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| {{Short description|Enzyme}} | |||
| {{cs1 config|name-list-style=vanc}} | |||
| {{Pfam_box | {{Pfam_box | ||
| | Symbol = SIR2 | | Symbol = SIR2 | ||
| Line 4: | Line 6: | ||
| | image = 1SZD.png | | image = 1SZD.png | ||
| | width = | | width = | ||
| | caption = Crystallographic structure of yeast ] (rainbow colored cartoon, ] = blue, ] = red) complexed with ] (], carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange) and a ] peptide (magenta) containing an acylated lysine residue (displayed as spheres) |
| caption = Crystallographic structure of yeast ] (rainbow colored cartoon, ] = blue, ] = red) complexed with ] (], carbon = white, oxygen = red, nitrogen = blue, phosphorus = orange) and a ] peptide (magenta) containing an acylated lysine residue (displayed as spheres)<ref name="pmid15150415">{{PDB|1szd}}; {{cite journal | vauthors = Zhao K, Harshaw R, Chai X, Marmorstein R | title = Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 101 | issue = 23 | pages = 8563–8 | date = June 2004 | pmid = 15150415 | pmc = 423234 | doi = 10.1073/pnas.0401057101 | bibcode = 2004PNAS..101.8563Z | doi-access = free }}</ref> | ||
| | Pfam = PF02146 | | Pfam = PF02146 | ||
| | Pfam_clan = CL0085 | | Pfam_clan = CL0085 | ||
| Line 17: | Line 19: | ||
| }} | }} | ||
| '''Sirtuins''' are a |
'''Sirtuins''' are a family of ] ]s involved in ].<ref name=Ye2017>{{cite journal |last1=Ye |first1=X |last2=Li |first2=M |last3=Hou |first3=T |last4=Gao |first4=T |last5=Zhu |first5=WG |last6=Yang |first6=Y |title=Sirtuins in glucose and lipid metabolism. |journal=Oncotarget |date=3 January 2017 |volume=8 |issue=1 |pages=1845–1859 |doi=10.18632/oncotarget.12157 |pmid=27659520 |pmc=5352102 |type=Review}}</ref><ref name="pmid17456799">{{cite journal | vauthors = Yamamoto H, Schoonjans K, Auwerx J | title = Sirtuin functions in health and disease | journal = Molecular Endocrinology | volume = 21 | issue = 8 | pages = 1745–55 | date = August 2007 | pmid = 17456799 | doi = 10.1210/me.2007-0079 | doi-access = free }}</ref> They are ancient in animal evolution and appear to possess a ] structure throughout all kingdoms of life.<ref name=Ye2017/> Chemically, sirtuins are a class of proteins that possess either mono-] or ] activity, including deacetylase, ], ], demyristoylase and ] activity.<ref name="pmid22076378">{{cite journal | vauthors = Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H | title = Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase | journal = Science | volume = 334 | issue = 6057 | pages = 806–9 | date = November 2011 | pmid = 22076378 | pmc = 3217313 | doi = 10.1126/science.1207861 | bibcode = 2011Sci...334..806D }}</ref><ref name="pmid23552949">{{cite journal | vauthors = Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H | title = SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine | journal = Nature | volume = 496 | issue = 7443 | pages = 110–3 | date = April 2013 | pmid = 23552949 | pmc = 3635073 | doi = 10.1038/nature12038 | bibcode = 2013Natur.496..110J }}</ref><ref name=":0">{{cite journal | vauthors = Rack JG, Morra R, Barkauskaite E, Kraehenbuehl R, Ariza A, Qu Y, Ortmayer M, Leidecker O, Cameron DR, Matic I, Peleg AY, Leys D, Traven A, Ahel I | title = Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens | journal = Molecular Cell | volume = 59 | issue = 2 | pages = 309–20 | date = July 2015 | pmid = 26166706 | pmc = 4518038 | doi = 10.1016/j.molcel.2015.06.013 }}</ref> The name Sir2 comes from the yeast gene '<u>s</u>ilent mating-type <u>i</u>nformation <u>r</u>egulation <u>2</u>',<ref>{{EntrezGene|23410}}</ref> the gene responsible for cellular regulation in ]. | ||
| From '']'' studies, sirtuins were thought to be implicated in influencing cellular processes like ], ], ], ]<ref name="pmid23325925">{{cite journal | vauthors = Preyat N, Leo O | title = Sirtuin deacylases: a molecular link between metabolism and immunity | journal = Journal of Leukocyte Biology | volume = 93 | issue = 5 | pages = 669–80 | date = May 2013 | pmid = 23325925 | doi = 10.1189/jlb.1112557 | s2cid = 3070941 }}</ref> and stress resistance, as well as energy efficiency and alertness during ].<ref name="pmid20668205">{{cite journal | vauthors = Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, Holtzman DM, Herzog ED, Imai S | title = SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus | journal = The Journal of Neuroscience | volume = 30 | issue = 30 | pages = 10220–32 | date = July 2010 | pmid = 20668205 | pmc = 2922851 | doi = 10.1523/JNEUROSCI.1385-10.2010 }}</ref> As of 2018, there was no ] that sirtuins affect human aging,<ref name="Shetty">{{cite journal | last1=Shetty | first1=Ashok K. | last2=Kodali | first2=Maheedhar | last3=Upadhya | first3=Raghavendra | last4=Madhu | first4=Leelavathi N. | title=Emerging anti-aging strategies - scientific basis and efficacy (Review)| journal=Aging and Disease | volume=9 | issue=6 | pages=1165–1184 | year=2018 | issn=2152-5250 | doi=10.14336/ad.2018.1026 |pmid=30574426|pmc=6284760}}</ref> and a 2022 review criticized researchers who propagate this claim.<ref>{{Cite journal |last=Brenner |first=Charles |date=2022-09-22 |title=Sirtuins are not conserved longevity genes |journal=Life Metabolism |volume=1 |issue=2 |pages=122–133 |doi=10.1093/lifemeta/loac025 |issn=2755-0230 |doi-access=free|pmid=37035412 |pmc=10081735 }}</ref> | |||
