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Showing Protein NAD-dependent protein deacetylase sirtuin-1 (HMDBP08879)

IdentificationBiological propertiesGene propertiesProtein propertiesExternal linksReferencesXMLShow 6 metabolites
Identification
HMDB Protein ID HMDBP08879
Secondary Accession Numbers
  • 14606
Name NAD-dependent protein deacetylase sirtuin-1
Synonyms
  1. SIR2-like protein 1
  2. hSIR2
  3. hSIRT1
  4. Regulatory protein SIR2 homolog 1
Gene Name SIRT1
Protein Type Unknown
Biological Properties
General Function Involved in zinc ion binding
Specific Function NAD-dependent protein deacetylase that links transcriptional regulation directly to intracellular energetics and participates in the coordination of several separated cellular functions such as cell cycle, response to DNA damage, metobolism, apoptosis and autophagy. Can modulate chromatin function through deacetylation of histones and can promote alterations in the methylation of histones and DNA, leading to transcriptional repression. Deacetylates a broad range of transcription factors and coregulators, thereby regulating target gene expression positively and negatively. Serves as a sensor of the cytosolic ratio of NAD(+)/NADH which is altered by glucose deprivation and metabolic changes associated with caloric restriction. Is essential in skeletal muscle cell differentiation and in response to low nutrients mediates the inhibitory effect on skeletal myoblast differentiation which also involves 5'-AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT). Component of the eNoSC (energy-dependent nucleolar silencing) complex, a complex that mediates silencing of rDNA in response to intracellular energy status and acts by recruiting histone-modifying enzymes. The eNoSC complex is able to sense the energy status of cell: upon glucose starvation, elevation of NAD(+)/NADP(+) ratio activates SIRT1, leading to histone H3 deacetylation followed by dimethylation of H3 at 'Lys-9' (H3K9me2) by SUV39H1 and the formation of silent chromatin in the rDNA locus. Deacetylates 'Lys-266' of SUV39H1, leading to its activation. Inhibits skeletal muscle differentiation by deacetylating PCAF and MYOD1. Deacetylates H2A and 'Lys-26' of HIST1H1E. Deacetylates 'Lys-16' of histone H4 (in vitro). Involved in NR0B2/SHP corepression function through chromatin remodeling: Recruited to LRH1 target gene promoters by NR0B2/SHP thereby stimulating histone H3 and H4 deacetylation leading to transcriptional repression. Proposed to contribute to genomic integrity via positive regulation of telomere length; however, reports on localization to pericentromeric heterochromatin are conflicting. Proposed to play a role in constitutive heterochromatin (CH) formation and/or maintenance through regulation of the available pool of nuclear SUV39H1. Upon oxidative/metabolic stress decreases SUV39H1 degradation by inhibiting SUV39H1 polyubiquitination by MDM2. This increase in SUV39H1 levels enhances SUV39H1 turnover in CH, which in turn seems to accelerate renewal of the heterochromatin which correlates with greater genomic integrity during stress response. Deacetylates 'Lys-382' of p53/TP53 and impairs its ability to induce transcription-dependent proapoptotic program and modulate cell senescence. Deacetylates TAF1B and thereby represses rDNA transcription by the RNA polymerase I. Deacetylates MYC, promotes the association of MYC with MAX and decreases MYC stability leading to compromised transformational capability. Deacetylates FOXO3 in response to oxidative stress thereby increasing its ability to induce cell cycle arrest and resistance to oxidative stress but inhibiting FOXO3-mediated induction of apoptosis transcriptional activity; also leading to FOXO3 ubiquitination and protesomal degradation. Appears to have a similar effect on MLLT7/FOXO4 in regulation of transcriptional activity and apoptosis. Deacetylates DNMT1; thereby impairs DNMT1 methyltransferase-independent transcription repressor activity, modulates DNMT1 cell cycle regulatory function and DNMT1-mediated gene silencing. Deacetylates RELA/NF-kappa-B p65 thereby inhibiting its transactivating potential and augments apoptosis in response to TNF-alpha. Deacetylates HIF1A, KAT5/TIP60, RB1 and HIC1. Deacetylates FOXO1 resulting in its nuclear retention and enhancement of its transcriptional activity leading to increased gluconeogenesis in liver. Inhibits E2F1 transcriptional activity and apoptotic function, possibly by deacetylation. Involved in HES1- and HEY2-mediated transcriptional repression. In cooperation with MYCN seems to be involved