Elucidation of the biosynthesis of carnosic acid and its reconstitution in yeast

Nat Commun. 2016 Oct 5:7:12942. doi: 10.1038/ncomms12942.

Abstract

Rosemary extracts containing the phenolic diterpenes carnosic acid and its derivative carnosol are approved food additives used in an increasingly wide range of products to enhance shelf-life, thanks to their high anti-oxidant activity. We describe here the elucidation of the complete biosynthetic pathway of carnosic acid and its reconstitution in yeast cells. Cytochrome P450 oxygenases (CYP76AH22-24) from Rosmarinus officinalis and Salvia fruticosa already characterized as ferruginol synthases are also able to produce 11-hydroxyferruginol. Modelling-based mutagenesis of three amino acids in the related ferruginol synthase (CYP76AH1) from S. miltiorrhiza is sufficient to convert it to a 11-hydroxyferruginol synthase (HFS). The three sequential C20 oxidations for the conversion of 11-hydroxyferruginol to carnosic acid are catalysed by the related CYP76AK6-8. The availability of the genes for the biosynthesis of carnosic acid opens opportunities for the metabolic engineering of phenolic diterpenes, a class of compounds with potent anti-oxidant, anti-inflammatory and anti-tumour activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abietanes / biosynthesis*
  • Abietanes / metabolism
  • Anti-Inflammatory Agents / chemistry
  • Antineoplastic Agents / chemistry
  • Antioxidants / chemistry
  • Escherichia coli / metabolism
  • Genetic Vectors
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mutagenesis
  • Mutagenesis, Site-Directed
  • Mutation
  • Oxidants / chemistry
  • Oxygen
  • Phylogeny
  • Rosmarinus / metabolism*
  • Saccharomyces cerevisiae / metabolism
  • Salvia / metabolism*
  • Spectrometry, Mass, Electrospray Ionization

Substances

  • Abietanes
  • Anti-Inflammatory Agents
  • Antineoplastic Agents
  • Antioxidants
  • Oxidants
  • ferruginol
  • carnosol
  • salvin
  • Oxygen