Open Access
Evidence for a Common Mechanism of SIRT1 Regulation by Allosteric Activators
Basil P. Hubbard,Ana P. Gomes,Han Dai,Jun Li,April Case,Thomas Considine,Thomas V. Riera,Jessica E. Lee,E. Sook Yen,Dudley W. Lamming,Eli Schuman,Linda Stevens,Alvin J. Y. Ling,Sean M. Armour,Shaday Michan,Huizhen Zhao,Yong Jiang,Sharon Sweitzer,Charles A. Blum,Jeremy S. Disch,Pui Yee Ng,Konrad T. Howitz,Anabela P. Rolo,Yoshitomo Hamuro,Joel Moss,Robert B. Perni,James L. Ellis,George P. Vlasuk,David A. Sinclair,Bradley L. Pentelute +29 more
TLDR
Yuan et al. as mentioned in this paper found that specific hydrophobic motifs found in SIRT1 substrates such as PGC-1α and FOXO3a facilitate SIRT 1 activation by STACs.Abstract:
It's a SIRT Intense attention has focused on the SIRT1 deacetylase as a possible target for anti-aging drugs. But unexpected complications in assays of SIRT1 activity have made it unclear whether compounds thought to be sirtuin-activating compounds (STACs) are really direct regulators of the enzyme. Further exploration of these effects by Hubbard et al. (p. 1216; see the Perspective by Yuan and Marmorstein) revealed that interaction of SIRT1 with certain substrates allows activation of SIRT1 by STACs and identified critical amino acids in SIRT1 required for these effects. Mouse myoblasts reconstituted with SIRT1 mutated at this amino acid lost their responsiveness to STACs. An interaction of the deacetylase SIRT1 with its substrate offers a possible explanation for some effects on aging. [Also see Perspective by Yuan and Marmorstein] 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, Glu230, 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.read more
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疟原虫var基因转换速率变化导致抗原变异[英]/Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A
TL;DR: PfPMP1)与感染红细胞、树突状组胞以及胎盘的单个或多个受体作用,在黏附及免疫逃避中起关键的作�ly.
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Phenolics and polyphenolics in foods, beverages and spices: Antioxidant activity and health effects – A review
TL;DR: A review of phenolic and polyphenolic compounds can be found in this article, which summarizes both the synthetic and natural phenolic antioxidants, emphasizing their mode of action, health effects, degradation products and toxicology.
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Declining NAD + Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging
Ana P. Gomes,Ana P. Gomes,Nathan L. Price,Alvin J. Y. Ling,Javid Moslehi,Magdalene K. Montgomery,Luis A. Rajman,James P. White,João S. Teodoro,Christiane D. Wrann,Basil P. Hubbard,Evi M. Mercken,Carlos M. Palmeira,Rafael de Cabo,Anabela P. Rolo,Nigel Turner,Eric L. Bell,David A. Sinclair,David A. Sinclair +18 more
TL;DR: It is shown that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits, and an alternate PGC-1α/β-independent pathway of nuclear-mitochondrial communication contributes to the decline in mitochondrial function with age.
SIRT1 and other sirtuins in metabolism
Hung-Chun Chang,Leonard Guarente +1 more
TL;DR: This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.
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50 years of protein acetylation: from gene regulation to epigenetics, metabolism and beyond
Eric Verdin,Melanie Ott +1 more
TL;DR: Progress accomplished during the past 50 years of histone acetyltransferases, histone deacetylases and acetyl-Lys-binding proteins, and the future of protein acetylation are reviewed.
References
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Journal ArticleDOI
Mechanism of Human SIRT1 Activation by Resveratrol
TL;DR: It is proposed that binding of resveratrol to SIRT1 promotes a conformational change that better accommodates the attached coumarin group.
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SRT1720, SRT2183, SRT1460, and Resveratrol Are Not Direct Activators of SIRT1
Michelle Pacholec,John E. Bleasdale,Boris A. Chrunyk,David Cunningham,Declan Flynn,Robert S. Garofalo,David A. Griffith,Matt Griffor,Pat Loulakis,Brandon Pabst,Xiayang Qiu,Brian J. Stockman,Venkataraman Thanabal,Alison H. Varghese,Jessica Ward,Jane M. Withka,Kay Ahn +16 more
TL;DR: It is concluded that SRT1720, its structurally related compounds SRT2183 and SRT1460, and resveratrol are not direct activators of SIRT1, which exhibits multiple off-target activities against receptors, enzymes, transporters, and ion channels.
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Human SirT1 Interacts with Histone H1 and Promotes Formation of Facultative Heterochromatin
Alejandro Vaquero,Michael Scher,Donghoon Lee,Hediye Erdjument-Bromage,Paul Tempst,Danny Reinberg +5 more
TL;DR: A model for SirT1-mediated heterochromatin formation is proposed that includes deacetylation of histone tails, recruitment and deacetolation of Histone H1, and spreading of hypomethylated H3-K79 with resultant silencing.
Journal ArticleDOI
Substrate-specific Activation of Sirtuins by Resveratrol
Matt Kaeberlein,Thomas McDonagh,Birgit Heltweg,Jeffrey Hixon,Eric A. Westman,Seth D. Caldwell,Andrew Napper,Rory A. J. Curtis,Peter S. DiStefano,Stanley Fields,Antonio Bedalov,Antonio Bedalov,Brian K. Kennedy +12 more
TL;DR: It is shown here that resveratrol is a substrate-specific activator of yeast Sir2 and human SirT1 and that in three different yeast strain backgrounds, resver atrol has no detectable effect on Sir2 activity in vivo, as measured by rDNA recombination, transcriptional silencing near telomeres, and life span.
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SIRT1 Modulation of the Acetylation Status, Cytosolic Localization, and Activity of LKB1 POSSIBLE ROLE IN AMP-ACTIVATED PROTEIN KINASE ACTIVATION
TL;DR: The results suggest that LKB1 deacetylation is regulated by SIRT1 and that this in turn influences its intracellular localization, association with STRAD, kinase activity, and ability to activate AMPK.