Document Detail


Thioesterase activity and acyl-CoA/fatty acid cross-talk of hepatocyte nuclear factor-4{alpha}.
MedLine Citation:
PMID:  15870076     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Hepatocyte nuclear factor-4alpha (HNF-4alpha) activity is modulated by natural and xenobiotic fatty acid and fatty acyl-CoA ligands as a function of their chain length, unsaturation, and substitutions. The acyl-CoA site of HNF-4alpha is reported here to consist of the E-F domain, to bind long-chain acyl-CoAs but not the respective free acids, and to catalyze the hydrolysis of bound fatty acyl-CoAs. The free acid pocket, previously reported in the x-ray structure of HNF-4alpha E-domain, entraps fatty acids but excludes acyl-CoAs. The acyl-CoA and free acid sites are distinctive and noncongruent. Free fatty acid products of HNF-4alpha thioesterase may exchange with free acids entrapped in the fatty acid pocket of HNF-4alpha. Cross-talk between the acyl-CoA and free fatty acid binding sites is abrogated by high affinity, nonhydrolyzable acyl-CoA ligands of HNF-4alpha that inhibit its thioesterase activity. Hence, HNF-4alpha transcriptional activity is controlled by its two interrelated acyl ligands and two binding sites interphased in tandem by the thioesterase activity. The acyl-CoA/free-acid and receptor/enzyme duality of HNF-4alpha extends the paradigm of nuclear receptors.
Authors:
Rachel Hertz; Bella Kalderon; Tamara Byk; Ina Berman; Ghadeer Za'tara; Raphael Mayer; Jacob Bar-Tana
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2005-05-03
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Jul 
Date Detail:
Created Date:  2005-06-27     Completed Date:  2005-08-16     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  24451-61     Citation Subset:  IM    
Affiliation:
Department of Human Nutrition and Metabolism, Hebrew University Medical School, Ein-Kerem, P. O. Box 12272, Jerusalem 91120, Israel.
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MeSH Terms
Descriptor/Qualifier:
Acyl Coenzyme A / metabolism*
Animals
Binding Sites
Boron Compounds / pharmacology
COS Cells
Cell Nucleus / metabolism
Crystallography, X-Ray
DNA, Complementary / metabolism
DNA-Binding Proteins / metabolism*
Dose-Response Relationship, Drug
Enzyme Inhibitors / pharmacology
Fatty Acids / chemistry,  metabolism*
Fluorescent Dyes / pharmacology
Hepatocyte Nuclear Factor 4
Kinetics
Ligands
Models, Biological
Phosphoproteins / metabolism*
Plasmids / metabolism
Protein Binding
Protein Structure, Tertiary
Rats
Recombinant Proteins / chemistry
Substrate Specificity
Thiolester Hydrolases / chemistry,  metabolism*
Transcription Factors / metabolism*
Transcription, Genetic
Transfection
Triazenes / pharmacology
Chemical
Reg. No./Substance:
0/4,4-difluoro-4-bora-3a,4a-diaza-s-indacene; 0/Acyl Coenzyme A; 0/Boron Compounds; 0/DNA, Complementary; 0/DNA-Binding Proteins; 0/Enzyme Inhibitors; 0/Fatty Acids; 0/Fluorescent Dyes; 0/Hepatocyte Nuclear Factor 4; 0/Ligands; 0/Phosphoproteins; 0/Recombinant Proteins; 0/Transcription Factors; 0/Triazenes; 76896-80-5/triacsin C; EC 3.1.2.-/Thiolester Hydrolases

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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