Ascaroside activity in Caenorhabditis elegans is highly dependent on chemical structure

Hollister, Kyle A.; Conner, Elizabeth S.; Zhang, Xinxing; Spell, Mark L.; Bernard, Gary M.; Patel, Pratik; Carvalho, Ana Carolina Gomes Vieira De; Butcher, Rebecca A.; Ragains, Justin R.

doi:10.1016/j.bmc.2013.07.018

Cited by 32 publications

(32 citation statements)

References 26 publications

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“…Ascarosides were synthesized as previously described (34), and (R)-6-hydroxyheptanoic acid and (R)-8-hydroxynonanoic acid were synthesized as described in SI Materials and Methods. CoA-thioesters of ascarosides, fatty acids, and hydroxylated fatty acids (1-9) were synthesized based on a previously described method for making fatty acylCoA thioesters (35) with modifications (SI Materials and Methods).…”

Section: Methodsmentioning

confidence: 99%

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Zhang

Feng

Chinta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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158

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Caenorhabditis elegans uses ascaroside pheromones to induce development of the stress-resistant dauer larval stage and to coordinate various behaviors. Peroxisomal β-oxidation cycles are required for the biosynthesis of the fatty acid-derived side chains of the ascarosides. Here we show that three acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, form different protein homo-and heterodimers with distinct substrate preferences. Mutations in the acyl-CoA oxidase genes acox-1, -2, and -3 led to specific defects in ascaroside production. When the acyl-CoA oxidases were expressed alone or in pairs and purified, the resulting acyl-CoA oxidase homo-and heterodimers displayed different sidechain length preferences in an in vitro activity assay. Specifically, an ACOX-1 homodimer controls the production of ascarosides with side chains with nine or fewer carbons, an ACOX-1/ACOX-3 heterodimer controls the production of those with side chains with seven or fewer carbons, and an ACOX-2 homodimer controls the production of those with ω-side chains with less than five carbons. Our results support a biosynthetic model in which β-oxidation enzymes act directly on the CoA-thioesters of ascaroside biosynthetic precursors. Furthermore, we identify environmental conditions, including high temperature and low food availability, that induce the expression of acox-2 and/or acox-3 and lead to corresponding changes in ascaroside production. Thus, our work uncovers an important mechanism by which C. elegans increases the production of the most potent dauer pheromones, those with the shortest side chains, under specific environmental conditions. dauer | pheromone | ascaroside | beta-oxidation | acyl-CoA oxidase

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Section: Methodsmentioning

confidence: 99%

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Zhang

Feng

Chinta

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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158

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“…Ascarosides were synthesized as described previously (28). Pentanoic, heptanoic, and nonanoic acid were purchased (Sigma).…”

Section: Methodsmentioning

confidence: 99%

Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans

Zhang

Jones

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Caenorhabditis elegans secretes ascarosides as pheromones to communicate with other worms and to coordinate the development and behavior of the population. Peroxisomal β-oxidation cycles shorten the side chains of ascaroside precursors to produce the short-chain ascaroside pheromones. Acyl-CoA oxidases, which catalyze the first step in these β-oxidation cycles, have different side chain-length specificities and enable C. elegans to regulate the production of specific ascaroside pheromones. Here, we determine the crystal structure of the acyl-CoA oxidase 1 (ACOX-1) homodimer and the ACOX-2 homodimer bound to its substrate. Our results provide a molecular basis for the substrate specificities of the acyl-CoA oxidases and reveal why some of these enzymes have a very broad substrate range, whereas others are quite specific. Our results also enable predictions to be made for the roles of uncharacterized acyl-CoA oxidases in C. elegans and in other nematode species. Remarkably, we show that most of the C. elegans acyl-CoA oxidases that participate in ascaroside biosynthesis contain a conserved ATP-binding pocket that lies at the dimer interface, and we identify key residues in this binding pocket. ATP binding induces a structural change that is associated with tighter binding of the FAD cofactor. Mutations that disrupt ATP binding reduce FAD binding and reduce enzyme activity. Thus, ATP may serve as a regulator of acyl-CoA oxidase activity, thereby directly linking ascaroside biosynthesis to ATP concentration and metabolic state.ascarosides | beta-oxidation | ATP | crystal structure | dauer pheromone

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“…50,51 For example, ascr#10, featuring a saturated 9-carbon side chain, strongly attracts hermaphrodites (Fig. 3), whereas ascr#3, which differs from ascr#10 only in that its side chain includes a double bond, acts as a deterrent (Fig.…”

Section: The Discovery Of Ascaroside-based Signalling In the Model mentioning

confidence: 99%

“…44,46 The indole ascaroside icas#9, featuring a saturated 5-carbon side chain, additionally exhibits dauer inducing activity, 45 whereas ascr#9, lacking the indole carboxy moiety, is not active in this assay. 51 Extensive HPLC-MS analyses of worm exo -metabolome and worm body extract samples have demonstrated that attachment of the tryptophan-derived indole carboxy moiety is tightly controlled. For example, the potent attraction pheromones icas#3 and icas#9 are present in almost identical amounts (Fig.…”

Section: The Discovery Of Ascaroside-based Signalling In the Model mentioning

confidence: 99%

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

Reuß

Schroeder

2015

Nat. Prod. Rep.

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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.

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Ascaroside activity in Caenorhabditis elegans is highly dependent on chemical structure

Cited by 32 publications

References 26 publications

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Acyl-CoA oxidase complexes control the chemical message produced by Caenorhabditis elegans

Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans

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

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