Abstract
The DAF-9 cytochrome P450 is a key regulator of dauer formation, developmental timing and longevity in the nematode Caenorhabditis elegans. Here we describe the first identified chemical inhibitor of DAF-9 and the first reported small-molecule tool that robustly induces dauer formation in typical culture conditions. This molecule (called dafadine) also inhibits the mammalian ortholog of DAF-9(CYP27A1), suggesting that dafadine can be used to interrogate developmental control and longevity in other animals.
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Change history
02 December 2011
In the version of this article initially published, the discovery and synthesis of the dafachronic acids was not attributed properly in two instances. On p. 892, the statement "the DAF-9 cytochrome P450 completes the synthesis of the dafachronic-acid hormones11,13" should have cited references 11, 13 and 14, and the statement "DAF-9 catalyzes two sequential oxidation steps at the C26 position to generate metabolites that are first hydroxylated and then carboxylated to products named Δ4- and Δ7-dafachronic acid, respectively13" should have cited reference 14 instead of 13. The errors have been corrected in the PDF and HTML versions of this article.
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Acknowledgements
We thank A. Antebi, N. Strushkevich, Y. Kohara, H.-J. Knölker, R. Martin, K.S. Pang, D. Mangelsdorf, R. Auchus, S. Wu, A. Orellana and J. Lund for reagents and advice. This work was supported by Canadian Institutes of Health Research grants to P.J.R. (MOP-68813), C.L.C. (MOP-97904), G.G. (MOP-81340) and C.N. (MOP-84305), a Natural Sciences and Engineering Research Council grant to C.L.C. (356873-08), a grant from the Canadian Cancer Society to G.G. (020380), and a Marie Curie fellowship to I.M.W. G.G. and P.J.R. are Canadian Research Chairs in Chemical Biology and Molecular Neurobiology, respectively.
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P.J.R., C.L.C. and G.M.L. conceived of the experiments and wrote the manuscript. G.M.L. and R.P. did all the worm experiments. L.M. and C.L.C. did all the cell culture and in vitro experiments. G.G. and C.N. provided the NovaCore library, expertise and guidance. G.M.L. and M.L.U. screened the NovaCore library for bioactivity in yeast. I.M.W. did the chemoinformatics.
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Supplementary Methods, Supplementary Figures 1–11 and Supplementary Tables 1–4 (PDF 6302 kb)
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Luciani, G., Magomedova, L., Puckrin, R. et al. Dafadine inhibits DAF-9 to promote dauer formation and longevity of Caenorhabditis elegans. Nat Chem Biol 7, 891–893 (2011). https://doi.org/10.1038/nchembio.698
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DOI: https://doi.org/10.1038/nchembio.698
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