Document Detail


Mechanism of human SIRT1 activation by resveratrol.
MedLine Citation:
PMID:  15749705     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The NAD+-dependent protein deacetylase family, Sir2 (or sirtuins), is important for many cellular processes including gene silencing, regulation of p53, fatty acid metabolism, cell cycle regulation, and life span extension. Resveratrol, a polyphenol found in wines and thought to harbor major health benefits, was reported to be an activator of Sir2 enzymes in vivo and in vitro. In addition, resveratrol was shown to increase life span in three model organisms through a Sir2-dependent pathway. Here, we investigated the molecular basis for Sir2 activation by resveratrol. Among the three enzymes tested (yeast Sir2, human SIRT1, and human SIRT2), only SIRT1 exhibited significant enzyme activation ( approximately 8-fold) using the commercially available Fluor de Lys kit (BioMol). To examine the requirements for resveratrol activation of SIRT1, we synthesized three p53 acetylpeptide substrates either lacking a fluorophore or containing a 7-amino-4-methylcoumarin (p53-AMC) or rhodamine 110 (p53-R110). Although SIRT1 activation was independent of the acetylpeptide sequence, resveratrol activation was completely dependent on the presence of a covalently attached fluorophore. Substrate competition studies indicated that the fluorophore decreased the binding affinity of the peptide, and, in the presence of resveratrol, fluorophore-containing substrates bound more tightly to SIRT1. Using available crystal structures, a model of SIRT1 bound to p53-AMC peptide was constructed. Without resveratrol, the coumarin of p53-AMC peptide is solvent-exposed and makes no significant contacts with SIRT1. We propose that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.
Authors:
Margie T Borra; Brian C Smith; John M Denu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2005-03-04
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  280     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2005 Apr 
Date Detail:
Created Date:  2005-04-25     Completed Date:  2005-06-21     Revised Date:  2013-06-03    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  17187-95     Citation Subset:  IM    
Affiliation:
Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
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MeSH Terms
Descriptor/Qualifier:
Antioxidants / pharmacology
Binding Sites
Binding, Competitive
Cell Cycle
Chromatography, High Pressure Liquid
Coloring Agents / pharmacology
Coumarins / chemistry*
Crystallography, X-Ray
Gene Silencing
Histidine / chemistry
Histone Deacetylases / metabolism*
Humans
Immunoprecipitation
Kinetics
Models, Chemical
Models, Molecular
Peptides / chemistry
Protein Binding
Protein Conformation
Rhodamines / pharmacology
Sirtuin 1
Sirtuin 2
Sirtuins / metabolism*
Stilbenes / pharmacology*
Substrate Specificity
Time Factors
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
F31 GM066366/GM/NIGMS NIH HHS; NIH 5 T32 GM08349/GM/NIGMS NIH HHS; R01 GM65386/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antioxidants; 0/Coloring Agents; 0/Coumarins; 0/Peptides; 0/Rhodamines; 0/Stilbenes; 0/Tumor Suppressor Protein p53; 13558-31-1/rhodamine 110; 71-00-1/Histidine; A4VZ22K1WT/coumarin; EC 3.5.1.-/SIRT1 protein, human; EC 3.5.1.-/SIRT2 protein, human; EC 3.5.1.-/Sirtuin 1; EC 3.5.1.-/Sirtuin 2; EC 3.5.1.-/Sirtuins; EC 3.5.1.98/Histone Deacetylases; Q369O8926L/resveratrol

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


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