Sirtuin Catalysis and Regulation*

Sirtuins are a family of NAD+-dependent protein deacetylases/deacylases that dynamically regulate transcription, metabolism, and cellular stress response. Their general positive link with improved health span in mammals, potential regulation of pathways mediated by caloric restriction, and growing links to human disease have spurred interest in therapeutics that target their functions. Here, we review the current understanding of the chemistry of catalysis, biological targets, and endogenous regulation of sirtuin activity. We discuss recent efforts to generate small-molecule regulators of sirtuin activity.

• Publication year

  2012

• Venue

  Journal of Biological Chemistry

• Publication date

  2012-10-18

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1074/jbc.R112.378877PMID 23086947PMCID PMC3522242
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

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  2013cited by this paper
• Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases

  2012cited by this paper
• SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function.

  2012cited by this paper
• The role of sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells

  2012cited by this paper
• Lysine Succinylation and Lysine Malonylation in Histones*

  2012cited by this paper
• The caloric restriction paradigm: Implications for healthy human aging

  2012cited by this paper
• The Bicyclic Intermediate Structure Provides Insights into the Desuccinylation Mechanism of Human Sirtuin 5 (SIRT5)*

  2012cited by this paper
• Thiosuccinyl peptides as Sirt5-specific inhibitors.

  2012cited by this paper
• Azalysine analogues as probes for protein lysine deacetylation and demethylation.

  2012cited by this paper
• SIRT3 Protein Deacetylates Isocitrate Dehydrogenase 2 (IDH2) and Regulates Mitochondrial Redox Status*♦

  2012cited by this paper
• Regulation of Glycolytic Enzyme Phosphoglycerate Mutase-1 by Sirt1 Protein-mediated Deacetylation♦

  2011cited by this paper
• Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction.

  2011cited by this paper
• The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD(+).

  2011cited by this paper
• Structure and Biochemical Functions of SIRT6*

  2011cited by this paper
• SIRT3 and cancer: tumor promoter or suppressor?

  2011cited by this paper
• Methyltransferase Set7/9 regulates p53 activity by interacting with Sirtuin 1 (SIRT1)

  2011cited by this paper
• The First Identification of Lysine Malonylation Substrates and Its Regulatory Enzyme*

  2011cited by this paper
• Peroxisome Proliferator-activated Receptor-γ Coactivator-1α Controls Transcription of the Sirt3 Gene, an Essential Component of the Thermogenic Brown Adipocyte Phenotype*

  2011cited by this paper
• Structure-based design of pseudopeptidic inhibitors for SIRT1 and SIRT2.

  2011cited by this paper
• Structure-based development of novel sirtuin inhibitors

  2011influential reference
• Sirtuin 1 in malignant transformation: friend or foe?

  2011cited by this paper
• Identification of lysine succinylation as a new post-translational modification.

  2011cited by this paper
• Functional Proteomics Establishes the Interaction of SIRT7 with Chromatin Remodeling Complexes and Expands Its Role in Regulation of RNA Polymerase I Transcription*

  2011cited by this paper
• Identification of Macrodomain Proteins as Novel O-Acetyl-ADP-ribose Deacetylases*

  2011cited by this paper
• SIRT1 modulation as a novel approach to the treatment of diseases of aging.

  2011cited by this paper
• Mechanism-based affinity capture of sirtuins.

  2011cited by this paper
• Functional Proteomics Establishes the Interaction of SIRT7 with Chromatin Remodeling Complexes and Expands Its Role in Regulation of RNA Polymerase I Transcription*

  2011cited by this paper
• Pathways and Subcellular Compartmentation of NAD Biosynthesis in Human Cells

  2011cited by this paper
• Dynamic Interplay between Histone H3 Modifications and Protein Interpreters: Emerging Evidence for a “Histone Language”

  2011cited by this paper
• 4-Hydroxynonenal inhibits SIRT3 via thiol-specific modification.

  2011cited by this paper
• SIRT6 Promotes DNA Repair Under Stress by Activating PARP1

  2011cited by this paper
• Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification.

