Wikipedia

Sirtuin

(Redirected from Sirt4)

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.

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)[1]
Identifiers
SymbolSIR2
PfamPF02146
Pfam clanCL0085
InterProIPR003000
PROSITEPS50305
SCOP21j8f / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1ici​, 1j8f​, 1m2g​, 1m2h​, 1m2j​, 1m2k​, 1m2n​, 1ma3​, 1q14​, 1q17​, 1q1a​, 1s5p​, 1s7g​, 1szc​, 1szd​, 1yc2​, 1yc5​

From in vitro studies, sirtuins were thought to be 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] and a 2022 review criticized researchers who propagate this claim.[11]

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.[12] 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).[13] 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.[14][15]

Actions and species distribution

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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).[16] 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

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Research on sirtuin protein was started in 1991 by Leonard Guarente of MIT.[17][18] 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 .[19]

Types

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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.[20] 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]

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[21] Histone Deacetylation Target[22] Non-Histone Deacetylation Target[22] Pathology[22]
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[23] Regulation of acetyl-CoA synthetase[24] 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.[25]

Ageing

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Although preliminary studies with resveratrol, an activator of deacetylases such as SIRT1,[26] led some scientists to speculate that resveratrol may extend lifespan, no clinical evidence for such an effect has been discovered, as of 2018.[10]

Tissue fibrosis

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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.[27]

DNA repair in laboratory studies

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SIRT1, SIRT6 and SIRT7 proteins are employed in DNA repair.[28] SIRT1 protein promotes homologous recombination in human cells and is involved in recombinational repair of DNA breaks.[29]

SIRT6 is a chromatin-associated protein and in mammalian cells is required for base excision repair of DNA damage.[30] SIRT6 deficiency in mice leads to a degenerative aging-like phenotype.[30] In addition, SIRT6 promotes the repair of DNA double-strand breaks.[31] Furthermore, over-expression of SIRT6 can stimulate homologous recombinational repair.[32]

SIRT7 knockout mice display features of premature aging.[33] SIRT7 protein is required for repair of double-strand breaks by non-homologous end joining.[33]

Inhibitors

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Certain sirtuin activity is inhibited by nicotinamide, which binds to a specific receptor site.[34] It is an inhibitor in vitro of SIRT1, but can be a stimulator in cells.[35]

Activators

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List of known sirtuin activator in vitro
Compound Target/Specificity References
Piceatannol SIRT1 [36]
SRT-1720 SIRT1 [36]
SRT-2104 SIRT1 [36]
Beta-Lapachone SIRT1 [36]
Cilostazol SIRT1 [36]
Quercetin and rutin derivatives SIRT6 [37]
Luteolin SIRT6 [37]
Fisetin SIRT6 [37]
Phenolic acid SIRT6 [37]
Fucoidan SIRT6 [38]
Curcumin SIRT1, SIRT6 [39]
Pirfenidone SIRT1 [40]
Myricetin SIRT6 [37]
Cyanidin SIRT6 [37]
Delphinidin SIRT6 [37]
Apigenin SIRT6 [37]
Butein SIRT6 [41]
Isoliquiritigenin SIRT6 [41]
Ferulic acid SIRT1 [41]
Berberine SIRT1 [41]
Catechin SIRT1 [41]
Malvidin SIRT1 [41]
Pterostilbene SIRT1 [41]
Tyrosol SIRT1 [41]


