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Science. 2018 Jun 15;360(6394):1235-1239. doi: 10.1126/science.aat4100. Epub 2018 May 3.

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

Author information

1
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK.
2
Université de Tours, EA2106 Biomolécules et Biotechnologies Végétales, Parc de Grandmont 37200 Tours, France.
3
Laboratorio de Ciencias Quimicas-UENF-Campos dos Goytacazes-RJ, 28013-602, Brazil.
4
Université de Tours, EA2106 Biomolécules et Biotechnologies Végétales, Parc de Grandmont 37200 Tours, France. sarah.oconnor@jic.ac.uk vincent.courdavault@univ-tours.fr.
5
Department of Biological Chemistry, John Innes Centre, Norwich Research Park, Norwich NR4 7UH, UK. sarah.oconnor@jic.ac.uk vincent.courdavault@univ-tours.fr.

Abstract

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.

PMID:
29724909
DOI:
10.1126/science.aat4100
[Indexed for MEDLINE]

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