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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Phytogenic / biosynthesis*
  • Antineoplastic Agents, Phytogenic / chemistry
  • Catharanthus / enzymology*
  • Catharanthus / genetics
  • Genes, Plant*
  • Hydrolases / genetics*
  • Indole Alkaloids / chemistry
  • Indole Alkaloids / metabolism
  • Quinolines / chemistry
  • Quinolines / metabolism
  • Vinblastine / biosynthesis*
  • Vinblastine / chemistry
  • Vinca Alkaloids / biosynthesis
  • Vinca Alkaloids / chemistry


  • Antineoplastic Agents, Phytogenic
  • Indole Alkaloids
  • Quinolines
  • Vinca Alkaloids
  • condylocarpine
  • stemmadenine
  • tabersonine
  • Vinblastine
  • Hydrolases
  • catharanthine