis of the anticancer drug vinblastine in Madagascar periwinkle. Science, 2018, 360 (6394), pp.1235-1239. ⟨10.1126/science.aat4100⟩. ⟨hal-02527609⟩