| Yeast Sir2 and some, but not all, sirtuins are ]s. Unlike other known protein deacetylases, which simply ] ]-] residues, the sirtuin-mediated deacetylation reaction couples ] ] to ] hydrolysis. This hydrolysis yields O-acetyl-ADP-], the deacetylated substrate and ], which is an ] of sirtuin activity itself. 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 |
Yeast Sir2 and some, but not all, sirtuins are ]s. Unlike other known protein deacetylases, which simply ] ]-] residues, the sirtuin-mediated deacetylation reaction couples ] ] to ]+ hydrolysis.<ref name="pmid32518153">{{cite journal | vauthors=Klein MA, Denu JM | title=Biological and catalytic functions of sirtuin 6 as targets for small-molecule modulators | journal=] | volume=295 | issue=32 | pages=11021–11041 | year=2020 | doi = 10.1074/jbc.REV120.011438| pmc= 7415977 | pmid=32518153| doi-access=free }}</ref> This hydrolysis yields O-acetyl-ADP-], the deacetylated substrate and ], which is an ] of sirtuin activity itself. These proteins utilize NAD+ to maintain cellular health and turn NAD+ to ].<ref>{{cite web|title=NMN vs NR: The Differences Between These 2 NAD+ Precursors|url=https://www.nmn.com/precursors/nmn-vs-nr|access-date=2021-01-04|website=www.nmn.com}}</ref> 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 ] (classes I, IIA, IIB and IV), which have a different protein fold and use Zn<sup>2+</sup> as a ].<ref>{{cite journal | vauthors = Bürger M, Chory J | title = Structural and chemical biology of deacetylases for carbohydrates, proteins, small molecules and histones | journal = Communications Biology | volume = 1 | pages = 217 | date = 2018 | pmid = 30534609 | pmc = 6281622 | doi = 10.1038/s42003-018-0214-4 }}</ref><ref>{{cite journal | vauthors = Marks PA, Xu WS | title = Histone deacetylase inhibitors: Potential in cancer therapy | journal = Journal of Cellular Biochemistry | volume = 107 | issue = 4 | pages = 600–8 | date = July 2009 | pmid = 19459166 | pmc = 2766855 | doi = 10.1002/jcb.22185 }}</ref> | Sirtuins that deacetylate histones are structurally and mechanistically distinct from other classes of ]s (classes I, IIA, IIB and IV), which have a different protein fold and use Zn<sup>2+</sup> as a ].<ref>{{cite journal | vauthors = Bürger M, Chory J | title = Structural and chemical biology of deacetylases for carbohydrates, proteins, small molecules and histones | journal = Communications Biology | volume = 1 | pages = 217 | date = 2018 | pmid = 30534609 | pmc = 6281622 | doi = 10.1038/s42003-018-0214-4 }}</ref><ref>{{cite journal | vauthors = Marks PA, Xu WS | title = Histone deacetylase inhibitors: Potential in cancer therapy | journal = Journal of Cellular Biochemistry | volume = 107 | issue = 4 | pages = 600–8 | date = July 2009 | pmid = 19459166 | pmc = 2766855 | doi = 10.1002/jcb.22185 }}</ref> | ||
| == |
== Actions and species distribution == | ||
| Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, ] is the name of one of the sirtuin-type proteins (see table below).<ref name="pmid15189148">{{cite journal | vauthors = Blander G, Guarente L | title = The Sir2 family of protein deacetylases | journal = Annual Review of Biochemistry | volume = 73 | issue = 1 | pages = 417–35 | year = 2004 | pmid = 15189148 | doi = 10.1146/annurev.biochem.73.011303.073651 |
Sirtuins are a family of signaling proteins involved in metabolic regulation.<ref name=Ye2017/><ref name=pmid17456799/> They are ancient in animal evolution and appear to possess a ] structure throughout all kingdoms of life.<ref name=Ye2017/> Whereas bacteria and archaea encode either one or two sirtuins, eukaryotes encode several sirtuins in their genomes. In yeast, roundworms, and fruitflies, ] is the name of one of the sirtuin-type proteins (see table below).<ref name="pmid15189148">{{cite journal | vauthors = Blander G, Guarente L | title = The Sir2 family of protein deacetylases | journal = Annual Review of Biochemistry | volume = 73 | issue = 1 | pages = 417–35 | year = 2004 | pmid = 15189148 | doi = 10.1146/annurev.biochem.73.011303.073651 | s2cid = 27494475 }}</ref> 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.<ref name="Ye2017" /> | ||
| == History == | |||
| Sirtuin family of proteins possess a ] structure throughout all kingdoms of life.<ref name="Ye2017">{{cite journal |last1=Ye |first1=X |last2=Li |first2=M |last3=Hou |first3=T |last4=Gao |first4=T |last5=Zhu |first5=WG |last6=Yang |first6=Y |title=Sirtuins in glucose and lipid metabolism. |journal=Oncotarget |date=3 January 2017 |volume=8 |issue=1 |pages=1845-1859 |doi=10.18632/oncotarget.12157 |pmid=27659520 |type=Review}}</ref> | |||
| Research on sirtuin protein was started in 1991 by ] of ].<ref name="url_MIT_PR">{{cite web | url = http://www.iht.com/articles/2006/11/08/healthscience/snwonder.php | title = The quest for a way around aging | author = Wade N | date = 2006-11-08 | work = Health & Science | publisher = International Herald Tribune | access-date = 2008-11-30}}</ref><ref name="urlMIT researchers uncover new information about anti-aging gene - MIT News Office">{{cite web | url = http://web.mit.edu/newsoffice/2000/guarente.html | title = MIT researchers uncover new information about anti-aging gene | date = 2000-02-16 | publisher = Massachusetts Institute of Technology, News Office | access-date = 2008-11-30}}</ref> 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 .<ref>{{cite journal |vauthors=Imai S, Armstrong CM, Kaeberlein M, Guarente L |s2cid= 2967911 |title= Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase |journal= Nature |volume= 403 |issue= 6771 |pages= 795–800 |year= 2000 |pmid= 10693811 |doi= 10.1038/35001622 |bibcode= 2000Natur.403..795I}}</ref> | |||
