Biology:Sirtuin 1

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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 (Saccharomyces cerevisiae) is Sir2. SIRT1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation (reaction to stressors, longevity).[4][5]

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. 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.[6] 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.[7][8]

In vitro, SIRT1 has been shown to deacetylate and thereby deactivate the p53 protein,[9] and may have a role in activating T helper 17 cells.[10]

Selective ligands

Activators

  • Lamin A is a protein that had been identified as a direct activator of Sirtuin 1 during a study on progeria.[11]
  • Resveratrol has been claimed to be an activator of Sirtuin 1,[12] 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.[13][14] Resveratrol increases the expression of SIRT1, meaning that it does increase the activity of SIRT1, though not necessarily by direct activation.[6] However, resveratrol was later shown to directly activate Sirtuin 1 against non-modified peptide substrates.[15][16] Resveratrol also enhances the binding between Sirtuin 1 and Lamin A.[11] In addition to resveratrol, a range of other plant-derived polyphenols have also been shown to interact with SIRT1.[17]
  • SRT-1720 was also claimed to be an activator,[12] but this now has been questioned.[18]
  • Methylene blue[19] by increasing NAD+/NADH ratio.
  • Metformin activates both PRKA and SIRT1.[20]

Although neither resveratrol or SRT1720 directly activate SIRT1, resveratrol, and probably SRT1720, indirectly activate SIRT1 by activation of AMP-activated protein kinase (AMPK),[21] which increases NAD+ levels (which is the cofactor required for SIRT1 activity).[22][23] Elevating NAD+ is a more direct and reliable way to activate SIRT1.[23]

Interactions

Sirtuin 1 has been shown in vitro to interact with ERR-alpha[7] and AIRE.[24]

Human Sirt1 has been reported having 136 direct interactions in interactomic studies involved in numerous processes.[25]

Sir2

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.[26] 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.[27][28]

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.[29][30]

In the roundworm, Caenorhabditis elegans, Sir-2.1 is used to denote the gene product most similar to yeast Sir2 in structure and activity.[31][32]

Method of action and observed effects

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.[33] They add the acetyl group from the protein to the ADP-ribose component of NAD+ to form O-acetyl-ADP-ribose. 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%,[34] 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.[34] 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.[35] 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.[35]

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.[36] Experiments in the nematode Caenorhabditis elegans and in the fruit fly Drosophila melanogaster[37] support these findings. (As of 2006), experiments in mice are underway.[27]

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 [38] Furthermore, calorie restriction can substantially prolong reproductive lifespan in yeast even in the absence of Sir2.[39]

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

In the fruit fly Drosophila melanogaster, the Sir2 gene does not seem to be essential; loss of a sirtuin gene has only very subtle effects.[36] However, mice lacking the SIRT1 gene (the sir2 biological equivalent) were smaller than normal at birth, often died early or became sterile.[40]

Inhibition of SIRT1

Human aging is characterized by a chronic, low-grade inflammation level,[41] and the pro-inflammatory transcription factor NF-κB is the main transcriptional regulator of genes related to inflammation.[42] SIRT1 inhibits NF-κB-regulated gene expression by deacetylating the RelA/p65 subunit of NF-κB at lysine 310.[43][44] But NF-κB more strongly inhibits SIRT1. NF-κB increases the levels of the microRNA miR-34a (which inhibits nicotinamide adenine dinucleotide NAD+ synthesis) by binding to its promoter region.[45] resulting in lower levels of SIRT1.

Both the SIRT1 enzyme and the poly ADP-ribose polymerase 1 (PARP1) enzyme require NAD+ for activation.[46] PARP1 is a DNA repair enzyme, so in conditions of high DNA damage, NAD+ levels can be reduced 20-30% thereby reducing SIRT1 activity.[46]

Homologous recombination

SIRT1 protein actively promotes homologous recombination (HR) in human cells, and likely promotes recombinational repair of DNA breaks.[47] SIRT1 mediated HR requires the WRN protein.[47] WRN protein functions in double-strand break repair by HR.[48] WRN protein is a RecQ helicase, and in its mutated form gives rise to Werner syndrome, a genetic condition in humans characterized by numerous features of premature aging. These findings link SIRT1 function to HR, a DNA repair process that is likely necessary for maintaining the integrity of the genome during aging.[47]

