Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.

General, high-yield metathesis reactions provide two related and comprehensive series of dithiabismuth heterocycles. The compounds are characterized by spectroscopic and X-ray crystallographic analysis. Monocycles 4), and 2-chloro-1,3-dithia-6-oxa-2-bismocane (5) are kinetically stable with respect to the tethered bicyclic derivatives 1,2-bis((1,3-dithia-2-bismolan-2-yl)thio)ethane ( 6), 1,3-bis((1,3-dithia-2-bisman-2yl)thio)propane ( 7), 1,4-bis((1,3-dithia-2-bismepan-2-yl)thio)butane (8), bis((1,3,6-trithia-2-bismocan-2-yl)thio)ethyl) sulfide ( 9), and bis(((1,3-dithia-6-oxa-2-bismocan-2-yl)thio)ethyl) ether (10). Mass spectrometry provides an excellent means of characterization of compounds of this nature and is responsible for the identification of monocyclic bismuthenium cations as general and dominant dissociation products. In addition, the atmospheric pressure chemical ionization technique reveals solvent coordination chemistry of the bismuthenium cations.

The recently discovered modular glucosides (MOGLs) form a large metabolite library derived from combinatorial assembly of moieties from amino acid, neurotransmitter, and lipid metabolism in the model organism C. elegans. Combining CRISPR-Cas9 genome editing, comparative metabolomics, and synthesis, we show that the carboxylesterase homologue Cel-CEST-1.2 is responsible for specific 2-O-acylation of diverse glucose scaffolds with a wide variety of building blocks, resulting in more than 150 different MOGLs. We further show that this biosynthetic role is conserved for the closest homologue of Cel-CEST-1.2 in the related nematode species C. briggsae, Cbr-CEST-2. Expression of Cel-cest-1.2 and MOGL biosynthesis are strongly induced by starvation conditions in C. elegans, one of the premier model systems for mechanisms connecting nutrition and physiology. Cel-cest-1.2-deletion results in early death of adult animals under starvation conditions, providing first insights into the biological functions of MOGLs.

Few nucleoside-derived natural products have been identified from animals, despite the ubiquity of nucleosides in living organisms. Here, we use a combination of synthesis and the emerging electron microscopy technique microcrystal electron diffraction to determine the structures of several N 3 -(β-glucopyranosyl)uric acid derivatives in Caenorhabditis elegans. These noncanonical gluconucleosides further integrate an ascaroside moiety, for which we present a shortened synthetic route. The production of a phosphorylated gluconucleoside is influenced by evolutionarily conserved insulin signaling.

Signaling molecules derived from attachment of diverse primary metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that lysosome-related organelles (LROs) are required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Both modular glucosides and ascarosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism. We further show that cholinesterase (cest) homologs that localize to the LROs are required for assembly of both modular ascarosides and glucosides, mediating formation of ester and amide linkages between subsets of building blocks. Their specific biosynthesis suggests that modular glucosides, like ascarosides, serve dedicated signaling functions. Further exploration of LRO function and cest homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.Abstract Figure