  2011cited by this paper
• Sirt5 Is a NAD-Dependent Protein Lysine Demalonylase and Desuccinylase

  2011influential reference
• SIRT3 substrate specificity determined by peptide arrays and machine learning.

  2011cited by this paper
• CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability

  2011cited by this paper
• Catalysis and Mechanistic Insights into Sirtuin Activation

  2011cited by this paper
• Reversible binding of zinc in Plasmodium falciparum Sir2: structure and activity of the apoenzyme.

  2010cited by this paper
• SIRT1 Activation by Small Molecules

  2010cited by this paper
• Sirt3 mediates reduction of oxidative damage and prevention of age-related hearing loss under caloric restriction.

  2010cited by this paper
• Sirt3-mediated deacetylation of evolutionarily conserved lysine 122 regulates MnSOD activity in response to stress.

  2010cited by this paper
• Sirtuin 3, a New Target of PGC-1α, Plays an Important Role in the Suppression of ROS and Mitochondrial Biogenesis

  2010cited by this paper
• Peptide Arrays Identify Isoform-Selective Substrates for Profiling Endogenous Lysine Deacetylase Activity

  2010cited by this paper
• GAPDH Mediates Nitrosylation of Nuclear Proteins

  2010cited by this paper
• Sirtuin chemical mechanisms.

  2010cited by this paper
• Design of a novel nucleoside analog as potent inhibitor of the NAD+ dependent deacetylase, SIRT2

  2010cited by this paper
• Function and metabolism of sirtuin metabolite O-acetyl-ADP-ribose.

  2010cited by this paper
• Ten years of NAD-dependent SIR2 family deacetylases: implications for metabolic diseases.

  2010cited by this paper
• SIRT 3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation

  2010cited by this paper
• Regulation of Cellular Metabolism by Protein Lysine Acetylation

  2010cited by this paper
• Rise of the Rival

  2010cited by this paper
• Transition state of ADP-ribosylation of acetyllysine catalyzed by Archaeoglobus fulgidus Sir2 determined by kinetic isotope effects and computational approaches.

  2010cited by this paper
• Faculty Opinions recommendation of SIRT1 activation by small molecules: kinetic and biophysical evidence for direct interaction of enzyme and activator.

  2010cited by this paper
• Development and characterization of lysine based tripeptide analogues as inhibitors of Sir2 activity.

  2009cited by this paper
• SIRT3 regulates fatty acid oxidation via reversible enzyme deacetylation

  2009cited by this paper
• Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions

  2009cited by this paper
• Identification and Characterization of Propionylation at Histone H3 Lysine 23 in Mammalian Cells*

  2009cited by this paper
• JNK1 Phosphorylates SIRT1 and Promotes Its Enzymatic Activity

  2009cited by this paper
• Identification and characterization of proteins interacting with SIRT1 and SIRT3: implications in the anti‐aging and metabolic effects of sirtuins

  2009cited by this paper
• Identification of a cell-active non-peptide sirtuin inhibitor containing N-thioacetyl lysine.

  2009cited by this paper
• Nicotinamide phosphoribosyltransferase (Nampt): a link between NAD biology, metabolism, and diseases.

  2009cited by this paper
• AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity

  2009cited by this paper
• SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle.

  2009cited by this paper
• DBC1 is a negative regulator of SIRT1

  2008cited by this paper
• The regulation of SIRT2 function by cyclin-dependent kinases affects cell motility

  2008cited by this paper
• Phosphorylation Regulates SIRT1 Function

  2008cited by this paper
• Structural insights into intermediate steps in the Sir2 deacetylation reaction.

  2008cited by this paper
• Negative regulation of the deacetylase SIRT1 by DBC1

  2008cited by this paper
• Lysine Propionylation and Butyrylation Are Novel Post-translational Modifications in Histones*S

  2007cited by this paper
• Active regulator of SIRT1 cooperates with SIRT1 and facilitates suppression of p53 activity.

  2007cited by this paper
• SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress.

  2007cited by this paper
• Mechanism-based inhibition of Sir2 deacetylases by thioacetyl-lysine peptide.

