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Mechanism of Human SIRT1 Activation by Resveratrol
Open accessAbstract
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.
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“In yeast, resveratrol has demonstrated its capacity to extend lifespan, implicating the potential of resveratrol as an anti-aging agent [81] with potential clinical implications.”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [81]
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“A key property of resveratrol is the activation of SIRT1, enhancing SIRT1-dependent cellular processes such as axonal protection, fat mobilization, and inhibition of NFκB-dependent transcription [81].”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [81]
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hSIR2SIRT1 Functions as an NAD-Dependent p53 Deacetylase
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Lagouge, M., Argmann, C., Gerhart-Hines, Z., Meziane, H., Lerin, C., Daussin, F., Messadeq, N., Milne, J., Lambert, P., Elliott, P., et al. (2006) · Cell · doi:10.1016/j.cell.2006.11.013 · Cited by 4,057
Therapeutic potential of resveratrol: the in vivo evidence
Baur, J. A., & Sinclair, D. A. (2006) · Nature Reviews Drug Discovery · doi:10.1038/nrd2060 · Cited by 3,958
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Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases
Park, S. J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A. L., et al. (2012) · Cell · doi:10.1016/j.cell.2012.01.017 · Cited by 1,370
Metadata
- 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
- hybrid
- doi.org
- Licence
- 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
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