Recent studies have revealed that Caenorhabditis elegans and other nematodes repurpose products from biochemical degradation pathways for the combinatorial assembly of complex modular structures that serve diverse signaling functions. Building blocks from neurotransmitter, amino acid, nucleoside and fatty acid metabolism are attached to scaffolds based on the dideoxyhexose ascarylose or glucose, resulting in hundreds of modular ascarosides and glucosides. Genome-wide association studies have identified carboxylesterases as the key enzymes mediating modular assembly, enabling rapid compound discovery via untargeted metabolomics and suggesting that modular metabolite biosynthesis originates from the ‘hijacking’ of conserved detoxification mechanisms. Modular metabolites thus represent a distinct biosynthetic strategy for generating structural and functional diversity in nematodes, complementing the primarily polyketide synthase- and nonribosomal peptide synthetase-derived universe of microbial natural products. Although many aspects of modular metabolite biosynthesis and function remain to be elucidated, their identification demonstrates how phenotype-driven compound discovery, untargeted metabolomics and genomic approaches can synergize to facilitate the annotation of metabolic dark matter.
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We thank B. Fox and J. Yu for helpful comments on the manuscript. This work was supported, in part, by the National Institutes of Health (R35GM131877) and the Howard Hughes Medical Institute.
The authors declare no competing interests.
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Wrobel, C.J.J., Schroeder, F.C. Repurposing degradation pathways for modular metabolite biosynthesis in nematodes. Nat Chem Biol 19, 676–686 (2023). https://doi.org/10.1038/s41589-023-01301-w