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

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Science  03 May 2018:
eaat4100
DOI: 10.1126/science.aat4100

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Abstract

Vinblastine, a potent anticancer drug, is produced by Madagascar periwinkle in small quantities: heterologous reconstitution of vinblastine biosynthesis could provide an additional source of this drug. The chemistry underlying vinblastine synthesis makes identification of the biosynthetic genes challenging. Here we identify the two missing steps of vinblastine biosynthesis in this plant, namely 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 herein characterized hydrolases. The pathways show how plants create chemical diversity and also enable development of heterologous platforms for generation of stemmadenine-derived bioactive compounds.

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