Cited by 915Sirtuins and Resveratrol in MedicineHistone Deacetylase Inhibitors ResearchNatural Antidiabetic Agents Studies

SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1

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Pacholec, Michelle, Bleasdale, John E., Chrunyk, Boris, Cunningham, David, Flynn, Declan, Garofalo, Robert S., Griffith, David, Griffor, Matt +9 more·2010·Journal of Biological Chemistry

Abstract

Sirtuins catalyze NAD(+)-dependent protein deacetylation and are critical regulators of transcription, apoptosis, metabolism, and aging. There are seven human sirtuins (SIRT1-7), and SIRT1 has been implicated as a key mediator of the pathways downstream of calorie restriction that have been shown to delay the onset and reduce the incidence of age-related diseases such as type 2 diabetes. Increasing SIRT1 activity, either by transgenic overexpression of the Sirt1 gene in mice or by pharmacological activation by small molecule activators resveratrol and SRT1720, has shown beneficial effects in rodent models of type 2 diabetes, indicating that SIRT1 may represent an attractive therapeutic target. Herein, we have assessed purported SIRT1 activators by employing biochemical assays utilizing native substrates, including a p53-derived peptide substrate lacking a fluorophore as well as the purified native full-length protein substrates p53 and acetyl-CoA synthetase1. SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol do not lead to apparent activation of SIRT1 with native peptide or full-length protein substrates, whereas they do activate SIRT1 with peptide substrate containing a covalently attached fluorophore. Employing NMR, surface plasmon resonance, and isothermal calorimetry techniques, we provide evidence that these compounds directly interact with fluorophore-containing peptide substrates. Furthermore, we demonstrate that SRT1720 neither lowers plasma glucose nor improves mitochondrial capacity in mice fed a high fat diet. SRT1720, SRT2183, SRT1460, and resveratrol exhibit multiple off-target activities against receptors, enzymes, transporters, and ion channels. Taken together, we conclude that SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1.

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Crossref · 10.1074/jbc.m109.088682

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  • Resveratrol may not directly activate SIRT1 but acts through AMPK, though direct SIRT1 activation is not fully excluded.

    “Recently, it was shown, however, that resveratrol may not activate SIRT1 directly (Beher et al., 2009; Pacholec et al., 2010), but rather exerts its effects on SIRT1 through activation of AMPK (Baur et al., 2006; Canto et al., 2009; Canto et al., 2010; Feige et al., 2008; Hawley et al., 2010; Um et al., 2010), although additional direct SIRT1 activation is not completely excluded (Dai et al., 2010”

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Authors
Pacholec, M., Bleasdale, J. E., Chrunyk, B., Cunningham, D., Flynn, D., Garofalo, R. S., Griffith, D., Griffor, M., Loulakis, P., Pabst, B., Qiu, X., Stockman, B., Thanabal, V., Varghese, A., Ward, J., Withka, J., & Ahn, K.
Affiliations
Pfizer (United States) (US)
Corresponding author
Ahn, Kay
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2010-03
Volume
285
Issue
11
Pages
8340-8351
ISSN
0021-9258 (ISSN-L)
OpenAlex
W2157860216
Cited by
915
References
48
Citations by year
2026: 31 · 2025: 22 · 2024: 20 · 2023: 19 · 2022: 31 · 2021: 42 · 2020: 55 · 2019: 36 · 2018: 37 · 2017: 40 · 2016: 65 · 2015: 69 · 2014: 74 · 2013: 80 · 2012: 99
FWCI
49.03
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Natural Antidiabetic Agents Studies
Keywords
SIRT1, sirtuin activators, SRT1720, resveratrol, p53, off-target effects, high-fat diet, type 2 diabetes, mitochondrial capacity, plasma glucose
MeSH terms
Resveratrol, Acetylation, Allosteric Regulation, Animals, Blood Glucose, Calorimetry, Diabetes Mellitus, Type 2, Dietary Fats, Enzyme Activation, Enzyme Inhibitors, Heterocyclic Compounds, 4 or More Rings, Humans, Mice, Obese, Rhodamines, Stilbenes, Substrate Specificity, Tumor Suppressor Protein p53, Nuclear Magnetic Resonance, Biomolecular, Surface Plasmon Resonance, Mice, Sirtuin 1

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