SIRT3

Sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae), also known as SIRT3, is a genecite web | title = Entrez Gene: SIRT3 sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23410| accessdate = ] cite journal | author = Schwer B, North BJ, Frye RA, Ott M, Verdin E | title = The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase | journal = J. Cell Biol. | volume = 158 | issue = 4 | pages = 647–57 | year = 2002 | month = August | pmid = 12186850 | pmc = 2174009 | doi = 10.1083/jcb.200205057 | url = | issn = ] encoding a protein, also called Sirt3.

This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. 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.cite web | title = Entrez Gene: SIRT3 sirtuin (silent mating type information regulation 2 homolog) 3 (S. cerevisiae)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=23410| accessdate = ]

tructure

While the crystal structure has not yet been solved, Sirt3 is a soluble protein located in the mitochondrial matrix, and contains a mitochondrial processing peptide at the n-terminus.

Function

Mitochondrial

Three sirtuins, Sirt3, Sirt4 and Sirt5, are located in mitochondria and have been implicated in regulating metabolic processes. Endogenous Sirt3 is a soluble protein located in the mitochondrial matrix.cite journal | author = Onyango P, Celic I, McCaffery JM, Boeke JD, Feinberg AP | title = SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 99 | issue = 21 | pages = 13653–8 | year = 2002 | month = October | pmid = 12374852 | pmc = 129731 | doi = 10.1073/pnas.222538099 | url = | issn = ] Overexpression of Sirt3 in cultured cells increases respiration and decreases the production of reactive oxygen species. Fasting increases Sirt3 expression in white and brown adipose tissue (WAT and BAT, respectively) and overexpression of Sirt3 in HIB1B brown adipocytes increases the expression of PGC-1α and UCP1, suggesting a role for Sirt3 in adaptive thermogenesis BAT. BAT is different from WAT because it harbors large numbers of mitochondria and is important for thermogenesis in rodents. Thermogenesis in BAT is mediated by the uncoupling protein 1 (UCP1), which induces proton leakage and thereby generates heat instead of ATP. Mechanistic insights into how Sirt3 affects thermogenesis in BAT is lacking and whether Sirt3 affects UCP1 activity directly is not known.

In addition to controlling metabolism at the transcriptional level, sirtuins also directly control the activity of metabolic enzymes. In "Salmonella enterica", the bacterial sirtuin CobB regulates the activity of the enzyme acetyl-coenzyme A (acetyl-CoA) synthetase. As mentioned above, orthologs of acetyl-CoA synthetase exist in the cytoplasm (AceCS1) and in mitochondria (AceCS2) in mammals. The presence of the sirtuin deacetylase Sirt3 in the mitochondrial matrix suggests the existence of lysine acetylated mitochondrial proteins. Indeed, Sirt3 deacetylates and activates the mammalian mitochondrial acetyl-coA synthetase (AceCS2). Furthermore, Sirt3 and AceCS2 are found complexed with one another, suggesting a critical role for control of AceCS2 activity by Sirt3.

Nuclear

In addition to its reported mitochondrial function, some researchers have proposed a very small pool of active nuclear SirT3 exists. This pool is reported to consist of the long form of SirT3 and has been suggested to have histone deacetylase activity.cite journal | author = Scher MB, Vaquero A, Reinberg D | title = SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress | journal = Genes Dev. | volume = 21 | issue = 8 | pages = 920–8 | year = 2007 | month = April | pmid = 17437997 | pmc = 1847710 | doi = 10.1101/gad.1527307 | url = | issn = ] The observation that SirT3 has nuclear activity came from a report that SirT3 protected cardiomyocytes from stress mediated cell death and that this effect was due to deacetylation of a nuclear factor, Ku-70.cite journal | author = Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP | title = SIRT3 is a stress responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku-70 | journal = Mol. Cell. Biol. | volume = | issue = | pages = | year = 2008 | month = August | pmid = 18710944 | doi = 10.1128/MCB.00426-08 | url = | issn = ]

