Sirtuin 1
Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.[1][2]
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).[3]
Function
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.[4]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. [5] [6][7][8][9][10]
Selective Ligands
Activators
- Resveratrol has been claimed to be an activator of Sirtuin 1,[11] however this has been disputed.[12][13] Studies show that resveratrol increases the expression level of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[14]
- SRT-1720 was also claimed to be an activator[11] but this now has been questioned.[15]
Interactions
Sirtuin 1 has been shown to interact with HEY2.[16], PGC1-alpha[7], and ERR-alpha [5]. 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.[17]
References
- ^ 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.
- ^ a b "Entrez Gene: SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23411.
- ^ Sinclair DA, Guarente L (March 2006). "Unlocking the Secrets of Longevity Genes". Scientific American. http://www.scientificamerican.com/article.cfm?id=unlocking-the-secrets-of-2006-03&page=3.
- ^ Sun C, Zhang F, Ge X, et al. (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.
- ^ a b 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. http://mend.endojournals.org/cgi/content/full/24/7/1349.
- ^ 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. http://www.nature.com/nature/journal/v434/n7029/full/nature03354.html.
- ^ a b 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. http://www.jbc.org/content/280/16/16456.long.
- ^ 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. http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6WSN-4MC1FXV-2&_user=209690&_coverDate=12%2F15%2F2006&_rdoc=1&_fmt=high&_orig=search&_origin=search&_sort=d&_docanchor=&view=c&_acct=C000014438&_version=1&_urlVersion=0&_userid=209690&md5=1ade5202b987dfd63ca0ff8761e7748e&searchtype=a.
- ^ Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J 3rd, 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. http://www.nature.com/nature/journal/v456/n7219/full/nature07349.html.
- ^ 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 (7214): 1056–60.. doi:10.1038/nature07813. PMID 19262508. http://www.nature.com/nature/journal/v458/n7241/full/nature07813.html.
- ^ a b Alcaín FJ, Villalba JM (April 2009). "Sirtuin activators". Expert Opin Ther Pat 19 (4): 403–14. doi:10.1517/13543770902762893. PMID 19441923.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Pacholec M, Chrunyk BA, Cunningham D, Flynn D, Griffith DA, 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. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2832984.
- ^ 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.
- ^ 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.
Further reading
- Frye RA (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.
- Frye RA (2000). "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins.". Biochem. Biophys. Res. Commun. 273 (2): 793–8. doi:10.1006/bbrc.2000.3000. PMID 10873683.
- Wiemann S, Weil B, Wellenreuther R, et al. (2001). "Toward a catalog of human genes and proteins: sequencing and analysis of 500 novel complete protein coding human cDNAs.". Genome Res. 11 (3): 422–35. doi:10.1101/gr.GR1547R. PMC 311072. PMID 11230166. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=311072.
- Luo J, Nikolaev AY, Imai S, et al. (2001). "Negative control of p53 by Sir2alpha promotes cell survival under stress.". Cell 107 (2): 137–48. doi:10.1016/S0092-8674(01)00524-4. PMID 11672522.
- Vaziri H, Dessain SK, Ng Eaton E, et al. (2001). "hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase.". Cell 107 (2): 149–59. doi:10.1016/S0092-8674(01)00527-X. PMID 11672523.
- Langley E, Pearson M, Faretta M, et al. (2002). "Human SIR2 deacetylates p53 and antagonizes PML/p53-induced cellular senescence.". EMBO J. 21 (10): 2383–96. doi:10.1093/emboj/21.10.2383. PMC 126010. PMID 12006491. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=126010.
- Bitterman KJ, Anderson RM, Cohen HY, et al. (2003). "Inhibition of silencing and accelerated aging by nicotinamide, a putative negative regulator of yeast sir2 and human SIRT1.". J. Biol. Chem. 277 (47): 45099–107. doi:10.1074/jbc.M205670200. PMID 12297502.
- Travers H, Spotswood HT, Moss PA, Turner BM (2002). "Human CD34+ hematopoietic progenitor cells hyperacetylate core histones in response to sodium butyrate, but not trichostatin A.". Exp. Cell Res. 280 (2): 149–58. doi:10.1006/excr.2002.5632. PMID 12413881.
- Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=139241.
- Takata T, Ishikawa F (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.
- Senawong T, Peterson VJ, Avram D, et al. (2003). "Involvement of the histone deacetylase SIRT1 in chicken ovalbumin upstream promoter transcription factor (COUP-TF)-interacting protein 2-mediated transcriptional repression.". J. Biol. Chem. 278 (44): 43041–50. doi:10.1074/jbc.M307477200. PMC 2819354. PMID 12930829. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2819354.
- Howitz KT, Bitterman KJ, Cohen HY, et al. (2003). "Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan.". Nature 425 (6954): 191–6. doi:10.1038/nature01960. PMID 12939617.
- Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs.". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID 14702039.
- Brunet A, Sweeney LB, Sturgill JF, et al. (2004). "Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase.". Science 303 (5666): 2011–5. doi:10.1126/science.1094637. PMID 14976264.
- Motta MC, Divecha N, Lemieux M, et al. (2004). "Mammalian SIRT1 represses forkhead transcription factors.". Cell 116 (4): 551–63. doi:10.1016/S0092-8674(04)00126-6. PMID 14980222.
- van der Horst A, Tertoolen LG, de Vries-Smits LM, et al. (2004). "FOXO4 is acetylated upon peroxide stress and deacetylated by the longevity protein hSir2(SIRT1).". J. Biol. Chem. 279 (28): 28873–9. doi:10.1074/jbc.M401138200. PMID 15126506.
- Yeung F, Hoberg JE, Ramsey CS, et al. (2004). "Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase.". EMBO J. 23 (12): 2369–80. doi:10.1038/sj.emboj.7600244. PMC 423286. PMID 15152190. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=423286.
- Deloukas P, Earthrowl ME, Grafham DV, et al. (2004). "The DNA sequence and comparative analysis of human chromosome 10.". Nature 429 (6990): 375–81. doi:10.1038/nature02462. PMID 15164054.
- Picard F, Kurtev M, Chung N, et al. (2004). "Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma.". Nature 429 (6993): 771–6. doi:10.1038/nature02583. PMC 2820247. PMID 15175761. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2820247.
- Cohen HY, Miller C, Bitterman KJ, et al. (2004). "Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.". Science 305 (5682): 390–2. doi:10.1126/science.1099196. PMID 15205477.
External links