Journal
SCIENCE
Volume 360, Issue 6394, Pages 1235-1238Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aat4100
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Funding
- European Research Council [311363]
- BBSRC [BB/J004561/1]
- Region Centre-Val de Loire, France (CatharSIS grant)
- Region Centre-Val de Loire, France (BioPROPHARM project-ARD)
- DFG [FR 3720/1-1]
- EMBO Long-Term Fellowships [ALTF 239-2015, ALTF 846-2016]
- French Embassy in Greece
- BBSRC
- BBSRC [BBS/E/J/000PR9790] Funding Source: UKRI
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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.
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