Sirtuin

Sirtuin From Wikipedia, the free encyclopedia Jump to navigationJump to search Sir2 family 1SZD.png Crystallographic structure of yeast sir2 (rainbow colored cartoon, N-terminus = blue, C-terminus = red) complexed with ADP (space-filling model, carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange) and a histone H4 peptide (magenta) containing an acylated lysine residue (displayed as spheres).[1] Identifiers Symbol SIR2 Pfam PF02146 Pfam clan CL0085 InterPro IPR003000 PROSITE PS50305 SCOP2 1j8f / SCOPe / SUPFAM Available protein structures: Sirtuins are a family of signaling proteins involved in metabolic regulation.[2][3] They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life.[2] Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity.[4][5][6] The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2',[7] the gene responsible for cellular regulation in yeast. From in vitro studies, sirtuins are implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation[8] and stress resistance, as well as energy efficiency and alertness during low-calorie situations.[9] As of 2018, there was no clinical evidence that sirtuins affect human aging.[10] Yeast Sir2 and some, but not all, sirtuins are protein deacetylases. Unlike other known protein deacetylases, which simply hydrolyze acetyl-lysine residues, the sirtuin-mediated deacetylation reaction couples lysine deacetylation to NAD+ hydrolysis.[11] This hydrolysis yields O-acetyl-ADP-ribose, the deacetylated substrate and nicotinamide, which is an inhibitor of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to nicotinamide (NAM).[12] The dependence of sirtuins on NAD+ links their enzymatic activity directly to the energy status of the cell via the cellular NAD+:NADH ratio, the absolute levels of NAD+, NADH or NAM or a combination of these variables. Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of histone deacetylases (classes I, IIA, IIB and IV), which have a different protein fold and use Zn2+ as a cofactor.[13][14] Contents 1 Actions and species distribution 2 History 3 Types 4 Aging 5 Tissue fibrosis 6 DNA repair 7 Inhibitors 8 Activators 9 See also 10 References 11 External links Actions and species distribution Sirtuins are a family of signaling proteins involved in metabolic regulation.[2][3] They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life.[2] Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, sir2 is the name of one of the sirtuin-type proteins (see table below).[15] Mammals possess seven sirtuins (SIRT1–7) that occupy different subcellular compartments: SIRT1, SIRT6 and SIRT7 are predominantly in the nucleus, SIRT2 in the cytoplasm, and SIRT3, SIRT4 and SIRT5 in the mitochondria.[2] History Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT.[16][17] Interest in the metabolism of NAD+ heightened after the year 2000 discovery by Shin-ichiro Imai and coworkers in the Guarente laboratory that sirtuins are NAD+-dependent protein deacetylases .[18] Types This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. Find sources: "Sirtuin" – news · newspapers · books · scholar · JSTOR (November 2019) (Learn how and when to remove this template message) The first sirtuin was identified in yeast (a lower eukaryote) and named sir2. In more complex mammals, there are seven known enzymes that act in cellular regulation, as sir2 does in yeast. These genes are designated as belonging to different classes (I-IV), depending on their amino acid sequence structure.[19] Several gram positive prokaryotes as well as the gram negative hyperthermophilic bacterium Thermotoga maritima possess sirtuins that are intermediate in sequence between classes, and these are placed in the "undifferentiated" or "U" class. In addition, several Gram positive bacteria, including Staphylococcus aureus and Streptococcus pyogenes, as well as several fungi carry macrodomain-linked sirtuins (termed "class M" sirtuins).