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

Zhang X, Li K, Jones RA, Bruner SD, Butcher RA
Proc Natl Acad Sci U S A 113 10055-60 (2016)
Related entries: 5k3g, 5k3h, 5k3i

Cited: 19 times
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Abstract

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.

Articles - 5k3j mentioned but not cited (1)

  1. Structural characterization of acyl-CoA oxidases reveals a direct link between pheromone biosynthesis and metabolic state in Caenorhabditis elegans. Zhang X, Li K, Jones RA, Bruner SD, Butcher RA. Proc Natl Acad Sci U S A 113 10055-10060 (2016)


Reviews citing this publication (3)

  1. Decoding chemical communication in nematodes. Butcher RA. Nat Prod Rep 34 472-477 (2017)
  2. Ascaroside Pheromones: Chemical Biology and Pleiotropic Neuronal Functions. Park JY, Joo HJ, Park S, Paik YK. Int J Mol Sci 20 E3898 (2019)
  3. Acyl CoA oxidase: from its expression, structure, folding, and import to its role in human health and disease. Kashyap I, Deb R, Battineni A, Nagotu S. Mol Genet Genomics 298 1247-1260 (2023)

Articles citing this publication (15)

  1. SIRT5 inhibits peroxisomal ACOX1 to prevent oxidative damage and is downregulated in liver cancer. Chen XF, Tian MX, Sun RQ, Zhang ML, Zhou LS, Jin L, Chen LL, Zhou WJ, Duan KL, Chen YJ, Gao C, Cheng ZL, Wang F, Zhang JY, Sun YP, Yu HX, Zhao YZ, Yang Y, Liu WR, Shi YH, Xiong Y, Guan KL, Ye D. EMBO Rep 19 e45124 (2018)
  2. Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms. Chung HL, Wangler MF, Marcogliese PC, Jo J, Ravenscroft TA, Zuo Z, Duraine L, Sadeghzadeh S, Li-Kroeger D, Schmidt RE, Pestronk A, Rosenfeld JA, Burrage L, Herndon MJ, Chen S, Members of Undiagnosed Diseases Network, Shillington A, Vawter-Lee M, Hopkin R, Rodriguez-Smith J, Henrickson M, Lee B, Moser AB, Jones RO, Watkins P, Yoo T, Mar S, Choi M, Bucelli RC, Yamamoto S, Lee HK, Prada CE, Chae JH, Vogel TP, Bellen HJ. Neuron 106 589-606.e6 (2020)
  3. A Single-Neuron Chemosensory Switch Determines the Valence of a Sexually Dimorphic Sensory Behavior. Fagan KA, Luo J, Lagoy RC, Schroeder FC, Albrecht DR, Portman DS. Curr Biol 28 902-914.e5 (2018)
  4. Enterovirus 71 induces neural cell apoptosis and autophagy through promoting ACOX1 downregulation and ROS generation. You L, Chen J, Liu W, Xiang Q, Luo Z, Wang W, Xu W, Wu K, Zhang Q, Liu Y, Wu J. Virulence 11 537-553 (2020)
  5. Small-molecule pheromones and hormones controlling nematode development. Butcher RA. Nat Chem Biol 13 577-586 (2017)
  6. Biosynthetic tailoring of existing ascaroside pheromones alters their biological function in C. elegans. Zhou Y, Wang Y, Zhang X, Bhar S, Jones Lipinski RA, Han J, Feng L, Butcher RA. Elife 7 e33286 (2018)
  7. Modular metabolite assembly in Caenorhabditis elegans depends on carboxylesterases and formation of lysosome-related organelles. Le HH, Wrobel CJ, Cohen SM, Yu J, Park H, Helf MJ, Curtis BJ, Kruempel JC, Rodrigues PR, Hu PJ, Sternberg PW, Schroeder FC. Elife 9 e61886 (2020)
  8. Intestinal peroxisomal fatty acid β-oxidation regulates neural serotonin signaling through a feedback mechanism. Bouagnon AD, Lin L, Srivastava S, Liu CC, Panda O, Schroeder FC, Srinivasan S, Ashrafi K. PLoS Biol 17 e3000242 (2019)
  9. Reimagining pheromone signalling in the model nematode Caenorhabditis elegans. Viney M, Harvey S. PLoS Genet 13 e1007046 (2017)
  10. Grifola frondosa (Maitake) Extract Reduces Fat Accumulation and Improves Health Span in C. elegans through the DAF-16/FOXO and SKN-1/NRF2 Signalling Pathways. Aranaz P, Peña A, Vettorazzi A, Fabra MJ, Martínez-Abad A, López-Rubio A, Pera J, Parladé J, Castellari M, Milagro FI, González-Navarro CJ. Nutrients 13 3968 (2021)
  11. Convergent evolution of small molecule pheromones in Pristionchus nematodes. Dong C, Weadick CJ, Truffault V, Sommer RJ. Elife 9 e55687 (2020)
  12. Social and sexual behaviors in C. elegans: the first fifty years. Portman DS. J Neurogenet 34 389-394 (2020)
  13. Chemical Signaling Regulates Axon Regeneration via the GPCR-Gqα Pathway in Caenorhabditis elegans. Shimizu T, Sugiura K, Sakai Y, Dar AR, Butcher RA, Matsumoto K, Hisamoto N. J Neurosci 42 720-730 (2022)
  14. Endocrine pheromones couple fat rationing to dauer diapause through HNF4α nuclear receptors. Gao C, Li Q, Yu J, Li S, Cui Q, Hu X, Chen L, Zhang SO. Sci China Life Sci 64 2153-2174 (2021)
  15. Natural genetic variation in the pheromone production of C. elegans. Lee D, Fox BW, Palomino DF, Panda O, Tenjo FJ, Koury EJ, Evans KS, Stevens L, Rodrigues PR, Kolodziej AR, Schroeder FC, Andersen EC. Proc Natl Acad Sci U S A 120 e2221150120 (2023)


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