An acyl-CoA thioesterase is essential for the biosynthesis of a key dauer pheromone in C. elegans

Subhradeep Bhar; Chi-Su Yoon; Kevin Mai; Jungsoo Han; Dilip V Prajapati; Yuting Wang; Candy L Steffen; Laura S Bailey; Kari B Basso; Rebecca A Butcher

doi:10.1016/j.chembiol.2023.12.006

An acyl-CoA thioesterase is essential for the biosynthesis of a key dauer pheromone in C. elegans

Cell Chem Biol. 2024 Jan 4:S2451-9456(23)00437-3. doi: 10.1016/j.chembiol.2023.12.006. Online ahead of print.

Authors

Affiliations

¹ Department of Chemistry, University of Florida, Gainesville, FL 32611, USA.
² Department of Chemistry, University of Florida, Gainesville, FL 32611, USA. Electronic address: butcher@chem.ufl.edu.

PMID: 38183989
DOI: 10.1016/j.chembiol.2023.12.006

Abstract

Methyl ketone (MK)-ascarosides represent essential components of several pheromones in Caenorhabditis elegans, including the dauer pheromone, which triggers the stress-resistant dauer larval stage, and the male-attracting sex pheromone. Here, we identify an acyl-CoA thioesterase, ACOT-15, that is required for the biosynthesis of MK-ascarosides. We propose a model in which ACOT-15 hydrolyzes the β-keto acyl-CoA side chain of an ascaroside intermediate during β-oxidation, leading to decarboxylation and formation of the MK. Using comparative metabolomics, we identify additional ACOT-15-dependent metabolites, including an unusual piperidyl-modified ascaroside, reminiscent of the alkaloid pelletierine. The β-keto acid generated by ACOT-15 likely couples to 1-piperideine to produce the piperidyl ascaroside, which is much less dauer-inducing than the dauer pheromone, asc-C6-MK (ascr#2, 1). The bacterial food provided influences production of the piperidyl ascaroside by the worm. Our work shows how the biosynthesis of MK- and piperidyl ascarosides intersect and how bacterial food may impact chemical signaling in the worm.

Keywords: ACOT-15; Caenorhabditis elegans; acyl-CoA thioesterase; anaferine; ascaroside; ascarosides; ascr#2; attraction; avoidance; beta-oxidation; dauer; hydroxylamine; lifespan; metabolomics; methyl ketone; natural products; pelletierine; pheromone; piperideine; piperidine; structure elucidation.