| == Types == | == Types == | ||
| {{more citations needed|section|date=November 2019}} | |||
| 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.<ref name="Frye">{{cite journal | vauthors = Frye RA | title = Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins | journal = Biochemical and Biophysical Research Communications | volume = 273 | issue = 2 | pages = 793–8 | date = July 2000 | pmid = 10873683 | doi = 10.1006/bbrc.2000.3000 }}</ref><ref>{{cite journal | vauthors = Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA | title = Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle | journal = Molecular and Cellular Biology | volume = 23 | issue = 9 | pages = 3173–85 | date = May 2003 | pmid = 12697818 | pmc = 153197 | doi = 10.1128/MCB.23.9.3173-3185.2003 }}</ref> Several Gram positive prokaryotes as well as the Gram negative hyperthermophilic bacterium '']'' possess sirtuins that are intermediate in sequence between classes and these are placed in the "undifferentiated" or "U" class.<ref name="Frye" /> In addition, several Gram positive bacteria, including '']'' and '']'', as well as several fungi carry ]-linked sirtuins (termed "class M" sirtuins).<ref name=":0" /> Most notable, the latter have an altered catalytic residue, which make them exclusive ADP-ribosyl transferases. | |||
| 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.<ref>{{cite journal | vauthors = Dryden SC, Nahhas FA, Nowak JE, Goustin AS, Tainsky MA | title = Role for human SIRT2 NAD-dependent deacetylase activity in control of mitotic exit in the cell cycle | journal = Molecular and Cellular Biology | volume = 23 | issue = 9 | pages = 3173–85 | date = May 2003 | pmid = 12697818 | pmc = 153197 | doi = 10.1128/MCB.23.9.3173-3185.2003 }}</ref> Several gram positive prokaryotes as well as the gram negative hyperthermophilic bacterium '']'' 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 '']'' and '']'', as well as several fungi carry ]-linked sirtuins (termed "class M" sirtuins).<ref name=":0" /> | |||
| {{hatnote|Yeast protein names may also be suffixed with "p" (e.g. Sir2p) to indicate the fact that it is a protein. This table does not use this convention to minimize cross-species confusion.}} | |||
| {| class="wikitable" style="text-align:center" | {| class="wikitable" style="text-align:center" | ||
| |- | |- | ||
| Line 39: | Line 45: | ||
| ! colspan="4" | Species | ! colspan="4" | Species | ||
| ! rowspan="2" | Intracellular<br />location | ! rowspan="2" | Intracellular<br />location | ||
| ! rowspan="2" | Activity | ! rowspan="2" width=250pt| Activity | ||
| ! rowspan="2" | Function | ! rowspan="2" width=150pt| Cellular Function | ||
| ! rowspan="2" |'''Catalytic Domains'''<ref>{{cite journal |last1=Chang |first1=Andrew R. |last2=Ferrer |first2=Christina M. |last3=Mostoslavsky |first3=Raul |date=2020-01-01 |title=SIRT6, a Mammalian Deacylase with Multitasking Abilities |journal=Physiological Reviews |language=en |volume=100 |issue=1 |pages=145–169 |doi=10.1152/physrev.00030.2018 |pmid=31437090|pmc=7002868 |doi-access=free }}</ref> | |||
| ! rowspan="2" |'''Histone Deacetylation Target'''<ref name=":1">{{cite journal |last1=Carafa |first1=Vincenzo |last2=Rotili |first2=Dante |last3=Forgione |first3=Mariantonietta |last4=Cuomo |first4=Francesca |last5=Serretiello |first5=Enrica |last6=Hailu |first6=Gebremedhin Solomon |last7=Jarho |first7=Elina |last8=Lahtela-Kakkonen |first8=Maija |last9=Mai |first9=Antonello |last10=Altucci |first10=Lucia |date=2016-05-25 |title=Sirtuin functions and modulation: from chemistry to the clinic |journal=Clinical Epigenetics |volume=8 |pages=61 |doi=10.1186/s13148-016-0224-3 |issn=1868-7075 |pmc=4879741 |pmid=27226812 |doi-access=free }}</ref> | |||
| ! rowspan="2" |'''Non-Histone Deacetylation Target'''<ref name=":1" /> | |||
| ! rowspan="2" |'''Pathology'''<ref name=":1" /> | |||
| |- | |- | ||
| ! Bacteria || Yeast || Mouse || Human | ! Bacteria || Yeast || Mouse || Human | ||
| |- | |- | ||
| | rowspan="4" | I || a || || Sir2 |
| rowspan="4" | I || a || || Sir2,<br />Hst1 || Sirt1 || ] || Nucleus, cytoplasm || Deacetylase || Metabolism inflammation | ||
| |244-498 (of 766aa) | |||
| |], H1K26ac, ] | |||
| |Hif-1α, Hif-2α, MYC, P53, BRCA1, FOXO3A, MyoD, Ku70, PPARγ, PCAF, Suv39h1, TGFB1, WRN, NBS1 | |||
| |Neurodegenerative diseases, Cancer: acute myeloid leukemia, colon, prostate, ovarian, glioma, breast, melanoma, lung adenocarcinoma | |||
| |- | |- | ||
| | rowspan="2" | b || || Hst2 |
| rowspan="2" | b || || Hst2 || Sirt2 || ] || Nucleus and cytoplasm || Deacetylase || Cell cycle, tumorigenesis | ||
| |65-340 (of 388aa) | |||
| |], ] | |||
| |Tubulin, Foxo3a, EIF5A, P53, G6PD, MYC | |||
| |Neurodegenerative diseases, Cancer: brain tissue, glioma | |||
| |- | |- | ||
| | || || Sirt3 || ] || |
| || || Sirt3 || ] || Mitochondria || Deacetylase || Metabolism | ||
| |126-382 (of 399aa) | |||
| |], H4K14ac | |||
| |SOD2, PDH, IDH2, GOT2, FoxO3a | |||
| |Neurodegenerative diseases, Cancer: B cell chronic lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, breast, gastric | |||
| |- | |- | ||
| | c || || Hst3 |
| c || || Hst3,<br />Hst4 || || || || || | ||
| | | |||
| | | |||
| | | |||
| | | |||
| |- | |- | ||
| | II || || || || Sirt4 || ] || |