in transcriptional repression of DUSP6/MAPK3 leading to MYCN stabilization by phosphorylation at 'Ser-62'. Deacetylates MEF2D. Required for antagonist-mediated transcription suppression of AR-dependent genes which may be linked to local deacetylation of histone H3. Represses HNF1A-mediated transcription. Required for the repression of ESRRG by CREBZF. Modulates AP-1 transcription factor activity. Deacetylates NR1H3 AND NR1H2 and deacetylation of NR1H3 at 'Lys-434' positively regulates transcription of NR1H3:RXR target genes, promotes NR1H3 proteosomal degradation and results in cholesterol efflux; a promoter clearing mechanism after reach round of transcription is proposed. Involved in lipid metabolism. Implicated in regulation of adipogenesis and fat mobilization in white adipocytes by repression of PPARG which probably involves association with NCOR1 and SMRT/NCOR2. Deacetylates ACSS2 leading to its activation, and HMGCS1. Involved in liver and muscle metabolism. Through deacteylation and activation of PPARGC1A is required to activate fatty acid oxidation in skeletel muscle under low-glucose conditions and is involved in glucose homeostasis. Involved in regulation of PPARA and fatty acid beta-oxidation in liver. Involved in positive regulation of insulin secretion in pancreatic beta cells in response to glucose; the function seems to imply transcriptional repression of UCP2. Proposed to deacetylate IRS2 thereby facilitating its insuline-induced tyrosine phosphorylation. Deacetylates SREBF1 isoform SREBP-1C thereby decreasing its stability and transactivation in lipogenic gene expression. Involved in DNA damage response by repressing genes which are involved in DNA repair, such as XPC and TP73, deacetylating XRCC6/Ku70, and faciliting recruitment of additional factors to sites of damaged DNA, such as SIRT1-deacetylated NBN can recruit ATM to initiate DNA repair and SIRT1-deacetylated XPA interacts with RPA2. Also involved in DNA repair of DNA double-strand breaks by homologous recombination and specifically single-strand annealing independently of XRCC6/Ku70 and NBN. Transcriptional suppression of XPC probably involves an E2F4:RBL2 suppressor complex and protein kinase B (AKT) signaling. Transcriptional suppression of TP73 probably involves E2F4 and PCAF. Deacetylates WRN thereby regulating its helicase and exonuclease activities and regulates WRN nuclear translocation in response to DNA damage. Deacetylates APEX1 at 'Lys-6' and 'Lys-7' and stimulates cellular AP endonuclease activity by promoting the association of APEX1 to XRCC1. Increases p53/TP53-mediated transcription-independent apoptosis by blocking nuclear translocation of cytoplasmic p53/TP53 and probably redirecting it to mitochondria. Deacetylates XRCC6/Ku70 at 'Lys-539' and 'Lys-542' causing it to sequester BAX away from mitochondria thereby inhibiting stress-induced apoptosis. Is involved in autophagy, presumably by deacetylating ATG5, ATG7 and MAP1LC3B/ATG8. Deacetylates AKT1 which leads to enhanced binding of AKT1 and PDK1 to PIP3 and promotes their activation. Proposed to play role in regulation of STK11/LBK1-dependent AMPK signaling pathways implicated in cellular senescence which seems to involve the regulation of the acetylation status of STK11/LBK1. Can deacetylate STK11/LBK1 and thereby increase its activity, cytoplasmic localization and association with STRAD; however, the relevance of such activity in normal cells is unclear. In endothelial cells is shown to inhibit STK11/LBK1 activity and to promote its degradation. Deacetylates SMAD7 at 'Lys-64' and 'Lys-70' thereby promoting its degradation. Deacetylates CIITA and augments its MHC class II transacivation and contributes to its stability. Deacteylates MECOM/EVI1. Isoform 2 is shown to deacetylate 'Lys-382' of p53/TP53, however with lower activity than isoform 1. In combination, the two isoforms exert an additive effect. Isoform 2 regulates p53/TP53 expression and cellular stress response and is in turn repressed by p53/TP53 presenting a SIRT1 isoform-dependent auto-regulatory loop. In case of HIV-1 infection, interacts with and deacetylates the viral Tat protein. The viral Tat protein inhibits SIRT1 deacetylation activity toward RELA/NF-kappa-B p65, thereby potentiates its transcriptional activity and SIRT1 is proposed to contribute to T-cell hyperactivation during infection. SirtT1 75 kDa fragment: catalytically inactive 75SirT1 may be involved in regulation of apoptosis. May be involved in protecting chondrocytes from apoptotic death by associating with cytochrome C and interfering with apoptosome assembly.
