Sirtuin 1

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SIRT1
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases SIRT1, SIR2L1, SIR2, hSIR2, SIR2alpha, Sirtuin 1
External IDs MGI: 2135607 HomoloGene: 56556 GeneCards: 23411
RNA expression pattern
PBB GE SIRT1 218878 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001142498
NM_001314049
NM_012238

NM_001159589
NM_001159590
NM_019812

RefSeq (protein)

NP_001135970.1
NP_036370.2
NP_001300978.1

NP_062786.1

Location (UCSC) Chr 10: 67.88 – 67.92 Mb Chr 10: 63.32 – 63.38 Mb
PubMed search [1] [2]
Wikidata
View/Edit Human View/Edit Mouse

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.[1][2][3]

SIRT1 stands for sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae), referring to the fact that its sirtuin homolog (biological equivalent across species) in yeast (S. cerevisiae) is Sir2. SIRT1 is an enzyme that deacetylates proteins that contribute to cellular regulation (reaction to stressors, longevity).[4]

Function[edit]

Sirtuin 1 is a member of the sirtuin family of proteins, homologs of the Sir2 gene in S. cerevisiae. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class I of the sirtuin family.[2]

Sirtuin 1 is downregulated in cells that have high insulin resistance and inducing its expression increases insulin sensitivity, suggesting the molecule is associated with improving insulin sensitivity.[5] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[6][7][8][9][10][11]

In mammals, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein.[12] SIRT1 also stimulates autophagy by preventing acetylation of proteins (via deacetylation), proteins required for autophagy as demonstrated in cultured cells and embryonic and neonatal tissues. This function provides a link between sirtuin expression and the cellular response to limited nutrients due to caloric restriction.[13] Furthermore, SIRT1 was shown to de-acetylate and affect the activity of both members of the PGC1-alpha/ERR-alpha complex, which are essential metabolic regulatory transcription factors.[6][7][8][9][10][11]

Selective ligands[edit]

Activators[edit]

  • Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on Progeria.[14]
  • Resveratrol has been claimed to be an activator of Sirtuin 1,[15] but this effect has been disputed based on the fact that the initially used activity assay, using a non-physiological substrate peptide, can produce artificial results.[16][17] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[5] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.[18][19] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.[14]
  • SRT-1720 was also claimed to be an activator,[15] but this now has been questioned.[20]

Interactions[edit]

Sirtuin 1 has been shown to interact with HEY2,[21] PGC1-alpha,[8] and ERR-alpha.[6] Mir-132 microRNA has been reported to interact with Sirtuin 1 mRNA, so as to reduce protein expression. This has been linked to insulin resistance in the obese.[22]

Human Sirt1 has been reported having 136 direct interactions in Interactomic studies involved in numerous processes.[23]

Sir2[edit]

Sir2 (whose homolog in mammals is known as SIRT1) was the first gene of the sirtuin genes to be found. It was found in budding yeast, and, since then, members of this highly conserved family have been found in nearly all organisms studied.[24] Sirtuins are hypothesized to play a key role in an organism's response to stresses (such as heat or starvation) and to be responsible for the lifespan-extending effects of calorie restriction.[25][26]

The three letter yeast gene symbol Sir stands for Silent Information Regulator while the number 2 is representative of the fact that it was the second SIR gene discovered and characterized.[27][28]

In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[29][30]

Method of action and observed effects[edit]

Sirtuins act primarily by removing acetyl groups from lysine residues within proteins in the presence of NAD+; thus, they are classified as "NAD+-dependent deacetylases" and have EC number 3.5.1.[31] They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose.

Sir2 is the only Class III histone deacetylase (HDAC) in budding yeast.'[32] The HDAC activity of Sir2 results in tighter packaging of chromatin and a reduction in transcription at the targeted gene locus. The silencing activity of Sir2 is most prominent at telomeric sequences, the hidden MAT loci (HM loci), and the ribosomal DNA (rDNA) locus (RDN1) from which ribosomal RNA is transcribed.