| II || || || || Sirt4 || ] || Mitochondria || ADP-ribosyl transferase || Insulin secretion | ||
| |45-314 (of 314aa) | |||
| |Unknown | |||
| |GDH, PDH | |||
| |Cancer: breast, colorectal | |||
| |- | |- | ||
| | style="height:38px" | III || || || || Sirt5 || ] || |
| style="height:38px" | III || || || || Sirt5 || ] || Mitochondria || Demalonylase, desuccinylase and deacetylase || Ammonia detoxification | ||
| |41-309 (of 310aa) | |||
| |Unknown | |||
| |CPS1 | |||
| |Cancer: pancreatic, breast, non-small cell lung carcinoma | |||
| |- | |- | ||
| | rowspan="2" | IV || a || || || Sirt6 || ] || |
| rowspan="2" | IV || a || || || Sirt6 || ] || Nucleus || Demyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylase || DNA repair, metabolism, ] secretion | ||
| |35-274 (of 355aa) | |||
| |], ] | |||
| |Unknown | |||
| |Cancer: breast, colon | |||
| |- | |- | ||
| | b || || || Sirt7 || ] || |
| b || || || Sirt7 || ] || Nucleolus || Deacetylase || ] ] | ||
| |90-331 (of 400aa) | |||
| |H3K18ac | |||
| |Hif-1α, Hif-2α | |||
| |Cancer: liver, testis, spleen, thyroid, breast | |||
| |- | |- | ||
| | U || || ]<ref name="pmid15019790">{{cite journal | vauthors = Zhao K, Chai X, Marmorstein R | title = Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli | journal = Journal of Molecular Biology | volume = 337 | issue = 3 | pages = 731–41 | date = March 2004 | pmid = 15019790 | doi = 10.1016/j.jmb.2004.01.060 }}</ref> | | U || || ]<ref name="pmid15019790">{{cite journal | vauthors = Zhao K, Chai X, Marmorstein R | title = Structure and substrate binding properties of cobB, a Sir2 homolog protein deacetylase from Escherichia coli | journal = Journal of Molecular Biology | volume = 337 | issue = 3 | pages = 731–41 | date = March 2004 | pmid = 15019790 | doi = 10.1016/j.jmb.2004.01.060 }}</ref> | ||
| || || || || || |
|| || || || || Regulation of ] synthetase<ref name="pmid18249170">{{cite journal | vauthors = Schwer B, Verdin E | title = Conserved metabolic regulatory functions of sirtuins | journal = Cell Metabolism | volume = 7 | issue = 2 | pages = 104–12 | date = February 2008 | pmid = 18249170 | doi = 10.1016/j.cmet.2007.11.006 | doi-access = free }}</ref> || metabolism | ||
| | | |||
| | | |||
| | | |||
| | | |||
| |- | |- | ||
| |M | |M | ||
| Line 73: | Line 119: | ||
| |ADP-ribosyl transferase | |ADP-ribosyl transferase | ||
| |ROS detoxification | |ROS detoxification | ||
| | | |||
| | | |||
| | | |||
| | | |||
| |} | |} | ||
| SIRT3, a mitochondrial protein deacetylase, plays a |
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.<ref name = "Choi_2014">{{cite journal | vauthors = Choi JE, Mostoslavsky R | title = Sirtuins, metabolism, and DNA repair | journal = Current Opinion in Genetics & Development | volume = 26 | pages = 24–32 | date = June 2014 | pmid = 25005742 | doi = 10.1016/j.gde.2014.05.005 | pmc = 4254145 }}</ref> | ||
| Since glutamine is a source of a-ketoglutarate used to replenish the TCA cycle, SIRT4 is important for its role in glutamine metabolism.<ref name = "Choi_2014" /> | |||
| == Ageing == | |||
| SIRT6 is shown in previous studies to be a critical epigenetic regulator of glucose metabolism. In a study, mice knockout with SIRT6 showed a fatal hypoglycemic phenotype. This resulted in death in a few weeks after birth and showed that hypoglycemia resulted mainly from increase of glucose uptake in brown adipose tissue and muscle.<ref name = "Choi_2014" /> | |||
| Although preliminary studies with ], an activator of deacetylases such as ],<ref name="Aunan2016">{{cite journal |last1=Aunan |first1=JR |last2=Watson |first2=MM |last3=Hagland |first3=HR |last4=Søreide |first4=K |title=Molecular and biological hallmarks of ageing. |journal=The British Journal of Surgery |date=January 2016 |volume=103 |issue=2 |pages=e29-46 |doi=10.1002/bjs.10053 |pmid=26771470 |s2cid=12847291 |type=Review (in vitro)|doi-access=free }}</ref> led some scientists to speculate that resveratrol may extend lifespan, no ] for such an effect has been discovered, as of 2018.<ref name=Shetty/> | |||
| based on North/Verdin diagram.<ref name="pmid15128440"/> | |||
| == Aging == | |||
| Although preliminary studies with ], a possible ] activator, led some scientists to speculate that resveratrol may extend lifespan, there was no ] for such an effect, as of 2018.<ref name="Shetty">{{cite journal | last=Shetty | first=Ashok K. | last2=Kodali | first2=Maheedhar | last3=Upadhya | first3=Raghavendra | last4=Madhu | first4=Leelavathi N. | title=Emerging anti-aging strategies - scientific basis and efficacy (Review)| journal=Aging and disease | volume=9 | issue=6 | year=2018 | issn=2152-5250 | doi=10.14336/ad.2018.1026 | page=1165|pmid=30574426|pmc=6284760}}</ref> | |||
| A study performed on transgenic mice overexpressing SIRT6, showed an increased lifespan of about 15% in males. The transgenic males displayed lower serum levels of insulin-like growth factor 1 (]) and changes in its metabolism, which may have contributed to the increased lifespan.<ref name="KanfiNaiman2012">{{cite journal | vauthors = Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY | title = The sirtuin SIRT6 regulates lifespan in male mice | journal = Nature | volume = 483 | issue = 7388 | pages = 218–21 | date = February 2012 | pmid = 22367546 | doi = 10.1038/nature10815 | bibcode = 2012Natur.483..218K }}</ref> | |||
| ==Tissue fibrosis== | ==Tissue fibrosis== | ||
| {{more medical citations needed|section|date=November 2019}} | |||