Clinical significance

The is a strong association between SIRT3 alleles and longevity in males.cite journal | author = Bellizzi D, Rose G, Cavalcante P, Covello G, Dato S, De Rango F, Greco V, Maggiolini M, Feraco E, Mari V, Franceschi C, Passarino G, De Benedictis G' | title = A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages | journal = Genomics | volume = 85 | issue = 2 | pages = 258–63 | year = 2005 | month = February | pmid = 15676284 | doi = 10.1016/j.ygeno.2004.11.003 | url = | issn = ]

References

Further reading

PBB_Further_reading
citations =
*cite journal | author=Bellizzi D, Dato S, Cavalcante P, "et al." |title=Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13. |journal=Genomics |volume=89 |issue= 1 |pages= 143–50 |year= 2007 |pmid= 17059877 |doi= 10.1016/j.ygeno.2006.09.004
*cite journal | author=Rual JF, Venkatesan K, Hao T, "et al." |title=Towards a proteome-scale map of the human protein-protein interaction network. |journal=Nature |volume=437 |issue= 7062 |pages= 1173–8 |year= 2005 |pmid= 16189514 |doi= 10.1038/nature04209
*cite journal | author=Bellizzi D, Rose G, Cavalcante P, "et al." |title=A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages. |journal=Genomics |volume=85 |issue= 2 |pages= 258–63 |year= 2005 |pmid= 15676284 |doi= 10.1016/j.ygeno.2004.11.003
*cite journal | author=Gerhard DS, Wagner L, Feingold EA, "et al." |title=The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). |journal=Genome Res. |volume=14 |issue= 10B |pages= 2121–7 |year= 2004 |pmid= 15489334 |doi= 10.1101/gr.2596504
*cite journal | author=Strausberg RL, Feingold EA, Grouse LH, "et al." |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899
*cite journal | author=Onyango P, Celic I, McCaffery JM, "et al." |title=SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localized to mitochondria. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 21 |pages= 13653–8 |year= 2002 |pmid= 12374852 |doi= 10.1073/pnas.222538099
*cite journal | author=Schwer B, North BJ, Frye RA, "et al." |title=The human silent information regulator (Sir)2 homologue hSIRT3 is a mitochondrial nicotinamide adenine dinucleotide-dependent deacetylase. |journal=J. Cell Biol. |volume=158 |issue= 4 |pages= 647–57 |year= 2002 |pmid= 12186850 |doi= 10.1083/jcb.200205057
*cite journal | author=Yang YH, Chen YH, Zhang CY, "et al." |title=Cloning and characterization of two mouse genes with homology to the yeast Sir2 gene. |journal=Genomics |volume=69 |issue= 3 |pages= 355–69 |year= 2001 |pmid= 11056054 |doi= 10.1006/geno.2000.6360
*cite journal | author=Frye RA |title=Phylogenetic classification of prokaryotic and eukaryotic Sir2-like proteins. |journal=Biochem. Biophys. Res. Commun. |volume=273 |issue= 2 |pages= 793–8 |year= 2000 |pmid= 10873683 |doi= 10.1006/bbrc.2000.3000
*cite journal | author=Frye RA |title=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. |journal=Biochem. Biophys. Res. Commun. |volume=260 |issue= 1 |pages= 273–9 |year= 1999 |pmid= 10381378 |doi= 10.1006/bbrc.1999.0897
*cite journal | author=Bonaldo MF, Lennon G, Soares MB |title=Normalization and subtraction: two approaches to facilitate gene discovery. |journal=Genome Res. |volume=6 |issue= 9 |pages= 791–806 |year= 1997 |pmid= 8889548 |doi=
*cite journal | author=Scher MB, Vaquero A, Reinberg D|title=SirT3 is a nuclear NAD+-dependent histone deacetylase that translocates to the mitochondria upon cellular stress. |journal=Genes Dev. |volume=21 |issue= 8 |pages= 920–928 |year= 2007 |pmid=17437997 |doi=
*cite journal | author=Sundaresan NR, Samant SA, Pillai VB, Rajamohan SB, Gupta MP|title=SIRT3 is a stress responsive deacetylase in cardiomyocytes that protects cells from stress-mediated cell death by deacetylation of Ku-70. |journal=Mol Cell Biol. |volume=Epub ahead of print |year= 2008 |pmid= 18710944 |doi=

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