Cited by 1,065Sirtuins and Resveratrol in MedicineHistone Deacetylase Inhibitors ResearchBiochemical and Molecular Research

Mechanism of Human SIRT1 Activation by Resveratrol

Open access
Borra, Margie T., Smith, Brian C., Denu, John M.·2005·Journal of Biological Chemistry

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1074/jbc.m501250200

Cites

68 of 68 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Smith, J. S., Brachmann, C. B., Celic, I., Kenna, M. A., Muhammad, S., Starai, V. J., Avalos, J. L., Escalante-Semerena, J. C., Grubmeyer, C., Wolberger, C., and Boeke, J. D. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 6658 -6663
  2. Landry, J., Sutton, A., Tafrov, S. T., Heller, R. C., Stebbins, J., Pillus, L., and Sternglanz, R. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 5807-5811
  3. Tanner, K. G., Landry, J., Sternglanz, R., and Denu, J. M. (2000) Proc. Natl. Acad. Sci. U. S. A. 97, 14178 -14182
  4. Tanny, J. C., and Moazed, D. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 415-420
  5. Langley, E., Pearson, M., Faretta, M., Bauer, U. M., Frye, R. A., Minucci, S., Pelicci, P. G., and Kouzarides, T. (2002) EMBO J. 21, 2383-2396
  6. Bedalov, A., Gatbonton, T., Irvine, W. P., Gottschling, D. E., and Simon, J. A. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 15113-15118

Cited by

Sorted by citations

Authors
Borra, M. T., Smith, B. C., & Denu, J. M.
Affiliations
University of Wisconsin–Madison (US)
Corresponding author
Denu, John M.
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2005-04
Volume
280
Issue
17
Pages
17187-17195
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2007842741
Cited by
1,065
References
68
Citations by year
2026: 27 · 2025: 29 · 2024: 29 · 2023: 39 · 2022: 62 · 2021: 45 · 2020: 59 · 2019: 58 · 2018: 62 · 2017: 35 · 2016: 52 · 2015: 72 · 2014: 48 · 2013: 73 · 2012: 72
FWCI
18.16
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (NIH 5 T32)
  • National Institute of General Medical Sciences (T32GM008349, F31GM066366, NIH 5T32 GM08349, R01GM065386)
Topics
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
Keywords
SIRT1, resveratrol, NAD+-dependent deacetylase, p53 acetylation, substrate affinity, conformational change, lifespan extension
MeSH terms
Resveratrol, Antioxidants, Binding Sites, Binding, Competitive, Cell Cycle, Chromatography, High Pressure Liquid, Coumarins, Coloring Agents, Histidine, Histone Deacetylases, Humans, Kinetics, Models, Chemical, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Rhodamines, Stilbenes, Substrate Specificity, Time Factors, Tumor Suppressor Protein p53, Crystallography, X-Ray, Gene Silencing, Sirtuins, Immunoprecipitation, Sirtuin 1, Sirtuin 2

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review