Pathways
  • Amphetamine addiction
Reactions
NAD + an acetylprotein → Niacinamide + O-acetyl-ADP-ribose + a protein details
GO Classification
Biological Process
regulation of protein import into nucleus, translocation
regulation of smooth muscle cell apoptotic process
spermatogenesis
regulation of glucose metabolic process
positive regulation of cell proliferation
negative regulation of apoptotic process
single strand break repair
negative regulation of fat cell differentiation
negative regulation of protein kinase B signaling cascade
DNA replication
methylation-dependent chromatin silencing
muscle organ development
negative regulation of I-kappaB kinase/NF-kappaB cascade
cellular response to tumor necrosis factor
response to insulin stimulus
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator
white fat cell differentiation
positive regulation of macroautophagy
positive regulation of cysteine-type endopeptidase activity involved in apoptotic process
triglyceride mobilization
rRNA processing
angiogenesis
fatty acid homeostasis
DNA synthesis involved in DNA repair
regulation of mitotic cell cycle
cell aging
negative regulation of NF-kappaB transcription factor activity
virus-host interaction
negative regulation of transcription from RNA polymerase II promoter
positive regulation of transcription from RNA polymerase II promoter
cellular triglyceride homeostasis
cellular response to starvation
negative regulation of cell growth
positive regulation of DNA repair
cholesterol homeostasis
regulation of bile acid biosynthetic process
negative regulation of transforming growth factor beta receptor signaling pathway
cellular glucose homeostasis
positive regulation of cholesterol efflux
ovulation from ovarian follicle
cellular response to hypoxia
transcription, DNA-dependent
cellular response to hydrogen peroxide
proteasomal ubiquitin-dependent protein catabolic process
cellular response to ionizing radiation
negative regulation of DNA damage response, signal transduction by p53 class mediator
chromatin silencing at rDNA
establishment of chromatin silencing
maintenance of chromatin silencing
negative regulation of androgen receptor signaling pathway
negative regulation of cAMP-dependent protein kinase activity
negative regulation of cellular response to testosterone stimulus
negative regulation of cellular senescence
negative regulation of helicase activity
negative regulation of peptidyl-lysine acetylation
negative regulation of prostaglandin biosynthetic process
negative regulation of TOR signaling cascade
peptidyl-lysine acetylation
peptidyl-lysine deacetylation
positive regulation of adaptive immune response
