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
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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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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
The Biochemistry of Sirtuins
TL;DR: The chemical mechanism of sirtuins provides novel opportunities for signaling and metabolic regulation of protein deacetylation and the biological, chemical, and structural characteristics of these unusual enzymes are discussed.
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CBP/p300-mediated acetylation of histone H3 on lysine 56.
TL;DR: It is shown that, in response to DNA damage, histones bearing acetylated K56 are assembled into chromatin in Drosophila and human cells, forming foci that colocalize with sites of DNA repair.
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The SIRT1 Deacetylase Suppresses Intestinal Tumorigenesis and Colon Cancer Growth
Ron Firestein,Gil Blander,Shaday Michan,Philipp Oberdoerffer,Shuji Ogino,Shuji Ogino,Jennifer Campbell,Anupama Bhimavarapu,Sandra Luikenhuis,Rafael de Cabo,Charles S. Fuchs,William C. Hahn,Leonard Guarente,David A. Sinclair +13 more
TL;DR: It is shown that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of Sirt1 in a β-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR.
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Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity
TL;DR: It is concluded that the pharmacological effects of resveratrol in various models are unlikely to be mediated by a direct enhancement of the catalytic activity of the SIRT1 enzyme.
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Sirtuins mediate mammalian metabolic responses to nutrient availability
TL;DR: The latest advances in the understanding of the function of sirtuins as regulators of mammalian metabolism are described and the role of these enzymes as mediators of nutrient availability is focused on.