A three enzyme system to generate the Strychnos alkaloid scaffold from a central biosynthetic intermediate

Nat Commun. 2017 Aug 22;8(1):316. doi: 10.1038/s41467-017-00154-x.

Abstract

Monoterpene indole alkaloids comprise a diverse family of over 2000 plant-produced natural products. This pathway provides an outstanding example of how nature creates chemical diversity from a single precursor, in this case from the intermediate strictosidine. The enzymes that elicit these seemingly disparate products from strictosidine have hitherto been elusive. Here we show that the concerted action of two enzymes commonly involved in natural product metabolism-an alcohol dehydrogenase and a cytochrome P450-produces unexpected rearrangements in strictosidine when assayed simultaneously. The tetrahydro-β-carboline of strictosidine aglycone is converted into akuammicine, a Strychnos alkaloid, an elusive biosynthetic transformation that has been investigated for decades. Importantly, akuammicine arises from deformylation of preakuammicine, which is the central biosynthetic precursor for the anti-cancer agents vinblastine and vincristine, as well as other biologically active compounds. This discovery of how these enzymes can function in combination opens a gateway into a rich family of natural products.The biosynthetic pathway of preakuammicine, a monoterpene precursor of the anti-cancer agent vinblastine, has remained largely unexplored. Here, the authors provide transcriptomic and biochemical data to identify two enzymes that, in tandem, convert strictosidine to akuammicine, the stable shunt product of preakuammicine.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Dehydrogenase / genetics
  • Alcohol Dehydrogenase / metabolism
  • Alkaloids / chemistry
  • Alkaloids / metabolism*
  • Base Sequence
  • Biological Products / chemistry
  • Biological Products / metabolism
  • Biosynthetic Pathways / genetics
  • Cytochrome P-450 Enzyme System / genetics
  • Cytochrome P-450 Enzyme System / metabolism
  • Indoles / chemistry
  • Indoles / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Models, Chemical
  • Molecular Structure
  • Plant Proteins / genetics
  • Plant Proteins / metabolism*
  • Strychnos / enzymology
  • Strychnos / genetics
  • Strychnos / metabolism*
  • Vinca Alkaloids / chemistry
  • Vinca Alkaloids / metabolism*

Substances

  • Alkaloids
  • Biological Products
  • Indoles
  • Isoenzymes
  • Plant Proteins
  • Vinca Alkaloids
  • strictosidine
  • Cytochrome P-450 Enzyme System
  • Alcohol Dehydrogenase
  • akuammicine