Combinatorial chemistry in nematodes: modular assembly of primary metabolism-derived building blocks

Abstract

The nematode Caenorhabditis elegans was the first animal to have its genome fully sequenced and has become an important model organism for biomedical research. However, like many other animal model systems, its metabolome remained largely uncharacterized, until recent investigations demonstrated the importance of small molecule-based signalling cascades for virtually every aspect of nematode biology. These studies have revealed that nematodes are amazingly skilled chemists: using simple building blocks from conserved primary metabolism and a strategy of modular assembly, C. elegans and other nematode species create complex molecular architectures to regulate their development and behaviour. These nematode-derived modular metabolites (NDMMs) are based on the dideoxysugars ascarylose or paratose, which serve as scaffolds for attachment of moieties from lipid, amino acid, carbohydrate, citrate, and nucleoside metabolism. Mutant screens and comparative metabolomics based on NMR spectroscopy and MS have so-far revealed several 100 different ascarylose (“ascarosides”) and a few paratose (“paratosides”) derivatives, many of which represent potent signalling molecules that can be active at femtomolar levels, regulating development, behaviour, body shape, and many other life history traits. NDMM biosynthesis appears to be carefully regulated as assembly of different modules proceeds with very high specificity. Preliminary biosynthetic studies have confirmed the primary metabolism origin of some NDMM building blocks, whereas the mechanisms that underlie their highly specific assembly are not understood. Considering their functions and biosynthetic origin, NDMMs represent a new class of natural products that cannot easily be classified as “primary” or “secondary”. We believe that the identification of new variants of primary metabolism-derived structures that serve important signalling functions in C. elegans and other nematodes provides a strong incentive for a comprehensive re-analysis of metabolism in higher animals, including humans.

Metabolite profiling of infection-associated metabolic markers of onchocerciasis

“…Further, the small molecule identifier database (SMID DB; http://smid-db.org) houses 179 small molecules from C.elegans and other nematodes [54, 55]. These small molecules derived from building blocks of primary metabolic pathways including lipid, amino acid and nucleoside pathways can exert diverse biological functions via conserved signaling cascades, including insulin signaling, TGF-b signaling, steroid biosynthesis, nuclear hormone receptors [56, 57]. It will be interesting to see if metabolite analyses of O. volvulus reveals similar or any additional nematode-derived metabolites that could be the source of some of the unknown metabolites found in the human serum.…”

Biosynthesis of Modular Ascarosides in C. elegans

“…Nematodes, including the model organisms Caenorhabditis elegans and Pristionchus pacificus , produce a great diversity of ascaroside derivatives [1] (Figure 1). These signaling molecules are involved in virtually all aspects of nematode life history, including the regulation of aging, [2] dauer development, [3] morphology, [4] and behavior, [5] often acting through evolutionarily conserved signaling pathways.…”

“…These signaling molecules are involved in virtually all aspects of nematode life history, including the regulation of aging, [2] dauer development, [3] morphology, [4] and behavior, [5] often acting through evolutionarily conserved signaling pathways. [1,6] The identification of the modular ascarosides demonstrated not only unexpected biosynthetic capabilities in an animal, but also provided an example of combinatorial generation of structural diversity that is reminiscent of synthetic combinatorial libraries in medicinal chemistry. [1] …”

“…[1,6] The identification of the modular ascarosides demonstrated not only unexpected biosynthetic capabilities in an animal, but also provided an example of combinatorial generation of structural diversity that is reminiscent of synthetic combinatorial libraries in medicinal chemistry. [1] …”

Co-option of neurotransmitter signaling for inter-organismal communication in C. elegans

“…C. elegans secretes a class of small molecules, the ascaroside pheromones, which serve diverse functions in inter-organismal chemical signaling (18)(19)(20). As a core feature, these molecules include an ascarylose sugar attached to a fatty acid-derived side chain that can be optionally decorated with building blocks from other primary metabolic pathways (21). Ascaroside production, and thus the profile of relayed chemical messages, is strongly dependent on the animal's sex, life stage, environment, and physiological state (22)(23)(24)(25).…”