title: A molecular mechanism for direct sirtuin activation by resveratrol.
abstract: Sirtuins are protein deacetylases regulating metabolism, stress responses, and aging processes, and they were suggested to mediate the lifespan extending effect of a low calorie diet. Sirtuin activation by the polyphenol resveratrol can mimic such lifespan extending effects and alleviate metabolic diseases. The mechanism of Sirtuin stimulation is unknown, hindering the development of improved activators. Here we show that resveratrol inhibits human Sirt3 and stimulates Sirt5, in addition to Sirt1, against fluorophore-labeled peptide substrates but also against peptides and proteins lacking the non-physiological fluorophore modification. We further present crystal structures of Sirt3 and Sirt5 in complex with fluorogenic substrate peptide and modulator. The compound acts as a top cover, closing the Sirtuin's polypeptide binding pocket and influencing details of peptide binding by directly interacting with this substrate. Our results provide a mechanism for the direct activation of Sirtuins by small molecules and suggest that activators have to be tailored to a specific Sirtuin/substrate pair.
authors.affiliation: Department of Biochemistry, University of Bayreuth, Bayreuth, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gertz
authors.forename: Giang Thi Tuyet
authors.initials: GT
authors.lastname: Nguyen
authors.forename: Frank
authors.initials: F
authors.lastname: Fischer
authors.forename: Benjamin
authors.initials: B
authors.lastname: Suenkel
authors.forename: Christine
authors.initials: C
authors.lastname: Schlicker
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fränzel
authors.forename: Jana
authors.initials: J
authors.lastname: Tomaschewski
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Aladini
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Dirk
authors.initials: D
authors.lastname: Wolters
authors.forename: Clemens
authors.initials: C
authors.lastname: Steegborn
mesh_terms: D000107:Acetylation / Q000187:drug effects; D031204:Caloric Restriction; D018360:Crystallography, X-Ray; D006801:Humans; D010455:Peptides / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000737:chemistry / Q000378:metabolism; D056566:Sirtuin 3 / Q000737:chemistry / Q000378:metabolism; D037761:Sirtuins / Q000737:chemistry / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D010455:Peptides; D013267:Stilbenes; C447939:SIRT1 protein, human; C466093:SIRT3 protein, human; C508544:SIRT5 protein, human; D056564:Sirtuin 1; D056566:Sirtuin 3; D037761:Sirtuins; D000077185:Resveratrol