  2007cited by this paper
• SIRT1 sumoylation regulates its deacetylase activity and cellular response to genotoxic stress

  2007cited by this paper
• Catalytic mechanism of a MYST family histone acetyltransferase.

  2007cited by this paper
• Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

  2007cited by this paper
• Acetyl-lysine Analog Peptides as Mechanistic Probes of Protein Deacetylases*

  2007cited by this paper
• N-Lysine Propionylation Controls the Activity of Propionyl-CoA Synthetase*

  2007cited by this paper
• Sirtuins deacetylate and activate mammalian acetyl-CoA synthetases

  2006cited by this paper
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  2006cited by this paper
• The structural basis of sirtuin substrate affinity.

  2006cited by this paper
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  2006cited by this paper
• Sir2 protein deacetylases: evidence for chemical intermediates and functions of a conserved histidine.

  2006influential reference
• The Structural basis of sirtuin substrate specificity

  2006cited by this paper
• Substrate and functional diversity of lysine acetylation revealed by a proteomics survey.

  2006cited by this paper
• SIRT1 top 40 hits: use of one-bead, one-compound acetyl-peptide libraries and quantum dots to probe deacetylase specificity.

  2006cited by this paper
• Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1.

  2005cited by this paper
• Mechanism of Human SIRT1 Activation by Resveratrol*

  2005cited by this paper
• Substrate-specific Activation of Sirtuins by Resveratrol*

  2005cited by this paper
• Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1.

  2005cited by this paper
• SIRT1 Shows No Substrate Specificity in Vitro*

  2005cited by this paper
• Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1

  2005cited by this paper
• Evolutionarily conserved and nonconserved cellular localizations and functions of human SIRT proteins.

  2005cited by this paper
• Modulation of NF‐κB‐dependent transcription and cell survival by the SIRT1 deacetylase

  2004cited by this paper
• Substrate specificity and kinetic mechanism of the Sir2 family of NAD+-dependent histone/protein deacetylases.

  2004influential reference
• Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin.

  2004cited by this paper
• Calorie Restriction Promotes Mammalian Cell Survival by Inducing the SIRT1 Deacetylase

  2004cited by this paper
• Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan

  2003cited by this paper
• Mechanism of Nicotinamide Inhibition and Transglycosidation by Sir2 Histone/Protein Deacetylases*

  2003cited by this paper
• Structure of a Sir2 enzyme bound to an acetylated p53 peptide.

  2002cited by this paper
• Structural Identification of 2′- and 3′-O-Acetyl-ADP-ribose as Novel Metabolites Derived from the Sir2 Family of β-NAD+-dependent Histone/Protein Deacetylases* 210

  2002cited by this paper
• Chemistry of gene silencing: the mechanism of NAD+-dependent deacetylation reactions.

  2001influential reference

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  2026cites this paper
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• Gut microbiota and epigenetic inheritance: implications for the development of IBD

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• Mechanistic basis of N-terminal domain-mediated allostery in SIRT6: integrating molecular dynamics simulations and biochemical assays.

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• Structural Insights Into centSIRT6: Bioinformatic Analysis of N308K and A313S Substitution Effects

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• Identification of 1-O-Galloyl -β-D-glucose as a potent activator of Sirtuin-1: an in-silico study.

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• The curious case of mitochondrial sirtuin in rewiring breast cancer metabolism: Mr Hyde or Dr Jekyll?

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• Epigenetic Drugs against Human DNA Viruses and Retroviruses.

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• Current Trends in Sirtuin Activator and Inhibitor Development

  2024cites this paper
• SIRT3 Activation a Promise in Drug Development? New Insights into SIRT3 Biology and Its Implications on the Drug Discovery Process

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  2024cites this paper
• The Structures, Functions, and Roles of Class III HDACs (Sirtuins) in Neuropsychiatric Diseases

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• The Enigmatic Role of SIRT2 in the Cardiovascular System: Deciphering its Protective and Detrimental Actions to Unlock New Avenues for Therapeutic Intervention.