References

  1. ↑ "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". Biochemical and Biophysical Research Communications 260 (1): 273–79. June 1999. doi:10.1006/bbrc.1999.0897. PMID 10381378. 
  2. ↑ 2.0 2.1 "Entrez Gene: SIRT1 sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23411. 
  3. ↑ SIRT1 human gene location in the UCSC Genome Browser.
  4. ↑ "Unlocking the Secrets of Longevity Genes". Scientific American 294 (3): 48–51, 54–7. March 2006. doi:10.1038/scientificamerican0306-48. PMID 16502611. Bibcode: 2006SciAm.294c..48S. 
  5. ↑ "Sirtuins in Neuroendocrine Regulation and Neurological Diseases". Frontiers in Neuroscience 12: 778. 2018. doi:10.3389/fnins.2018.00778. PMID 30416425. 
  6. ↑ 6.0 6.1 "SIRT1 improves insulin sensitivity under insulin-resistant conditions by repressing PTP1B". Cell Metabolism 6 (4): 307–19. October 2007. doi:10.1016/j.cmet.2007.08.014. PMID 17908559. 
  7. ↑ 7.0 7.1 "An acetylation switch modulates the transcriptional activity of estrogen-related receptor alpha". Molecular Endocrinology 24 (7): 1349–58. July 2010. doi:10.1210/me.2009-0441. PMID 20484414. 
  8. ↑ "AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity". Nature 458 (7241): 1056–60. April 2009. doi:10.1038/nature07813. PMID 19262508. Bibcode: 2009Natur.458.1056C. 
  9. ↑ EntrezGene 23411 Human Sirt1
  10. ↑ "NAD⁺ in aging, metabolism, and neurodegeneration". Science 350 (6265): 1208–13. December 2015. doi:10.1126/science.aac4854. PMID 26785480. Bibcode: 2015Sci...350.1208V. 
  11. ↑ 11.0 11.1 "Resveratrol rescues SIRT1-dependent adult stem cell decline and alleviates progeroid features in laminopathy-based progeria". Cell Metabolism 16 (6): 738–50. December 2012. doi:10.1016/j.cmet.2012.11.007. PMID 23217256. 
  12. ↑ 12.0 12.1 "Sirtuin activators". Expert Opinion on Therapeutic Patents 19 (4): 403–14. April 2009. doi:10.1517/13543770902762893. PMID 19441923. 
  13. ↑ "Substrate-specific activation of sirtuins by resveratrol". The Journal of Biological Chemistry 280 (17): 17038–45. April 2005. doi:10.1074/jbc.M500655200. PMID 15684413. 
  14. ↑ "Resveratrol is not a direct activator of SIRT1 enzyme activity". Chemical Biology & Drug Design 74 (6): 619–24. December 2009. doi:10.1111/j.1747-0285.2009.00901.x. PMID 19843076. 
  15. ↑ "Sirt1 activation by resveratrol is substrate sequence-selective". Aging 5 (3): 151–54. March 2013. doi:10.18632/aging.100542. PMID 23524286. 
  16. ↑ "Evidence for a common mechanism of SIRT1 regulation by allosteric activators". Science 339 (6124): 1216–19. March 2013. doi:10.1126/science.1231097. PMID 23471411. Bibcode: 2013Sci...339.1216H. 
  17. ↑ "Therapeutic role of sirtuins in neurodegenerative disease and their modulation by polyphenols". Neuroscience and Biobehavioral Reviews 73: 39–47. November 2016. doi:10.1016/j.neubiorev.2016.11.022. PMID 27914941. 
  18. ↑ "SRT1720, SRT2183, SRT1460, and resveratrol are not direct activators of SIRT1". The Journal of Biological Chemistry 285 (11): 8340–51. March 2010. doi:10.1074/jbc.M109.088682. PMID 20061378. 
  19. ↑ "SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis". European Journal of Pharmacology 727: 115–24. March 2014. doi:10.1016/j.ejphar.2014.01.035. PMID 24486702. 
  20. ↑ "Metformin alleviates hepatosteatosis by restoring SIRT1-mediated autophagy induction via an AMP-activated protein kinase-independent pathway". Autophagy 11 (1): 46–59. 2015. doi:10.4161/15548627.2014.984271. PMID 25484077. 
  21. ↑ "Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications". Journal of Cellular Physiology 234 (10): 17212–17231. 2019. doi:10.1002/jcp.28528. PMID 30916407. 
  22. ↑ "SIRT1 Modulators in Experimentally Induced Liver Injury". Oxidative Medicine and Cellular Longevity 2019: 8765954. 2019. doi:10.1155/2019/8765954. PMID 31281594. 
  23. ↑ 23.0 23.1 "Targeting sirtuin 1 to improve metabolism: all you need is NAD(+)?". Pharmacological Reviews 64 (1): 166–187. 2012. doi:10.1124/pr.110.003905. PMID 22106091. 
  24. ↑ "The deacetylase Sirt1 is an essential regulator of Aire-mediated induction of central immunological tolerance.". Nature Immunology 16 (7): 737–45. July 2015. doi:10.1038/ni.3194. PMID 26006015. 
