Document Detail

Synthesis and activity of dafachronic acid ligands for the C. elegans DAF-12 nuclear hormone receptor.
MedLine Citation:
PMID:  19196833     Owner:  NLM     Status:  MEDLINE    
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.
Kamalesh K Sharma; Zhu Wang; Daniel L Motola; Carolyn L Cummins; David J Mangelsdorf; Richard J Auchus
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-02-05
Journal Detail:
Title:  Molecular endocrinology (Baltimore, Md.)     Volume:  23     ISSN:  1944-9917     ISO Abbreviation:  Mol. Endocrinol.     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-28     Completed Date:  2009-07-13     Revised Date:  2010-09-23    
Medline Journal Info:
Nlm Unique ID:  8801431     Medline TA:  Mol Endocrinol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  640-8     Citation Subset:  IM    
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
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MeSH Terms
Caenorhabditis elegans Proteins / metabolism*
Cell Line
Cholestenes / chemical synthesis*,  chemistry,  metabolism*
Molecular Structure
Receptors, Cytoplasmic and Nuclear / metabolism*
Trans-Activators / chemical synthesis,  chemistry,  metabolism
Grant Support
//Howard Hughes Medical Institute
Reg. No./Substance:
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

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