Contribution of the Peroxisomal acox Gene to the Dynamic Balance of Daumone Production in Caenorhabditis elegans*

Joo, Hyoe Jin; Kim, Kwang Youl; Yim, Yong Hyeon; Jin, You Xun; Kim, Heekyeong; Kim, Mun Young; Paik, Young Ki

doi:10.1074/jbc.m110.122663

Cited by 65 publications

(92 citation statements)

References 21 publications

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“…Ascaroside production has been shown to be influenced by a variety of factors, including developmental stage (21), temperature (3,19), and sex (8), although interpretation of these results is often complicated by the fact that they were obtained by changing multiple variables at the same time (21) or by using longterm, mixed-larval stage cultures (3,19). Starvation has been suggested to increase the ratio of asc-ΔC9 to asc-ωC3 in longterm, mixed-stage cultures (11).…”

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confidence: 99%

“…Four peroxisomal enzymes, an acyl-CoA oxidase (ACOX-1), enoyl-CoA hydratase (MAOC-1), (3R)-hydroxyacyl-CoA dehydrogenase (DHS-28), and 3-ketoacylCoA thiolase (DAF-22), have been implicated in the β-oxidation cycles for ascaroside biosynthesis (Fig. 1C) (11,(17)(18)(19). These enzymes are homologous to mammalian peroxisomal enzymes that process very long chain fatty acids, branched-chain fatty acids, and bile acid intermediates (20).…”

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confidence: 99%

“…Biosynthesis of the side chains of the ascarosides requires peroxisomal β-oxidation cycles that shorten the side chains by two carbons per cycle (11,(17)(18)(19). Four peroxisomal enzymes, an acyl-CoA oxidase (ACOX-1), enoyl-CoA hydratase (MAOC-1), (3R)-hydroxyacyl-CoA dehydrogenase (DHS-28), and 3-ketoacylCoA thiolase (DAF-22), have been implicated in the β-oxidation cycles for ascaroside biosynthesis (Fig.…”

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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.

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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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.

158

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“…S1 A and B) (8)(9)(10)(11)(12)(13). C. elegans makes ascarosides with long side chains and then shortens these side chains through β-oxidation to make the short-chain ascaroside pheromones (3)(4)(5)(6)(7). These pheromones enable C. elegans to coordinate the development and behavior of the population.…”

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confidence: 99%

“…In the nematode C. elegans, peroxisomal β-oxidation not only functions in primary metabolism, but also has been coopted in the biosynthesis of a class of secondary metabolites known as the ascarosides (3)(4)(5)(6)(7). These ascarosides, which are secreted as pheromones, are derivatives of the 3,6-dideoxy-L-sugar ascarylose and are modified with fatty acid-derived side chains of various lengths (SI Appendix, Fig.…”

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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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Synthesis of Photoaffinity‐Labeled Daumone Analogs

Kim¹,

Paik

2015

Bulletin Korean Chem Soc

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Contribution of the Peroxisomal acox Gene to the Dynamic Balance of Daumone Production in Caenorhabditis elegans*

Cited by 65 publications

References 21 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

Synthesis of Photoaffinity‐Labeled Daumone Analogs

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