Linking Genomic and Metabolomic Natural Variation Uncovers Nematode Pheromone Biosynthesis. Issue 6 (21st June 2018)

• Record Type: Journal Article
• Authors: Falcke, Jan M.; Bose, Neelanjan; Artyukhin, Alexander B.; Rödelsperger, Christian; Markov, Gabriel V.; Yim, Joshua J.; Grimm, Dominik; Claassen, Marc H.; Panda, Oishika; Baccile, Joshua A.; Zhang, Ying K.; Le, Henry H.; Jolic, Dino; Schroeder, Frank C.; Sommer, Ralf J.
• Is Part Of: Cell chemical biology. Volume 25:Issue 6(2018)
• Page Start: 787
• Page End: 796.e12
• Publication Date: 2018-06-21
• Subjects: biosynthesis -- GWAS -- metabolome -- ascarosides -- nematode-derived modular metabolites -- carboxylesterase -- dauer development -- Pristionchus pacificus -- Caenorhabditis elegans; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.04.004
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: GWAS identifies a gene required for modular ascaroside biosynthesis Ppa- UAR-1 is required for attachment of a nucleobase-derived moiety to ascarylose Heterologous expression of Ppa- UAR-1 in C . elegans produced a non-natural ascaroside Natural variation-based approaches can uncover unanticipated biosynthetic pathways Abstract : A small-molecule library, the ascarosides, regulates the life history of Caenorhabditis elegans and Pristionchus pacificus . GWAS combined with metabolomics of P . pacificus natural isolates revealed a putative carboxylesterase, Ppa-uar-1, involved in attaching a pyrimidine-derived moiety in the biosynthesis of a major dauer pheromone component.