| Along with aging, many organs in the body have the same molecular mechanisms. These organs include the heart, vascular wall, lungs, kidney, liver, and the skin. Pathways and molecules in tissue fibrosis are regulated by SIRTs. This is the result of a decline in SIRT levels, as well as restoration of SIRT. SIRT elevation protects against aging and tissue fibrosis, however, extreme levels of SIRT are destructive. This elevation is the outcome of the activation of SIRTs. Through regulation of fibrosis-mediating pathways, sirtuins apply antifibrotic effects. It becomes difficult to classify the mechanistic effects of sirtuins because they are diverse. SIRTs interact with specific pathways and intracellular signaling molecules. Some of these pathways and signaling molecules include adenosine monophosphate-activated protein kinase (AMPK)-angiotensin-converting enzyme 2 (ACE2) signaling, manganese superoxide dismutase (MnSOD), mammalian target of rapamycin, and more.<ref>{{cite journal | vauthors = Wyman AE, Atamas SP | title = Sirtuins and Accelerated Aging in Scleroderma | journal = Current Rheumatology Reports | volume = 20 | issue = 4 | pages = 16 | date = March 2018 | pmid = 29550994 | pmc = 5942182 | doi = 10.1007/s11926-018-0724-6 }}</ref> | |||
| A 2018 review indicated that SIRT levels are lower in tissues from people with ], and such reduced SIRT levels may increase risk of ] through modulation of the ] ].<ref>{{cite journal | vauthors = Wyman AE, Atamas SP | title = Sirtuins and accelerated aging in scleroderma | journal = Current Rheumatology Reports | volume = 20 | issue = 4 | pages = 16 | date = March 2018 | pmid = 29550994 | pmc = 5942182 | doi = 10.1007/s11926-018-0724-6 }}</ref> | |||
| ==DNA repair== | ==DNA repair in laboratory studies== | ||
| ], ] and ] proteins are employed in ].<ref name="pmid28406750">{{cite journal | vauthors = Vazquez BN, Thackray JK, Serrano L | title = Sirtuins and DNA damage repair: SIRT7 comes to play | journal = Nucleus | volume = 8 | issue = 2 | pages = 107–115 | date = March 2017 | pmid = 28406750 | pmc = 5403131 | doi = 10.1080/19491034.2016.1264552 }}</ref> SIRT1 protein promotes ] in human cells and is involved in recombinational repair of ] breaks.<ref name="pmid20097625">{{cite journal | vauthors = Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmüller L, Gatz SA | title = Role of SIRT1 in homologous recombination | journal = DNA Repair | volume = 9 | issue = 4 | pages = 383–93 | date = April 2010 | pmid = 20097625 | doi = 10.1016/j.dnarep.2009.12.020 }}</ref> | ], ] and ] proteins are employed in ].<ref name="pmid28406750">{{cite journal | vauthors = Vazquez BN, Thackray JK, Serrano L | title = Sirtuins and DNA damage repair: SIRT7 comes to play | journal = Nucleus | volume = 8 | issue = 2 | pages = 107–115 | date = March 2017 | pmid = 28406750 | pmc = 5403131 | doi = 10.1080/19491034.2016.1264552 }}</ref> SIRT1 protein promotes ] in human cells and is involved in recombinational repair of ] breaks.<ref name="pmid20097625">{{cite journal | vauthors = Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmüller L, Gatz SA | title = Role of SIRT1 in homologous recombination | journal = DNA Repair | volume = 9 | issue = 4 | pages = 383–93 | date = April 2010 | pmid = 20097625 | doi = 10.1016/j.dnarep.2009.12.020 }}</ref> | ||
| SIRT6 is a ]-associated protein and in mammalian cells is required for ] of ].<ref name="pmid16439206">{{cite journal | vauthors = Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW | title = Genomic instability and aging-like phenotype in the absence of mammalian SIRT6 | journal = Cell | volume = 124 | issue = 2 | pages = 315–29 | date = January 2006 | pmid = 16439206 | doi = 10.1016/j.cell.2005.11.044 }}</ref> SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.<ref name="pmid16439206" /> In addition, SIRT6 promotes the repair of DNA double-strand breaks.<ref name="pmid20157594">{{cite journal |
SIRT6 is a ]-associated protein and in mammalian cells is required for ] of ].<ref name="pmid16439206">{{cite journal |display-authors=3| vauthors = Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW | title = Genomic instability and aging-like phenotype in the absence of mammalian SIRT6 | journal = Cell | volume = 124 | issue = 2 | pages = 315–29 | date = January 2006 | pmid = 16439206 | doi = 10.1016/j.cell.2005.11.044 | s2cid = 18517518 | doi-access = free }}</ref> SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.<ref name="pmid16439206" /> In addition, SIRT6 promotes the repair of DNA double-strand breaks.<ref name="pmid20157594">{{cite journal|display-authors=3| vauthors = McCord RA, Michishita E, Hong T, Berber E, Boxer LD, Kusumoto R, Guan S, Shi X, Gozani O, Burlingame AL, Bohr VA, Chua KF | title = SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair | journal = Aging | volume = 1 | issue = 1 | pages = 109–21 | date = January 2009 | pmid = 20157594 | pmc = 2815768 | doi = 10.18632/aging.100011 }}</ref> Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.<ref name="pmid22753495">{{cite journal | vauthors = Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A | title = Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 29 | pages = 11800–5 | date = July 2012 | pmid = 22753495 | pmc = 3406824 | doi = 10.1073/pnas.1200583109 | bibcode = 2012PNAS..10911800M | doi-access = free }}</ref> | ||
| SIRT7 knockout mice display features of ].<ref name="pmid27225932">{{cite journal | |
