The nematode Caenorhabditis elegans secretes a family of pheromones called the ascarosides to induce development of the dauer larval stage, as well as to coordinate various behaviors. The ascarosides are derivatives of the 3,6-dideoxy-L-sugar ascarylose with different fatty acid-derived side chains. We are using a multidisciplinary approach, including RNAi-based screens, metabolomics, in vitro enzyme assays, organic synthesis of biosynthetic intermediates, and X-ray crystallography, to study the ascaroside biosynthetic pathway. We have shown that peroxisomal β-oxidation cycles shorten long-chain ascaroside precursors to the shorter chain, ascaroside pheromones. Acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, form different protein homo- and heterodimers with distinct side chain length preferences. Mutations in the acyl-CoA oxidase genes, acox-1, -2, and -3, led to specific defects in ascaroside production. When the acyl-CoA oxidases were expressed alone or in pairs and purified, the resulting acyl-CoA oxidase homo- and heterodimers displayed different side chain length preferences in an in vitro activity assay. Specifically, an ACOX-1 homodimer controls the production of ascarosides with side chains with nine or fewer carbons, an ACOX-1/ACOX-3 heterodimer controls the production of those with side chains with seven or fewer carbons, and an ACOX-2 homodimer controls the production of those with ω-side chains with less than five carbons. Our results support a biosynthetic model in which β-oxidation enzymes act directly on the CoA-thioesters of ascaroside biosynthetic precursors. Furthermore, we identify specific environmental conditions, including high temperature and low food availability, which induce the expression of acox-2 and/or acox-3 and lead to corresponding changes in ascaroside production. Thus, we have uncovered an important mechanism by which C. elegans increases the production of the most potent dauer pheromones, those with the shortest side chains, under stressful environmental conditions. Furthermore, we have identified additional peroxisomal enzymes that are responsible for the biosynthesis of pheromones with specific modifications to their fatty acid side chains. Our work demonstrates how C. elegans controls the chemical message that it communicates to the rest of the population in response to changing environmental conditions. .
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