Limited overexpression of the Sir2 gene results in a lifespan extension of about 30%,[32] if the lifespan is measured as the number of cell divisions the mother cell can undergo before cell death. Concordantly, deletion of Sir2 results in a 50% reduction in lifespan.[32] In particular, the silencing activity of Sir2, in complex with Sir3 and Sir4, at the HM loci prevents simultaneous expression of both mating factors which can cause sterility and shortened lifespan.[33] Additionally, Sir2 activity at the rDNA locus is correlated with a decrease in the formation of rDNA circles. Chromatin silencing, as a result of Sir2 activity, reduces homologous recombination between rDNA repeats, which is the process leading to the formation of rDNA circles. As accumulation of these rDNA circles is the primary way in which yeast are believed to "age", then the action of Sir2 in preventing accumulation of these rDNA circles is a necessary factor in yeast longevity.[33]

Starving of yeast cells leads to a similarly extended lifespan, and indeed starving increases the available amount of NAD+ and reduces nicotinamide, both of which have the potential to increase the activity of Sir2. Furthermore, removing the Sir2 gene eliminates the life-extending effect of caloric restriction.[34] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster[35] support these findings. As of 2006, experiments in mice are underway.[25]

However, some other findings call the above interpretation into question. If one measures the lifespan of a yeast cell as the amount of time it can live in a non-dividing stage, then silencing the Sir2 gene actually increases lifespan [36] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[37]

In organisms more complicated than yeast, it appears that Sir2 acts by deacetylation of several other proteins besides histones.

Resveratrol is a substance that has been shown through experiment to have a number of life-extending and health benefits in various species; it also increases the activity of Sir2, which is the postulated reason for its beneficial effects. Resveratrol is produced by plants when they are stressed, and it is possible that plants use the substance to increase their own Sir2 activity in order to survive periods of stress.[25] Although there is mounting evidence for this hypothesis, its validity is debated.[38][39][20][40]

In the fruit fly Drosophilia melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[34] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[41]

References[edit]

