Linking Genomic and Metabolomic Natural Variation Uncovers Nematode Pheromone Biosynthesis

Cell Chem Biol. 2018 Jun 21;25(6):787-796.e12. doi: 10.1016/j.chembiol.2018.04.004. Epub 2018 May 17.


In the nematodes Caenorhabditis elegans and Pristionchus pacificus, a modular library of small molecules control behavior, lifespan, and development. However, little is known about the final steps of their biosynthesis, in which diverse building blocks from primary metabolism are attached to glycosides of the dideoxysugar ascarylose, the ascarosides. We combine metabolomic analysis of natural isolates of P. pacificus with genome-wide association mapping to identify a putative carboxylesterase, Ppa-uar-1, that is required for attachment of a pyrimidine-derived moiety in the biosynthesis of ubas#1, a major dauer pheromone component. Comparative metabolomic analysis of wild-type and Ppa-uar-1 mutants showed that Ppa-uar-1 is required specifically for the biosynthesis of ubas#1 and related metabolites. Heterologous expression of Ppa-UAR-1 in C. elegans yielded a non-endogenous ascaroside, whose structure confirmed that Ppa-uar-1 is involved in modification of a specific position in ascarosides. Our study demonstrates the utility of natural variation-based approaches for uncovering biosynthetic pathways.

Keywords: Caenorhabditis elegans; GWAS; Pristionchus pacificus; ascarosides; biosynthesis; carboxylesterase; dauer development; metabolome; nematode-derived modular metabolites.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carboxylic Ester Hydrolases / genetics
  • Carboxylic Ester Hydrolases / metabolism
  • Genomics*
  • Metabolomics*
  • Nematoda / genetics*
  • Nematoda / metabolism*
  • Pheromones / biosynthesis*
  • Pheromones / chemistry
  • Pheromones / genetics*


  • Pheromones
  • Carboxylic Ester Hydrolases