SIRT7 knockout mice display features of ].<ref name="pmid27225932">{{cite journal |display-authors=3|vauthors = Vazquez BN, Thackray JK, Simonet NG, Kane-Goldsmith N, Martinez-Redondo P, Nguyen T, Bunting S, Vaquero A, Tischfield JA, Serrano L | title = SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair | journal = The EMBO Journal | volume = 35 | issue = 14 | pages = 1488–503 | date = July 2016 | pmid = 27225932 | pmc = 4884211 | doi = 10.15252/embj.201593499 }}</ref> SIRT7 protein is required for repair of double-strand breaks by ].<ref name="pmid27225932" /> | ||
| These findings suggest that SIRT1, SIRT6 and SIRT7 facilitate DNA repair and that this repair slows the aging process (see ]). | |||
| == Inhibitors == | == Inhibitors == | ||
| Certain sirtuin activity is inhibited by ], which binds to a specific receptor site.<ref name="pmid15780941">{{cite journal | vauthors = Avalos JL, Bever KM, Wolberger C | title = Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme | journal = Molecular Cell | volume = 17 | issue = 6 | pages = 855–68 | date = March 2005 | pmid = 15780941 | doi = 10.1016/j.molcel.2005.02.022 | doi-access = free }}</ref> It is an inhibitor in vitro of SIRT1, but can be a stimulator in cells.<ref name=“pmid28417163”>{{cite journal | vauthors = Hwang ES, Song SB | title = Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells | journal = Cell Mol Life Sci | volume = 74 | issue = 18 | pages = 3347–3362 | date = September 2017 | pmid = 28417163 | doi = 10.1007/s00018-017-2527-8 | doi-access = free | pmc = 11107671 }}</ref> | |||
| == Activators == | |||
| {| class="wikitable sortable" | |||
| |+ List of known sirtuin activator ''in vitro'' | |||
| |- | |||
| ! Compound !! Target/Specificity !! References | |||
| |- | |||
| | ]|| SIRT1 || <ref name="ManjulaEtal">{{cite journal |last1=Manjula |first1=Ramu |last2=Anuja |first2=Kumari |last3=Alcain |first3=Francisco J. |title=SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases |journal=Frontiers in Pharmacology |date=12 January 2021 |volume=11 |page=585821 |doi=10.3389/fphar.2020.585821 |pmid=33597872 |pmc=7883599 |doi-access=free}}</ref> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="ManjulaEtal" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="ManjulaEtal" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="ManjulaEtal" /> | |||
| |- | |||
| | ]|| SIRT1|| <ref name="ManjulaEtal" /> | |||
| |- | |||
| | ] and rutin derivatives || SIRT6 || <ref name="RahnastoRillaPolyphenols">{{cite journal |last1=Rahnasto-Rilla |first1=Minna |last2=Tyni |first2=Jonna |last3=Huovinen |first3=Marjo |last4=Jarho |first4=Elina |last5=Kulikowicz |first5=Tomasz |last6=Ravichandran |first6=Sarangan |last7=A. Bohr |first7=Vilhelm |last8=Ferrucci |first8=Luigi |last9=Lahtela-Kakkonen |first9=Maija |last10=Moaddel |first10=Ruin |display-authors=3 |date=7 March 2018 |title=Natural polyphenols as sirtuin 6 modulators |journal=Scientific Reports |language=en |volume=8 |issue=1 |pages=4163 |bibcode=2018NatSR...8.4163R |doi=10.1038/s41598-018-22388-5 |pmc=5841289 |pmid=29515203}}</ref> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref>{{cite journal|display-authors=3|last1=Rahnasto-Rilla |first1=Minna K. |last2=McLoughlin |first2=Padraig |last3=Kulikowicz |first3=Tomasz |last4=Doyle |first4=Maire |last5=Bohr |first5=Vilhelm A. |last6=Lahtela-Kakkonen |first6=Maija |last7=Ferrucci |first7=Luigi |last8=Hayes |first8=Maria |last9=Moaddel |first9=Ruin |title=The Identification of a SIRT6 Activator from Brown Algae Fucus distichus |journal=Marine Drugs |date=21 June 2017 |volume=15 |issue=6 |page=190 |doi=10.3390/md15060190 |pmid=28635654 |pmc=5484140 |doi-access=free }}</ref> | |||
| |- | |||
| | ]|| SIRT1, SIRT6 || <ref>{{cite journal|display-authors=3|last1=Grabowska |first1=Wioleta |last2=Suszek |first2=Małgorzata |last3=Wnuk |first3=Maciej |last4=Lewinska |first4=Anna |last5=Wasiak |first5=Emilia |last6=Sikora |first6=Ewa |last7=Bielak-Zmijewska |first7=Anna |title=Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature |journal=Oncotarget |date=28 March 2016 |volume=7 |issue=15 |pages=19201–19213 |doi=10.18632/oncotarget.8450 |pmid=27034011 |pmc=4991376 }}</ref> | |||
| |- | |||
| | ]|| SIRT1 || <ref>{{cite journal |last1=Sandoval-Rodriguez |first1=Ana |last2=Monroy-Ramirez |first2=Hugo Christian |last3=Meza-Rios |first3=Alejandra |last4=Garcia-Bañuelos |first4=Jesus |last5=Vera-Cruz |first5=Jose |last6=Gutiérrez-Cuevas |first6=Jorge |last7=Silva-Gomez |first7=Jorge |last8=Staels |first8=Bart |last9=Dominguez-Rosales |first9=Jose |last10=Galicia-Moreno |first10=Marina |last11=Vazquez-Del Mercado |first11=Monica |last12=Navarro-Partida |first12=Jose |last13=Santos-Garcia |first13=Arturo |last14=Armendariz-Borunda |first14=Juan| display-authors=3|title=Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK |journal=Hepatology Communications |date=March 2020 |volume=4 |issue=3 |pages=434–449 |doi=10.1002/hep4.1474 |pmid=32140659 |pmc=7049672 }}</ref> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="RahnastoRillaPolyphenols" /> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="DaSilva">{{cite thesis |last1=da Silva |first1=Julie Pires |title=Rôle de la sirtuine 1 dans la modulation des réponses apoptotique et autophagique du coeur au stress du réticulum endoplasmique |date=31 May 2018 |publisher=Université Paris Saclay (COmUE) |url=https://tel.archives-ouvertes.fr/tel-01894468 |type=phdthesis |language=fr}}</ref> | |||
