Worms are amazingly skilled chemists: using simple building blocks from conserved primary metabolism and a strategy of modular assembly, nematodes such as the model organism C. elegans create complex molecular architectures to regulate almost every aspect of their development and behavior. Phenotypes regulated by this combinatorial library of small-molecule signals include lifespan, dauer formation, phenotypic plasticity, mating, aggregation, dispersal, and other behaviors. Most of the identified compounds are based on the dideoxysugars ascarylose or paratose, which serve as scaffolds for attachment of moieties from amino acid, carbohydrate, neurotransmitter, lipid, and nucleoside metabolism, including an unusual xylopyranose-based adenosine derivative. The resulting signaling molecules can be active at femtomolar concentrations, such that encountering just a few molecules per minute is sufficient for worms to respond. Motivated by this unexpected structural and functional diversity, we have embarked on a systematic characterization of the C. elegans metabolome combining mutant screens and 2D NMR/HPLC-MS-based comparative metabolomics. We find that most small molecules in C. elegans remain undescribed and that even important primary metabolite classes may include non-canonical compounds. Our screen has produced evidence for several thousand different metabolites of yet undetermined structures, ranging from simple lipids, amino acid derivatives, and nucleosides to complex modular assemblies. Their identification and subsequent quantification in genome-wide mutant screens will, akin to transcriptional profiling, provide a new basis for the study of metabolism and evolutionarily conserved signaling pathways in model organisms.

Worm language: A natural combinatorial library and a xylopyranose-based nucleoside

249th National Meeting (2015)

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