Comparative metabolomics reveals a natural combinatorial library and a xylopyranose-based nucleoside in nematodes

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 life history. These 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, i.e. encountering just a few molecules is sufficient for worms to respond.

Motivated by this unexpected structural and functional diversity, we are pursuing a systematic characterization of the C. elegans metabolome combining mutant screens and 2D NMR/HPLC-MS-based comparative metabolomics. 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.