positive regulation of cAMP-dependent protein kinase activity
positive regulation of cellular senescence
positive regulation of chromatin silencing
positive regulation of insulin receptor signaling pathway
positive regulation of macrophage apoptotic process
positive regulation of MHC class II biosynthetic process
protein destabilization
protein ubiquitination
pyrimidine dimer repair by nucleotide-excision repair
regulation of endodeoxyribonuclease activity
regulation of peroxisome proliferator activated receptor signaling pathway
Cellular Component
cytoplasm
nucleolus
nuclear euchromatin
PML body
chromatin silencing complex
nuclear inner membrane
nuclear heterochromatin
rDNA heterochromatin
Function
ion binding
cation binding
metal ion binding
binding
nucleotide binding
catalytic activity
hydrolase activity
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds
transition metal ion binding
zinc ion binding
nad or nadh binding
nad binding
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides
Molecular Function
metal ion binding
NAD+ binding
transcription corepressor activity
NAD-dependent histone deacetylase activity (H3-K9 specific)
Process
metabolic process
macromolecule metabolic process
protein amino acid deacetylation
gene silencing
chromatin silencing
cellular process
biological regulation
regulation of biological process
regulation of metabolic process
regulation of macromolecule metabolic process
regulation of gene expression
regulation of transcription
post-translational protein modification
macromolecule modification
protein modification process
Cellular Location
  1. Nucleus
  2. PML body
Gene Properties
Chromosome Location 10
Locus 10q21.3
SNPs SIRT1
Gene Sequence 
>2244 bp
ATGGCGGACGAGGCGGCCCTCGCCCTTCAGCCCGGCGGCTCCCCCTCGGCGGCGGGGGCC
GACAGGGAGGCCGCGTCGTCCCCCGCCGGGGAGCCGCTCCGCAAGAGGCCGCGGAGAGAT
GGTCCCGGCCTCGAGCGGAGCCCGGGCGAGCCCGGTGGGGCGGCCCCAGAGCGTGAGGTG
CCGGCGGCGGCCAGGGGCTGCCCGGGTGCGGCGGCGGCGGCGCTGTGGCGGGAGGCGGAG
GCAGAGGCGGCGGCGGCAGGCGGGGAGCAAGAGGCCCAGGCGACTGCGGCGGCTGGGGAA
GGAGACAATGGGCCGGGCCTGCAGGGCCCATCTCGGGAGCCACCGCTGGCCGACAACTTG
TACGACGAAGACGACGACGACGAGGGCGAGGAGGAGGAAGAGGCGGCGGCGGCGGCGATT
GGGTACCGAGATAACCTTCTGTTCGGTGATGAAATTATCACTAATGGTTTTCATTCCTGT
GAAAGTGATGAGGAGGATAGAGCCTCACATGCAAGCTCTAGTGACTGGACTCCAAGGCCA
CGGATAGGTCCATATACTTTTGTTCAGCAACATCTTATGATTGGCACAGATCCTCGAACA
ATTCTTAAAGATTTATTGCCGGAAACAATACCTCCACCTGAGTTGGATGATATGACACTG
TGGCAGATTGTTATTAATATCCTTTCAGAACCACCAAAAAGGAAAAAAAGAAAAGATATT
AATACAATTGAAGATGCTGTGAAATTACTGCAAGAGTGCAAAAAAATTATAGTTCTAACT
GGAGCTGGGGTGTCTGTTTCATGTGGAATACCTGACTTCAGGTCAAGGGATGGTATTTAT
GCTCGCCTTGCTGTAGACTTCCCAGATCTTCCAGATCCTCAAGCGATGTTTGATATTGAA
