title: Evidence for a common mechanism of SIRT1 regulation by allosteric activators.
abstract: A molecule that treats multiple age-related diseases would have a major impact on global health and economics. The SIRT1 deacetylase has drawn attention in this regard as a target for drug design. Yet controversy exists around the mechanism of sirtuin-activating compounds (STACs). We found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT1 activation by STACs. A single amino acid in SIRT1, Glu(230), located in a structured N-terminal domain, was critical for activation by all previously reported STAC scaffolds and a new class of chemically distinct activators. In primary cells reconstituted with activation-defective SIRT1, the metabolic effects of STACs were blocked. Thus, SIRT1 can be directly activated through an allosteric mechanism common to chemically diverse STACs.
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Basil P
authors.initials: BP
authors.lastname: Hubbard
authors.forename: Ana P
authors.initials: AP
authors.lastname: Gomes
authors.forename: Han
authors.initials: H
authors.lastname: Dai
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: April W
authors.initials: AW
authors.lastname: Case
authors.forename: Thomas
authors.initials: T
authors.lastname: Considine
authors.forename: Thomas V
authors.initials: TV
authors.lastname: Riera
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Lee
authors.forename: Sook Yen
authors.initials: SY
authors.lastname: E
authors.forename: Dudley W
authors.initials: DW
authors.lastname: Lamming
authors.forename: Bradley L
authors.initials: BL
authors.lastname: Pentelute
authors.forename: Eli R
authors.initials: ER
authors.lastname: Schuman
authors.forename: Linda A
authors.initials: LA
authors.lastname: Stevens
authors.forename: Alvin J Y
authors.initials: AJ
authors.lastname: Ling
authors.forename: Sean M
authors.initials: SM
authors.lastname: Armour
authors.forename: Shaday
authors.initials: S
authors.lastname: Michan
authors.forename: Huizhen
authors.initials: H
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Jiang
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Sweitzer
authors.forename: Charles A
authors.initials: CA
authors.lastname: Blum
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Disch
authors.forename: Pui Yee
authors.initials: PY
authors.lastname: Ng
authors.forename: Konrad T
authors.initials: KT
authors.lastname: Howitz
authors.forename: Anabela P
authors.initials: AP
authors.lastname: Rolo
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Hamuro
authors.forename: Joel
authors.initials: J
authors.lastname: Moss
authors.forename: Robert B
authors.initials: RB
authors.lastname: Perni
authors.forename: James L
authors.initials: JL
authors.lastname: Ellis
authors.forename: George P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
mesh_terms: D000494:Allosteric Regulation; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D002478:Cells, Cultured; D004789:Enzyme Activation; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics; D018698:Glutamic Acid / Q000737:chemistry / Q000235:genetics; D006576:Heterocyclic Compounds, 4 or More Rings / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D051379:Mice; D008969:Molecular Sequence Data; D032446:Myoblasts / Q000187:drug effects / Q000201:enzymology; D017434:Protein Structure, Tertiary; D000077185:Resveratrol; D056564:Sirtuin 1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D006576:Heterocyclic Compounds, 4 or More Rings; C525424:SRT1460; D013267:Stilbenes; D018698:Glutamic Acid; D056564:Sirtuin 1; D000077185:Resveratrol