| |- | |||
| | ]|| SIRT6 || <ref name="DaSilva" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="DaSilva" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="DaSilva" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="DaSilva" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="DaSilva" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="DaSilva" /> | |||
| |- | |||
| | ]|| SIRT1 || <ref name="DaSilva" /> | |||
| |} | |||
| == See also == | == See also == | ||
| Line 110: | Line 208: | ||
| == References == | == References == | ||
| {{ |
{{Reflist}} | ||
| == External links == | == External links == | ||
| * {{MeshName|Sirtuins}} | * {{MeshName|Sirtuins}} | ||
| * {{cite web | url = http://www.technologyreview.com/biomedicine/21719/ | title = How Cells Age: Parallels between mice and yeast uncover a potentially universal aging mechanism | author = Rice J | date = 2008-11-26 | format = | work = Technology Review | publisher = Massachusetts Institute of Technology | pages = | archive-url = | archive-date = | quote = | access-date = 2008-12-20}} | |||
| {{Carbon-nitrogen non-peptide hydrolases}} | {{Carbon-nitrogen non-peptide hydrolases}} | ||
| {{Glycosyltransferases}} | {{Glycosyltransferases}} | ||
| {{Intracellular signaling peptides and proteins}} | {{Intracellular signaling peptides and proteins}} | ||
| {{Authority control}} | |||
| ] | ] | ||
Latest revision as of 11:13, 11 October 2024
EnzymeProtein family
| Sir2 family | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
 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) | |||||||||||
| Identifiers | |||||||||||
| Symbol | SIR2 | ||||||||||
| Pfam | PF02146 | ||||||||||
| Pfam clan | CL0085 | ||||||||||
| InterPro | IPR003000 | ||||||||||
| PROSITE | PS50305 | ||||||||||
| SCOP2 | 1j8f / SCOPe / SUPFAM | ||||||||||
| |||||||||||
Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.
From in vitro studies, sirtuins were thought to be implicated in influencing cellular processes like aging, transcription, apoptosis, inflammation and stress resistance, as well as energy efficiency and alertness during low-calorie situations. As of 2018, there was no clinical evidence that sirtuins affect human aging, and a 2022 review criticized researchers who propagate this claim.
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. 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). 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 Zn as a cofactor.
Actions and species distribution
Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. 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). 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.
History
Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT. 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 .
Types
 | This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources in this section. Unsourced material may be challenged and removed. Find sources: "Sirtuin" – news · newspapers · books · scholar · JSTOR (November 2019) (Learn how and when to remove this 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. 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).
Yeast protein names may also be suffixed with "p" (e.g. Sir2p) to indicate the fact that it is a protein. This table does not use this convention to minimize cross-species confusion.| Class | Subclass | Species | Intracellular location |
Activity | Cellular Function | Catalytic Domains | Histone Deacetylation Target | Non-Histone Deacetylation Target | Pathology | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Bacteria | Yeast | Mouse | Human | |||||||||
| I | a | Sir2, Hst1 |
Sirt1 | SIRT1 | Nucleus, cytoplasm | Deacetylase | Metabolism inflammation | 244-498 (of 766aa) | H3K9ac, H1K26ac, H4K16ac | Hif-1α, Hif-2α, MYC, P53, BRCA1, FOXO3A, MyoD, Ku70, PPARγ, PCAF, Suv39h1, TGFB1, WRN, NBS1 | Neurodegenerative diseases, Cancer: acute myeloid leukemia, colon, prostate, ovarian, glioma, breast, melanoma, lung adenocarcinoma | |
| b | Hst2 | Sirt2 | SIRT2 | Nucleus and cytoplasm | Deacetylase | Cell cycle, tumorigenesis | 65-340 (of 388aa) | H3K56ac, H4K16ac | Tubulin, Foxo3a, EIF5A, P53, G6PD, MYC | Neurodegenerative diseases, Cancer: brain tissue, glioma | ||
| Sirt3 | SIRT3 | Mitochondria | Deacetylase | Metabolism | 126-382 (of 399aa) | H3K56ac, H4K14ac | SOD2, PDH, IDH2, GOT2, FoxO3a | Neurodegenerative diseases, Cancer: B cell chronic lymphocytic leukemia, mantle cell lymphoma, chronic lymphocytic leukemia, breast, gastric | ||||
| c | Hst3, Hst4 |
|||||||||||
| II | Sirt4 | SIRT4 | Mitochondria | ADP-ribosyl transferase | Insulin secretion | 45-314 (of 314aa) | Unknown | GDH, PDH | Cancer: breast, colorectal | |||
| III | Sirt5 | SIRT5 | Mitochondria | Demalonylase, desuccinylase and deacetylase | Ammonia detoxification | 41-309 (of 310aa) | Unknown | CPS1 | Cancer: pancreatic, breast, non-small cell lung carcinoma | |||
| IV | a | Sirt6 | SIRT6 | Nucleus | Demyristoylase, depalmitoylase, ADP-ribosyl transferase and deacetylase | DNA repair, metabolism, TNF secretion | 35-274 (of 355aa) | H3K9ac, H3K56ac | Unknown | Cancer: breast, colon | ||
| b | Sirt7 | SIRT7 | Nucleolus | Deacetylase | rRNA transcription | 90-331 (of 400aa) | H3K18ac | Hif-1α, Hif-2α | Cancer: liver, testis, spleen, thyroid, breast | |||
| U | cobB | Regulation of acetyl-CoA synthetase | metabolism | |||||||||
| M | SirTM | 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.