TATTTCAGAAAAGATCCAAGACCATTCTTCAAGTTTGCAAAGGAAATATATCCTGGACAA
TTCCAGCCATCTCTCTGTCACAAATTCATAGCCTTGTCAGATAAGGAAGGAAAACTACTT
CGCAACTATACCCAGAACATAGACACGCTGGAACAGGTTGCGGGAATCCAAAGGATAATT
CAGTGTCATGGTTCCTTTGCAACAGCATCTTGCCTGATTTGTAAATACAAAGTTGACTGT
GAAGCTGTACGAGGAGATATTTTTAATCAGGTAGTTCCTCGATGTCCTAGGTGCCCAGCT
GATGAACCGCTTGCTATCATGAAACCAGAGATTGTGTTTTTTGGTGAAAATTTACCAGAA
CAGTTTCATAGAGCCATGAAGTATGACAAAGATGAAGTTGACCTCCTCATTGTTATTGGG
TCTTCCCTCAAAGTAAGACCAGTAGCACTAATTCCAAGTTCCATACCCCATGAAGTGCCT
CAGATATTAATTAATAGAGAACCTTTGCCTCATCTGCATTTTGATGTAGAGCTTCTTGGA
GACTGTGATGTCATAATTAATGAATTGTGTCATAGGTTAGGTGGTGAATATGCCAAACTT
TGCTGTAACCCTGTAAAGCTTTCAGAAATTACTGAAAAACCTCCACGAACACAAAAAGAA
TTGGCTTATTTGTCAGAGTTGCCACCCACACCTCTTCATGTTTCAGAAGACTCAAGTTCA
CCAGAAAGAACTTCACCACCAGATTCTTCAGTGATTGTCACACTTTTAGACCAAGCAGCT
AAGAGTAATGATGATTTAGATGTGTCTGAATCAAAAGGTTGTATGGAAGAAAAACCACAG
GAAGTACAAACTTCTAGGAATGTTGAAAGTATTGCTGAACAGATGGAAAATCCGGATTTG
AAGAATGTTGGTTCTAGTACTGGGGAGAAAAATGAAAGAACTTCAGTGGCTGGAACAGTG
AGAAAATGCTGGCCTAATAGAGTGGCAAAGGAGCAGATTAGTAGGCGGCTTGATGGTAAT
CAGTATCTGTTTTTGCCACCAAATCGTTACATTTTCCATGGCGCTGAGGTATATTCAGAC
TCTGAAGATGACGTCTTATCCTCTAGTTCTTGTGGCAGTAACAGTGATAGTGGGACATGC
CAGAGTCCAAGTTTAGAAGAACCCATGGAGGATGAAAGTGAAATTGAAGAATTCTACAAT
GGCTTAGAAGATGAGCCTGATGTTCCAGAGAGAGCTGGAGGAGCTGGATTTGGGACTGAT
GGAGATGATCAAGAGGCAATTAATGAAGCTATATCTGTGAAACAGGAAGTAACAGACATG
AACTATCCATCAAACAAATCATAG
Protein Properties
Number of Residues 747
Molecular Weight 50496.105
Theoretical pI 4.775
Pfam Domain Function
Signals Not Available
Transmembrane Regions Not Available
Protein Sequence 
>NAD-dependent deacetylase sirtuin-1
MADEAALALQPGGSPSAAGADREAASSPAGEPLRKRPRRDGPGLERSPGEPGGAAPEREV
PAAARGCPGAAAAALWREAEAEAAAAGGEQEAQATAAAGEGDNGPGLQGPSREPPLADNL
YDEDDDDEGEEEEEAAAAAIGYRDNLLFGDEIITNGFHSCESDEEDRASHASSSDWTPRP
RIGPYTFVQQHLMIGTDPRTILKDLLPETIPPPELDDMTLWQIVINILSEPPKRKKRKDI
NTIEDAVKLLQECKKIIVLTGAGVSVSCGIPDFRSRDGIYARLAVDFPDLPDPQAMFDIE
YFRKDPRPFFKFAKEIYPGQFQPSLCHKFIALSDKEGKLLRNYTQNIDTLEQVAGIQRII
QCHGSFATASCLICKYKVDCEAVRGDIFNQVVPRCPRCPADEPLAIMKPEIVFFGENLPE
QFHRAMKYDKDEVDLLIVIGSSLKVRPVALIPSSIPHEVPQILINREPLPHLHFDVELLG
DCDVIINELCHRLGGEYAKLCCNPVKLSEITEKPPRTQKELAYLSELPPTPLHVSEDSSS
PERTSPPDSSVIVTLLDQAAKSNDDLDVSESKGCMEEKPQEVQTSRNVESIAEQMENPDL
KNVGSSTGEKNERTSVAGTVRKCWPNRVAKEQISRRLDGNQYLFLPPNRYIFHGAEVYSD
SEDDVLSSSSCGSNSDSGTCQSPSLEEPMEDESEIEEFYNGLEDEPDVPERAGGAGFGTD
GDDQEAINEAISVKQEVTDMNYPSNKS
GenBank ID Protein 7555471
UniProtKB/Swiss-Prot ID Q96EB6
UniProtKB/Swiss-Prot Entry Name SIRT1_HUMAN
PDB IDs Not Available
GenBank Gene ID AF083106
GeneCard ID SIRT1
GenAtlas ID SIRT1
HGNC ID HGNC:14929
References
General References
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