| Synthesis and activity of dafachronic acid ligands for the C. elegans DAF-12 nuclear hormone receptor. | |
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MedLine Citation:
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PMID: 19196833 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The nuclear hormone receptor DAF-12 from Caenorhabditis elegans is activated by dafachronic acids, which derive from sterols upon oxidation by DAF-9, a cytochrome P450. DAF-12 activation is a critical checkpoint in C. elegans for acquisition of reproductive competence and for entry into adulthood rather than dauer diapause. Previous studies implicated the (25S)-Delta(7)-dafachronic acid isomer as the most potent compound, but the (25S)-Delta(4)-isomer was also identified as an activator of DAF-12. To explore the tolerance of DAF-12 for structural variations in the ligand and to enable further studies requiring large amounts of ligands for DAF-12 and homologs in other nematodes, we synthesized (25R)- and (25S)-isomers of five dafachronic acids differing in A/B-ring configurations. Both the (25S)- and (25R)-Delta(7)-dafachronic acids are potent transcriptional activators in a Gal4-transactivation assay using HEK-293 cells, with EC(50) values of 23 and 33 nm, respectively, as are (25S)- and (25R)-Delta(4)-dafachronic acids, with EC(50) values of 23 and 66 nm, respectively. The (25S)- and (25R)-Delta(5)-isomers were much less potent, with EC(50) values approaching 1000 nm, and saturated 5alpha- and 5beta-dafachronic acids showed mostly intermediate potencies. Rescue assays using daf- 9-null mutants confirmed the results from transactivation experiments, but this in vivo assay accentuated the greater potencies of the (25S)-epimers, particularly for the (25S)-Delta(7)-isomer. We conclude that DAF-12 accommodates a large range of structural variation in ligand geometry, but (25S)-Delta(7)-dafachronic acid is the most potent and probably biologically relevant isomer. Potency derives more from the A/B-ring configuration than from the stereochemistry at C-25. |
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Authors:
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Kamalesh K Sharma; Zhu Wang; Daniel L Motola; Carolyn L Cummins; David J Mangelsdorf; Richard J Auchus |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-02-05 |
Journal Detail:
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Title: Molecular endocrinology (Baltimore, Md.) Volume: 23 ISSN: 1944-9917 ISO Abbreviation: Mol. Endocrinol. Publication Date: 2009 May |
Date Detail:
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Created Date: 2009-04-28 Completed Date: 2009-07-13 Revised Date: 2010-09-23 |
Medline Journal Info:
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Nlm Unique ID: 8801431 Medline TA: Mol Endocrinol Country: United States |
Other Details:
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Languages: eng Pagination: 640-8 Citation Subset: IM |
Affiliation:
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Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Caenorhabditis elegans Proteins / metabolism* Cell Line Cholestenes / chemical synthesis*, chemistry, metabolism* Humans Isomerism Ligands Molecular Structure Receptors, Cytoplasmic and Nuclear / metabolism* Trans-Activators / chemical synthesis, chemistry, metabolism |
| Grant Support | |
ID/Acronym/Agency:
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//Howard Hughes Medical Institute |
| Chemical | |
Reg. No./Substance:
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0/Caenorhabditis elegans Proteins; 0/Cholestenes; 0/DAF-12 protein, C elegans; 0/Ligands; 0/Receptors, Cytoplasmic and Nuclear; 0/Trans-Activators; 0/dafachronic acid |
| Comments/Corrections | |
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