[6] Class Subclass Species Intracellular location Activity Function Bacteria Yeast Mouse Human I a Sir2 or Sir2p, Hst1 or Hst1p Sirt1 SIRT1 Nucleus, cytoplasm Deacetylase Metabolism inflammation b Hst2 or Hst2p Sirt2 SIRT2 Nucleus and cytoplasm Deacetylase Cell cycle, tumorigenesis Sirt3 SIRT3 Mitochondria Deacetylase Metabolism c Hst3 or Hst3p, Hst4 or Hst4p II Sirt4 SIRT4 Mitochondria ADP-ribosyl transferase Insulin secretion III Sirt5 SIRT5 Mitochondria Demalonylase, desuccinylase and deacetylase Ammonia detoxification IV a Sirt6 SIRT6 Nucleus Demyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylase DNA repair, metabolism, TNF secretion b Sirt7 SIRT7 Nucleolus Deacetylase rRNA transcription U cobB[20] Regulation of acetyl-CoA synthetase[21] metabolism M SirTM[6] ADP-ribosyl transferase ROS detoxification SIRT3, a mitochondrial protein deacetylase, plays a role in the regulation of multiple metabolic proteins like isocitrate dehydrogenase of the TCA cycle. It also plays a role in skeletal muscle as a metabolic adaptive response. Since glutamine is a source of a-ketoglutarate used to replenish the TCA cycle, SIRT4 is involved in glutamine metabolism.[22] Aging Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1,[23] led some scientists to speculate that resveratrol may extend lifespan, there was no clinical evidence for such an effect, as of 2018.[10] Tissue fibrosis This section needs more medical references for verification or relies too heavily on primary sources. Please review the contents of the section and add the appropriate references if you can. Unsourced or poorly sourced material may be challenged and removed. Find sources: "Sirtuin" – news · newspapers · books · scholar · JSTOR (November 2019) Rod of Asclepius2.svg A 2018 review indicated that SIRT levels are lower in tissues from people with scleroderma, and such reduced SIRT levels may increase risk of fibrosis through modulation of the TGF-β signaling pathway.[24] DNA repair SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair.[25] SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks.[26] SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage.[27] SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.[27] In addition, SIRT6 promotes the repair of DNA double-strand breaks.[28] Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.[29] SIRT7 knockout mice display features of premature aging.[30] SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining.[30] Inhibitors Sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site.[31] Activators This section may require cleanup to meet Wikipedia's quality standards. The specific problem is: French. Please help improve this section if you can. (April 2022) (Learn how and when to remove this template message) List of known sirtuin activator in vitro Compound Target/Specificity References Piceatannol SIRT1 [32] SRT1720 (paeonol) SIRT1 [32] SRT2104 SIRT1 [32] β-Lapachone SIRT1 [32] Cilostazol SIRT1 [32] Cyanidine and Oligomeric proanthocyanidins (OPC) SIRT6 [33] Quercétine and rutin derivatives SIRT6 [33] Luteolin SIRT6 [33] Catechin and Epicatechins SIRT6 [33] Fisétine SIRT6 [33] Phenolic acids SIRT6 [33] Fucoidan SIRT6 [34] Curcumin SIRT1, SIRT6 [35] Pirfenidone SIRT1 [36] Myricetin SIRT6 [33] Cyanidin SIRT6 [33] Delphinidin SIRT6 [33] apigenin SIRT6 [33] buteine SIRT6 [37] Isoliquiritigenin SIRT6 [37] Ferulic acid SIRT1 [37] Berberine SIRT1 [37] Catechine SIRT1 [37] Malvidine SIRT1 [37] Pterostilbene SIRT1 [37] tyrosol SIRT1 [37] See also Biological immortality Histone deacetylases or HDACs Trichostatin A References PDB: 1szd​; Zhao K, Harshaw R, Chai X, Marmorstein R (June 2004). 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External links Sirtuins at the US National Library of Medicine Medical Subject Headings (MeSH) vte Hydrolases: carbon-nitrogen non-peptide (EC 3.5) vte Transferases: glycosyltransferases (EC 2.4) vte Intracellular signaling peptides and proteins Authority control: National libraries Edit this at Wikidata Czech Republic Categories: EnzymesAging-related enzymesAging-related proteins Navigation menu Not logged in Talk Contributions Create account Log in ArticleTalk ReadEditView history Search Search Wikipedia Main page Contents Current events Random article About Wikipedia Contact us Donate Contribute Help Learn to edit Community portal Recent changes Upload file Tools What links here Related changes Special pages Permanent link Page information Cite this page Wikidata item Print/export Download as PDF Printable version Languages Deutsch Español فارسی Français 한국어 Italiano 日本語 Português Русский 6 more Edit links This page was last edited on 11 April 2022, at 11:03 (UTC). 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