  25. ↑ "Interactomic and pharmacological insights on human sirt-1". Frontiers in Pharmacology 3: 40. 2012. doi:10.3389/fphar.2012.00040. PMID 22470339. 
  26. ↑ "Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins". Biochemical and Biophysical Research Communications 273 (2): 793–98. July 2000. doi:10.1006/bbrc.2000.3000. PMID 10873683. 
  27. ↑ 27.0 27.1 "Unlocking the secrets of longevity genes". Scientific American 294 (3): 48–51, 54–57. March 2006. doi:10.1038/scientificamerican0306-48. PMID 16502611. Bibcode: 2006SciAm.294c..48S. 
  28. ↑ "CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability". EMBO Reports 12 (10): 1069–76. September 2011. doi:10.1038/embor.2011.151. PMID 21836635. 
  29. ↑ "Four genes responsible for a position effect on expression from HML and HMR in Saccharomyces cerevisiae". Genetics 116 (1): 9–22. May 1987. doi:10.1093/genetics/116.1.9. PMID 3297920. PMC 1203125. http://www.genetics.org/cgi/pmidlookup?view=long&pmid=3297920. 
  30. ↑ "Sirtuins: Sir2-related NAD-dependent protein deacetylases". Genome Biology 5 (5): 224. 2004. doi:10.1186/gb-2004-5-5-224. PMID 15128440. 
  31. ↑ WormBase Protein Summary: Sir-2.1
  32. ↑ http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239 "Skyscape Content: Do antiaging approaches promote longevity?". http://mediwire.skyscape.com/main/Default.aspx?P=Content&ArticleID=174239.  Skyscape Content: Do antiaging approaches promote longevity?
  33. ↑ The Sir2 protein family from EMBL's InterPro database
  34. ↑ 34.0 34.1 "Regulation of lifespan by histone deacetylase". Ageing Research Reviews 1 (3): 313–26. June 2002. doi:10.1016/S1568-1637(02)00003-X. PMID 12067588. https://zenodo.org/record/1260264. 
  35. ↑ 35.0 35.1 "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms". Genes & Development 13 (19): 2570–80. October 1999. doi:10.1101/gad.13.19.2570. PMID 10521401. 
  36. ↑ 36.0 36.1 EntrezGene 34708 Drosophila Sir2
  37. ↑ "Sir2 mediates longevity in the fly through a pathway related to calorie restriction". Proceedings of the National Academy of Sciences of the United States of America 101 (45): 15998–6003. November 2004. doi:10.1073/pnas.0404184101. PMID 15520384. Bibcode: 2004PNAS..10115998R. 
  38. ↑ "Sir2 blocks extreme life-span extension". Cell 123 (4): 655–67. November 2005. doi:10.1016/j.cell.2005.08.042. PMID 16286010. 
  39. ↑ "Sir2-independent life span extension by calorie restriction in yeast". PLOS Biology 2 (9): E296. September 2004. doi:10.1371/journal.pbio.0020296. PMID 15328540. 
  40. ↑ "The mammalian SIR2alpha protein has a role in embryogenesis and gametogenesis". Molecular and Cellular Biology 23 (1): 38–54. January 2003. doi:10.1128/MCB.23.1.38-54.2003. PMID 12482959. 
  41. ↑ "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases". The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences 69 (S1): S4–S9. June 2014. doi:10.1093/gerona/glu057. PMID 24833586. 
  42. ↑ "The nuclear factor NF-kappaB pathway in inflammation". Cold Spring Harbor Perspectives in Biology 1 (6): a001651. December 2009. doi:10.1101/cshperspect.a001651. PMID 20457564. 
  43. ↑ "Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase". The EMBO Journal 23 (12): 2369–80. June 2004. doi:10.1038/sj.emboj.7600244. PMID 15152190. 
  44. ↑ "Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders". Cellular Signalling 25 (10): 1939–48. October 2013. doi:10.1016/j.cellsig.2013.06.007. PMID 23770291. 
  45. ↑ "Relevance of SIRT1-NF-κB Axis as Therapeutic Target to Ameliorate Inflammation in Liver Disease". International Journal of Molecular Sciences 21 (11): 3858. 2020. doi:10.3390/ijms21113858. PMID 32485811. 
  46. ↑ 46.0 46.1 "Antagonistic crosstalk between SIRT1, PARP-1, and -2 in the regulation of chronic inflammation associated with aging and metabolic diseases". Integrative Medicine Research 3 (4): 198–203. 2014. doi:10.1016/j.imr.2014.09.005. PMID 28664098. 
  47. ↑ 47.0 47.1 47.2 "Role of SIRT1 in homologous recombination". DNA Repair (Amst.) 9 (4): 383–93. 2010. doi:10.1016/j.dnarep.2009.12.020. PMID 20097625. 
  48. ↑ "Recombinational DNA repair and human disease". Mutat. Res. 509 (1–2): 49–78. 2002. doi:10.1016/s0027-5107(02)00224-5. PMID 12427531. https://zenodo.org/record/1259665. 

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