  1. ^ Frye RA (June 1999). "Characterization of five human cDNAs with homology to the yeast SIR2 gene: Sir2-like proteins (sirtuins) metabolize NAD and may have protein ADP-ribosyltransferase activity". Biochem. Biophys. Res. Commun. 260 (1): 273–9. doi:10.1006/bbrc.1999.0897. PMID 10381378. 
  2. ^ a b "Entrez Gene: SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)". 
  3. ^ SIRT1 human gene location in the UCSC Genome Browser.
  4. ^ Sinclair DA, Guarente L (March 2006). "Unlocking the Secrets of Longevity Genes". Scientific American. 
  5. ^ a b Sun C, Zhang F, Ge X, Yan T, Chen X, Shi X, Zhai Q (October 2007). "SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B". Cell Metab. 6 (4): 307–19. doi:10.1016/j.cmet.2007.08.014. PMID 17908559. 
  6. ^ a b c Wilson BJ, Tremblay AM, Deblois G, Sylvain-Drolet G, Giguère V (Jul 2010). "An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha". Mol. Endocrinol. 24 (7): 1349–58. doi:10.1210/me.2009-0441. PMID 20484414. 
  7. ^ a b Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P (Mar 2005). "Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1". Nature 434 (7029): 113–8. doi:10.1038/nature03354. PMID 15744310. 
  8. ^ a b c Nemoto S, Fergusson MM, Finkel T (Apr 2005). "SIRT1 functionally interacts with the metabolic regulator and transcriptional coactivator PGC-1{alpha}". J. Biol. Chem. 280 (16): 16456–60. doi:10.1074/jbc.M501485200. PMID 15716268. 
  9. ^ a b Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (Dec 2006). "Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha". Cell 127 (6): 1109–22. doi:10.1016/j.cell.2006.11.013. PMID 17112576. 
  10. ^ a b Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J, Olefsky J, Guarente L, Montminy M (Nov 2008). "A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange". Nature 456 (7219): 269–73. doi:10.1038/nature07349. PMC 2597669. PMID 18849969. 
  11. ^ a b Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J (Apr 2009). "AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity". Nature 458 (7241): 1056–60. doi:10.1038/nature07813. PMC 3616311. PMID 19262508. 
  12. ^ EntrezGene 23411 Human Sirt1
  13. ^ Lee, I. H.; Cao, L.; Mostoslavsky, R.; Lombard, D. B.; Liu, J.; Bruns, N. E.; Tsokos, M.; Alt, F. W.; Finkel, T. (2008). "A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy". Proceedings of the National Academy of Sciences 105 (9): 3374–9. doi:10.1073/pnas.0712145105. 
  14. ^ a b Liu B, Ghosh S, Yang X, Zheng H, Liu X, Wang Z, Jin G, Zheng B, Kennedy BK, Suh Y, Kaeberlein M, Tryggvason K, Zhou Z (2012). "Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria". Cell Metab. 16 (6): 738–50. doi:10.1016/j.cmet.2012.11.007. PMID 23217256. 
  15. ^ a b Alcaín FJ, Villalba JM (April 2009). "Sirtuin activators". Expert Opin Ther Pat 19 (4): 403–14. doi:10.1517/13543770902762893. PMID 19441923. 
  16. ^ Kaeberlein M, McDonagh T, Heltweg B, Hixon J, Westman EA, Caldwell SD, Napper A, Curtis R, DiStefano PS, Fields S, Bedalov A, Kennedy BK (April 2005). "Substrate-specific activation of sirtuins by resveratrol". J. Biol. Chem. 280 (17): 17038–45. doi:10.1074/jbc.M500655200. PMID 15684413. 
  17. ^ Beher D, Wu J, Cumine S, Kim KW, Lu SC, Atangan L, Wang M (December 2009). "Resveratrol is not a direct activator of SIRT1 enzyme activity". Chem Biol Drug Des 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076. 
  18. ^ Lakshminarasimhan M, Rauh D, Schutkowski M, Steegborn C (Mar 2013). "Sirt1 activation by resveratrol is substrate sequence-selective". Aging (Albany NY) 5 (3): 151–4. PMID 23524286. 
  19. ^ Hubbard BP, Gomes AP, Dai H, Li J, Case AW, Considine T, Riera TV, Lee JE, E SY, Lamming DW, Pentelute BL, Schuman ER, Stevens LA, Ling AJ, Armour SM, Michan S, Zhao H, Jiang Y, Sweitzer SM, Blum CA, Disch JS, Ng PY, Howitz KT, Rolo AP, Hamuro Y, Moss J, Perni RB, Ellis JL, Vlasuk GP, Sinclair DA (Mar 2013). "Evidence for a common mechanism of SIRT1 regulation by allosteric activators". Science 339 (6124): 1216–9. doi:10.1126/science.1231097. PMID 23471411. 
  20. ^ a b Pacholec M, Bleasdale JE, Chrunyk B, Cunningham D, Flynn D, Garofalo RS, Griffith D, Griffor M, Loulakis P, Pabst B, Qiu X, Stockman B, Thanabal V, Varghese A, Ward J, Withka J, Ahn K (January 2010). "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1". J. Biol. Chem. 285 (11): 8340–51. doi:10.1074/jbc.M109.088682. PMC 2832984. PMID 20061378. 