Ageing
Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1, led some scientists to speculate that resveratrol may extend lifespan, no clinical evidence for such an effect has been discovered, as of 2018.
Tissue fibrosis
 | This section needs more reliable 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) |  |
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.
DNA repair in laboratory studies
SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair. SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks.
SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage. SIRT6 deficiency in mice leads to a degenerative aging-like phenotype. In addition, SIRT6 promotes the repair of DNA double-strand breaks. Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.
SIRT7 knockout mice display features of premature aging. SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining.
Inhibitors
Certain sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site. It is an inhibitor in vitro of SIRT1, but can be a stimulator in cells.
Activators
| Compound | Target/Specificity | References |
|---|---|---|
| Piceatannol | SIRT1 | |
| SRT-1720 | SIRT1 | |
| SRT-2104 | SIRT1 | |
| Beta-Lapachone | SIRT1 | |
| Cilostazol | SIRT1 | |
| Quercetin and rutin derivatives | SIRT6 | |
| Luteolin | SIRT6 | |
| Fisetin | SIRT6 | |
| Phenolic acid | SIRT6 | |
| Fucoidan | SIRT6 | |
| Curcumin | SIRT1, SIRT6 | |
| Pirfenidone | SIRT1 | |
| Myricetin | SIRT6 | |
| Cyanidin | SIRT6 | |
| Delphinidin | SIRT6 | |
| Apigenin | SIRT6 | |
| Butein | SIRT6 | |
| Isoliquiritigenin | SIRT6 | |
| Ferulic acid | SIRT1 | |
| Berberine | SIRT1 | |
| Catechin | SIRT1 | |
| Malvidin | SIRT1 | |
| Pterostilbene | SIRT1 | |
| Tyrosol | SIRT1 |
See also
References
- PDB: 1szd; Zhao K, Harshaw R, Chai X, Marmorstein R (June 2004). "Structural basis for nicotinamide cleavage and ADP-ribose transfer by NAD(+)-dependent Sir2 histone/protein deacetylases". Proceedings of the National Academy of Sciences of the United States of America. 101 (23): 8563–8. Bibcode:2004PNAS..101.8563Z. doi:10.1073/pnas.0401057101. PMC 423234. PMID 15150415.
- ^ Ye X, Li M, Hou T, Gao T, Zhu WG, Yang Y (3 January 2017). "Sirtuins in glucose and lipid metabolism". Oncotarget (Review). 8 (1): 1845–1859. doi:10.18632/oncotarget.12157. PMC 5352102. PMID 27659520.
- ^ Yamamoto H, Schoonjans K, Auwerx J (August 2007). "Sirtuin functions in health and disease". Molecular Endocrinology. 21 (8): 1745–55. doi:10.1210/me.2007-0079. PMID 17456799.
- Du J, Zhou Y, Su X, Yu JJ, Khan S, Jiang H, Kim J, Woo J, Kim JH, Choi BH, He B, Chen W, Zhang S, Cerione RA, Auwerx J, Hao Q, Lin H (November 2011). "Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase". Science. 334 (6057): 806–9. Bibcode:2011Sci...334..806D. doi:10.1126/science.1207861. PMC 3217313. PMID 22076378.
- Jiang H, Khan S, Wang Y, Charron G, He B, Sebastian C, Du J, Kim R, Ge E, Mostoslavsky R, Hang HC, Hao Q, Lin H (April 2013). "SIRT6 regulates TNF-α secretion through hydrolysis of long-chain fatty acyl lysine". Nature. 496 (7443): 110–3. Bibcode:2013Natur.496..110J. doi:10.1038/nature12038. PMC 3635073. PMID 23552949.
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- EntrezGene 23410
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External links
- Sirtuins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
| Hydrolases: carbon-nitrogen non-peptide (EC 3.5) | |
|---|---|
| 3.5.1: Linear amides / Amidohydrolases | |
| 3.5.2: Cyclic amides/ Amidohydrolases | |
| 3.5.3: Linear amidines/ Ureohydrolases | |
| 3.5.4: Cyclic amidines/ Aminohydrolases | |
| 3.5.5: Nitriles/ Aminohydrolases | |
| 3.5.99: Other | |
| Intracellular signaling peptides and proteins | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| MAP | |||||||||||||||
| Calcium | |||||||||||||||
| G protein |
| ||||||||||||||
| Cyclin | |||||||||||||||
| Lipid | |||||||||||||||
| Other protein kinase |
| ||||||||||||||
| Other protein phosphatase |
| ||||||||||||||
| Apoptosis | |||||||||||||||
| GTP-binding protein regulators | |||||||||||||||
| Other | |||||||||||||||
| see also deficiencies of intracellular signaling peptides and proteins | |||||||||||||||