Small-Molecule Allosteric Activators of Sirtuins

Sinclair, David A.; Guarente, Leonard

doi:10.1146/annurev-pharmtox-010611-134657

Cited by 196 publications

(162 citation statements)

References 128 publications

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“…Resveratrol, a phytochemical, is a naturally occurring antioxidant and free radical scavenger. During the past decade, investigators have demonstrated that the sirtuin family of proteins, especially sirtuin 1 (SIRT1), are among the intracellular targets for resveratrol (31), although other targets are also described (32,33). Our previously published study demonstrated augmented expression of SIRT1 in rats subjected to trauma and severe hemorrhage and treated with resveratrol (23).…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

Ayub

Poulose

Raju

2015

Mol Med

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Resveratrol has been shown to potentiate mitochondrial function and extend longevity; however, there is no evidence to support whether resveratrol can improve survival or prolong life following hemorrhagic shock. We sought to determine whether (a) resveratrol can improve survival following hemorrhage and resuscitation and (b) prolong life in the absence of resuscitation. Using a hemorrhagic injury (HI) model in the rat, we describe for the first time that the naturally occurring small molecule, resveratrol, may be an effective adjunct to resuscitation fluid. In a series of three sets of experiments we show that resveratrol administration during resuscitation improves survival following HI (p < 0.05), resveratrol and its synthetic mimic SRT1720 can significantly prolong life in the absence of resuscitation fluid (<30 min versus up to 4 h; p < 0.05), and resveratrol as well as SRT1720 restores left ventricular function following HI. We also found significant changes in the expression level of mitochondria-related transcription factors Ppar-α and Tfam, as well as Pgc-1α in the left ventricular tissues of rats subjected to HI and treated with resveratrol. The results indicate that resveratrol is a strong candidate adjunct to resuscitation following severe hemorrhage.

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Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

Ayub

Poulose

Raju

2015

Mol Med

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“…2 There is growing consensus that the induction of autophagy by nutritional, pharmacological or genetic interventions can reduce age-related pathologies (such as neurodegenerative diseases or type 2 diabetes) and/or extend longevity. [3][4][5][6] This applies to caloric restriction or intermediate fasting, 7 continuous or intermittent medication of rapamycin, [8][9][10] administration of the sirtuin 1-activator resveratrol, 11,12 external supply of the polyamine spermidine, 13 or genetic ablation of p53.…”

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confidence: 99%

Spermidine induces autophagy by inhibiting the acetyltransferase EP300

et al. 2014

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Several natural compounds found in health-related food items can inhibit acetyltransferases as they induce autophagy. Here we show that this applies to anacardic acid, curcumin, garcinol and spermidine, all of which reduce the acetylation level of cultured human cells as they induce signs of increased autophagic flux (such as the formation of green fluorescent protein-microtubuleassociated protein 1A/1B-light chain 3 (GFP-LC3) puncta and the depletion of sequestosome-1, p62/SQSTM1) coupled to the inhibition of the mammalian target of rapamycin complex 1 (mTORC1). We performed a screen to identify the acetyltransferases whose depletion would activate autophagy and simultaneously inhibit mTORC1. The knockdown of only two acetyltransferases (among 43 candidates) had such effects: EP300 (E1A-binding protein p300), which is a lysine acetyltranferase, and NAA20 (N(α)-acetyltransferase 20, also known as NAT5), which catalyzes the N-terminal acetylation of methionine residues. Subsequent studies validated the capacity of a pharmacological EP300 inhibitor, C646, to induce autophagy in both normal and enucleated cells (cytoplasts), underscoring the capacity of EP300 to repress autophagy by cytoplasmic (non-nuclear) effects. Notably, anacardic acid, curcumin, garcinol and spermidine all inhibited the acetyltransferase activity of recombinant EP300 protein in vitro. Altogether, these results support the idea that EP300 acts as an endogenous repressor of autophagy and that potent autophagy inducers including spermidine de facto act as EP300 inhibitors. Macroautophagy (herein referred to as 'autophagy') consist in the sequestration of cytoplasmic material in autophagosomes, followed by their fusion with lysosomes for the bulk degradation of autophagic cargo by lysosomal hydrolases.1 This phenomenon can be measured by following the redistribution of green fluorescent protein-microtubule-associated protein 1A/1B-light chain 3 (GFP-LC3) fusion proteins from a diffuse location to autophagosomes (that results in the formation of the so-called GFP-LC3 'puncta'), the diminution of the overall abundance of autophagic substrates (such as sequestosome-1, p62/SQSTM1), and the stereotyped activation of proautophagic signals (such as the inhibition of the mammalian target of rapamycin complex 1, mTORC1). 2There is growing consensus that the induction of autophagy by nutritional, pharmacological or genetic interventions can reduce age-related pathologies (such as neurodegenerative diseases or type 2 diabetes) and/or extend longevity. [3][4][5][6] This applies to caloric restriction or intermediate fasting, 7 continuous or intermittent medication of rapamycin, [8][9][10] administration of the sirtuin 1-activator resveratrol, 11,12 external supply of the polyamine spermidine, 13 or genetic ablation of p53.14 In all these cases, inhibition of autophagy by deleting or silencing relevant genes abolishes the extension of health span and/or lifespan. [13][14][15][16][17] Moreover, direct induction of autophagy by transgenic expression of autophag...

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“…Much research is focused on the development of novel strategies to activate or inhibit sirtuin function (58,59). Several small molecule compounds were developed to achieve this goal (22, 30, 58, 60 -65).…”

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confidence: 99%

Insights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins

Knyphausen

Boor

Kuhlmann

et al. 2016

Journal of Biological Chemistry

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Sirtuins are NAD؉ -dependent lysine deacylases, regulating a variety of cellular processes. The nuclear Sirt1, the cytosolic Sirt2, and the mitochondrial Sirt3 are robust deacetylases, whereas the other sirtuins have preferences for longer acyl chains. Most previous studies investigated sirtuin-catalyzed deacylation on peptide substrates only. We used the genetic code expansion concept to produce natively folded, site-specific, and lysine-acetylated Sirt1-3 substrate proteins, namely Ras-related nuclear, p53, PEPCK1, superoxide dismutase, cyclophilin D, and Hsp10, and analyzed the deacetylation reaction. Some acetylated proteins such as Ras-related nuclear, p53, and Hsp10 were robustly deacetylated by Sirt1-3. However, other reported sirtuin substrate proteins such as cyclophilin D, superoxide dismutase, and PEPCK1 were not deacetylated. Using a structural and functional approach, we describe the ability of Sirt1-3 to deacetylate two adjacent acetylated lysine residues. The dynamics of this process have implications for the lifetime of acetyl modifications on di-lysine acetylation sites and thus constitute a new mechanism for the regulation of proteins by acetylation. Our studies support that, besides the primary sequence context, the protein structure is a major determinant of sirtuin substrate specificity.

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Small-Molecule Allosteric Activators of Sirtuins

Cited by 196 publications

References 128 publications

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

Resveratrol Improves Survival and Prolongs Life Following Hemorrhagic Shock

Spermidine induces autophagy by inhibiting the acetyltransferase EP300

Insights into Lysine Deacetylation of Natively Folded Substrate Proteins by Sirtuins

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