  21. ^ Takata T, Ishikawa F (January 2003). "Human Sir2-related protein SIRT1 associates with the bHLH repressors HES1 and HEY2 and is involved in HES1- and HEY2-mediated transcriptional repression". Biochem. Biophys. Res. Commun. 301 (1): 250–7. doi:10.1016/S0006-291X(02)03020-6. PMID 12535671. 
  22. ^ Strum JC, Johnson JH, Ward J, Xie H, Feild J, Hester A, Alford A, Waters KM (2009). "MicroRNA 132 regulates nutritional stress-induced chemokine production through repression of SirT1". Mol. Endocrinol. 23 (11): 1876–84. doi:10.1210/me.2009-0117. PMID 19819989. 
  23. ^ Sharma A, Gautam V, Costantini S, Paladino A, Colonna G (2012). "Interactomic and pharmacological insights on human sirt-1". Front Pharmacol 3: 40. doi:10.3389/fphar.2012.00040. PMC 3311038. PMID 22470339. 
  24. ^ Frye, R (2000). "Phylogenetic Classification of Prokaryotic and Eukaryotic Sir2-like Proteins". Biochemical and Biophysical Research Communications 273 (2): 793–8. doi:10.1006/bbrc.2000.3000. PMID 10873683. 
  25. ^ a b c Sinclair, David A.; Guarente, Lenny (2006). "Unlocking the Secrets of Longevity Genes". Scientific American 294 (3): 48–51, 54–7. doi:10.1038/scientificamerican0306-48. PMID 16502611. 
  26. ^ Noriega, Lilia G.; Feige, Jérôme N.; Canto, Carles; Yamamoto, Hiroyasu; Yu, Jiujiu; Herman, Mark A.; Mataki, Chikage; Kahn, Barbara B.; Auwerx, Johan (2011-10-01). "CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability". EMBO reports 12 (10): 1069–1076. doi:10.1038/embor.2011.151. ISSN 1469-3178. PMC 3185337. PMID 21836635. 
  27. ^ Rine, Jasper; Herskowitz, Ira (May 1987). "Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae". Genetics 116 (1): 9–22. PMC 1203125. PMID 3297920. 
  28. ^ North, Brian J; Verdin, Eric (2004). "Sirtuins: Sir2-related NAD-dependent protein deacetylases.". Genome Biology 5 (5): 224. doi:10.1186/gb-2004-5-5-224. PMC 416462. PMID 15128440. 
  29. ^ WormBase Protein Summary: Sir-2.1
  30. ^ http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239[dead link] Skyscape Content: Do antiaging approaches promote longevity?
  31. ^ The Sir2 protein family from EMBL's InterPro database
  32. ^ a b c Chang, K; Min, KT (2002). "Regulation of lifespan by histone deacetylase". Ageing Research Reviews 1 (3): 313–26. doi:10.1016/S1568-1637(02)00003-X. PMID 12067588. 
  33. ^ a b Kaeberlein, M.; McVey, M.; Guarente, L. (1999). "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms". Genes & Development 13 (19): 2570–80. doi:10.1101/gad.13.19.2570. PMC 317077. PMID 10521401. 
  34. ^ a b EntrezGene 34708 Drosophilia Sir2
  35. ^ Rogina, B.; Helfand, SL (2004). "Sir2 mediates longevity in the fly through a pathway related to calorie restriction". Proceedings of the National Academy of Sciences 101 (45): 15998–6003. doi:10.1073/pnas.0404184101. PMC 528752. PMID 15520384. 
  36. ^ Fabrizio, Paola; Gattazzo, Cristina; Battistella, Luisa; Wei, Min; Cheng, Chao; McGrew, Kristen; Longo, Valter D. (2005). "Sir2 Blocks Extreme Life-Span Extension". Cell 123 (4): 655–67. doi:10.1016/j.cell.2005.08.042. PMID 16286010. 
  37. ^ Kaeberlein, Matt; Kirkland, Kathryn T.; Fields, Stanley; Kennedy, Brian K. (2004). "Sir2-Independent Life Span Extension by Calorie Restriction in Yeast". PLoS Biology 2 (9): e296. doi:10.1371/journal.pbio.0020296. PMC 514491. PMID 15328540. 
  38. ^ Kaeberlein, M.; McDonagh, T; Heltweg, B; Hixon, J; Westman, EA; Caldwell, SD; Napper, A; Curtis, R; et al. (2005). "Substrate-specific Activation of Sirtuins by Resveratrol". Journal of Biological Chemistry 280 (17): 17038–45. doi:10.1074/jbc.M500655200. PMID 15684413. 
  39. ^ Borra, M. T.; Smith, BC; Denu, JM (2005). "Mechanism of Human SIRT1 Activation by Resveratrol". Journal of Biological Chemistry 280 (17): 17187–95. doi:10.1074/jbc.M501250200. PMID 15749705. 
  40. ^ Beher, Dirk; Wu, John; Cumine, Suzanne; Kim, Ki Won; Lu, Shu-Chen; Atangan, Larissa; Wang, Minghan (2009). "Resveratrol is Not a Direct Activator of SIRT1 Enzyme Activity". Chemical Biology & Drug Design 74 (6): 619–24. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076. 
  41. ^ McBurney, M. W.; Yang, X.; Jardine, K.; Hixon, M.; Boekelheide, K.; Webb, J. R.; Lansdorp, P. M.; Lemieux, M. (2003). "The Mammalian SIR2 Protein Has a Role in Embryogenesis and Gametogenesis". Molecular and Cellular Biology 23 (1): 38–54. doi:10.1128/MCB.23.1.38-54.2003. PMC 140671. PMID 12482959. 

Further reading[edit]

External links[edit]