See also

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References

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  1. ^ 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.
  2. ^ a b c d e 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.
  3. ^ a b 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.
  4. ^ 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.
  5. ^ 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.
  6. ^ a b c 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 (July 2015). "Identification of a Class of Protein ADP-Ribosylating Sirtuins in Microbial Pathogens". Molecular Cell. 59 (2): 309–20. doi:10.1016/j.molcel.2015.06.013. PMC 4518038. PMID 26166706.
  7. ^ EntrezGene 23410
  8. ^ Preyat N, Leo O (May 2013). "Sirtuin deacylases: a molecular link between metabolism and immunity". Journal of Leukocyte Biology. 93 (5): 669–80. doi:10.1189/jlb.1112557. PMID 23325925. S2CID 3070941.
  9. ^ Satoh A, Brace CS, Ben-Josef G, West T, Wozniak DF, Holtzman DM, Herzog ED, Imai S (July 2010). "SIRT1 promotes the central adaptive response to diet restriction through activation of the dorsomedial and lateral nuclei of the hypothalamus". The Journal of Neuroscience. 30 (30): 10220–32. doi:10.1523/JNEUROSCI.1385-10.2010. PMC 2922851. PMID 20668205.
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  28. ^ Vazquez BN, Thackray JK, Serrano L (March 2017). "Sirtuins and DNA damage repair: SIRT7 comes to play". Nucleus. 8 (2): 107–115. doi:10.1080/19491034.2016.1264552. PMC 5403131. PMID 28406750.
  29. ^ Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmüller L, Gatz SA (April 2010). "Role of SIRT1 in homologous recombination". DNA Repair. 9 (4): 383–93. doi:10.1016/j.dnarep.2009.12.020. PMID 20097625.
  30. ^ a b Mostoslavsky R, Chua KF, Lombard DB, et al. (January 2006). "Genomic instability and aging-like phenotype in the absence of mammalian SIRT6". Cell. 124 (2): 315–29. doi:10.1016/j.cell.2005.11.044. PMID 16439206. S2CID 18517518.
  31. ^ McCord RA, Michishita E, Hong T, et al. (January 2009). "SIRT6 stabilizes DNA-dependent protein kinase at chromatin for DNA double-strand break repair". Aging. 1 (1): 109–21. doi:10.18632/aging.100011. PMC 2815768. PMID 20157594.
  32. ^ Mao Z, Tian X, Van Meter M, Ke Z, Gorbunova V, Seluanov A (July 2012). "Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence". Proceedings of the National Academy of Sciences of the United States of America. 109 (29): 11800–5. Bibcode:2012PNAS..10911800M. doi:10.1073/pnas.1200583109. PMC 3406824. PMID 22753495.
  33. ^ a b Vazquez BN, Thackray JK, Simonet NG, et al. (July 2016). "SIRT7 promotes genome integrity and modulates non-homologous end joining DNA repair". The EMBO Journal. 35 (14): 1488–503. doi:10.15252/embj.201593499. PMC 4884211. PMID 27225932.
  34. ^ Avalos JL, Bever KM, Wolberger C (March 2005). "Mechanism of sirtuin inhibition by nicotinamide: altering the NAD(+) cosubstrate specificity of a Sir2 enzyme". Molecular Cell. 17 (6): 855–68. doi:10.1016/j.molcel.2005.02.022. PMID 15780941.
  35. ^ Hwang ES, Song SB (September 2017). "Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells". Cell Mol Life Sci. 74 (18): 3347–3362. doi:10.1007/s00018-017-2527-8. PMC 11107671. PMID 28417163.
  36. ^ a b c d e Manjula R, Anuja K, Alcain FJ (12 January 2021). "SIRT1 and SIRT2 Activity Control in Neurodegenerative Diseases". Frontiers in Pharmacology. 11: 585821. doi:10.3389/fphar.2020.585821. PMC 7883599. PMID 33597872.
  37. ^ a b c d e f g h Rahnasto-Rilla M, Tyni J, Huovinen M, et al. (7 March 2018). "Natural polyphenols as sirtuin 6 modulators". Scientific Reports. 8 (1): 4163. Bibcode:2018NatSR...8.4163R. doi:10.1038/s41598-018-22388-5. PMC 5841289. PMID 29515203.
  38. ^ Rahnasto-Rilla MK, McLoughlin P, Kulikowicz T, et al. (21 June 2017). "The Identification of a SIRT6 Activator from Brown Algae Fucus distichus". Marine Drugs. 15 (6): 190. doi:10.3390/md15060190. PMC 5484140. PMID 28635654.
  39. ^ Grabowska W, Suszek M, Wnuk M, et al. (28 March 2016). "Curcumin elevates sirtuin level but does not postpone in vitro senescence of human cells building the vasculature". Oncotarget. 7 (15): 19201–19213. doi:10.18632/oncotarget.8450. PMC 4991376. PMID 27034011.
  40. ^ Sandoval-Rodriguez A, Monroy-Ramirez HC, Meza-Rios A, et al. (March 2020). "Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK". Hepatology Communications. 4 (3): 434–449. doi:10.1002/hep4.1474. PMC 7049672. PMID 32140659.
  41. ^ a b c d e f g h da Silva JP (31 May 2018). Rôle de la sirtuine 1 dans la modulation des réponses apoptotique et autophagique du coeur au stress du réticulum endoplasmique (phdthesis) (in French). Université Paris Saclay (COmUE).
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