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  2024cites this paper
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• Inhibition of Sirtuin Deacylase Activity by Peroxynitrite.

  2024cites this paper
• Drugs Targeting Sirtuin 2 Exhibit Broad-Spectrum Anti-Infective Activity

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  2024cites this paper
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  2024cites this paper
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  2024cites this paper
• Chronotherapeutic and Epigenetic Regulation of Circadian Rhythms: Nicotinamide Adenine Dinucleotide-Sirtuin Axis

  2024cites this paper
• SIRT-Associated Attenuation of Cellular Senescence in Vascular Wall.

  2024cites this paper
• The SIRT-1/Nrf2/HO-1 Axis: Guardians of Neuronal Health in Neurological Disorders.

  2024cites this paper
• BubR1 and SIRT2: Insights into Aneuploidy, Aging, and Cancer.

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  2024cites this paper
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  2024cites this paper
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  2024cites this paper
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  2023cites this paper
• Nicotinamide Adenine Dinucleotide (NAD+)-Dependent Signaling in Neurological Disorders

  2023cites this paper
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  2023cites this paper
• Epigenetic Regulation in Oral Squamous Cell Carcinoma Microenvironment: A Comprehensive Review

  2023cites this paper
• Discussion on structure classification and regulation function of histone deacetylase and their inhibitor

  2023cites this paper
• The Role of Sirtuin 1 (SIRT1) in Neurodegeneration

  2023cites this paper
• Bioluminescence Assay of Lysine Deacylase Sirtuin Activity

  2023cites this paper
• An allosteric inhibitor of sirtuin 2 deacetylase activity exhibits broad-spectrum antiviral activity

  2023cites this paper
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  2023cites this paper
• Diosgenin attenuates non-alcoholic fatty liver disease in type 2 diabetes through regulating SIRT6-related fatty acid uptake.

  2023cites this paper
• Natural Phytochemicals as SIRT Activators—Focus on Potential Biochemical Mechanisms

  2023cites this paper
• Premature senescence and cardiovascular disease following cancer treatments: mechanistic insights

  2023cites this paper
• NAD+, Axonal Maintenance, and Neurological Disease

  2023cites this paper
• Epigenetic Reprogramming of the Glucose Metabolic Pathways by the Chromatin Effectors During Cancer.

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• LncRNA DLEU2 regulates sirtuins and mitochondrial respiratory chain complex IV: a novel pathway in obesity and offspring’s health

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  2022cites this paper
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  2022cites this paper
• Identification and molecular modeling of novel endogenous activator proteins of Sirt-1: an in silico study

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• Metabolic Control of Germline Formation and Differentiation in Mammals

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• Sirtuins promote brain homeostasis, preventing Alzheimer’s disease through targeting neuroinflammation

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• Prediction and confirmation of a switch-like region within the N-terminal domain of hSIRT1

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  2022cites this paper
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  2022cites this paper
• Cancer treatment-induced NAD+ depletion in premature senescence and late cardiovascular complications

  2022cites this paper
• The impact of diet upon mitochondrial physiology (Review)

  2022cites this paper
• Decylubiquinone Inhibits Colorectal Cancer Growth Through Upregulating Sirtuin2

  2022cites this paper
• Assays to Study Enzymatic and Non‐Enzymatic Protein Lysine Acetylation In Vitro

  2021cites this paper
• Regulation of SIRT2 by Wnt/β-catenin signaling pathway in colorectal cancer cells.

  2021cites this paper
• Post-translational Lysine Ac(et)ylation in Bacteria: A Biochemical, Structural, and Synthetic Biological Perspective

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• Sirtuin Oxidative Post-translational Modifications

  2021cites this paper
• Emerging roles of Sirtuin 2 in cardiovascular diseases

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• Sirtuin Modulators in Cellular and Animal Models of Human Diseases

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• SIRT4 is an early regulator of branched-chain amino acid catabolism that promotes adipogenesis.

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• SIRT6 transcriptionally regulates fatty acid transport by suppressing PPARγ

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• An amber obligate active site-directed ligand evolution technique for phage display

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