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Q8K2C6

- SIR5_MOUSE

UniProt

Q8K2C6 - SIR5_MOUSE

Protein

NAD-dependent protein deacylase sirtuin-5, mitochondrial

Gene

Sirt5

Organism
Mus musculus (Mouse)
Status
Reviewed - Annotation score: 5 out of 5- Experimental evidence at protein leveli
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    • History
      Entry version 97 (01 Oct 2014)
      Sequence version 1 (01 Oct 2002)
      Previous versions | rss
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    Functioni

    NAD-dependent lysine demalonylase and desuccinylase that specifically removes malonyl and succinyl groups on target proteins. Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting. Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species. Has weak NAD-dependent protein deacetylase activity; however this activity may not be physiologically relevant in vivo. Can deacetylate cytochrome c (CYCS) and a number of other proteins in vitro such as Uox.5 Publications

    Catalytic activityi

    NAD+ + a malonylprotein = nicotinamide + O-malonyl-ADP-ribose + a protein.UniRule annotation
    NAD+ + a succinylprotein = nicotinamide + O-succinyl-ADP-ribose + a protein.UniRule annotation

    Cofactori

    Binds 1 zinc ion per subunit.UniRule annotation

    Sites

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Binding sitei102 – 1021SubstrateUniRule annotation
    Binding sitei105 – 1051SubstrateUniRule annotation
    Active sitei158 – 1581Proton acceptorUniRule annotation
    Metal bindingi166 – 1661ZincUniRule annotation
    Metal bindingi169 – 1691ZincUniRule annotation
    Metal bindingi207 – 2071ZincUniRule annotation
    Metal bindingi212 – 2121ZincUniRule annotation
    Binding sitei293 – 2931NAD; via amide nitrogenUniRule annotation

    Regions

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Nucleotide bindingi58 – 7720NADUniRule annotationAdd
    BLAST
    Nucleotide bindingi140 – 1434NADUniRule annotation
    Nucleotide bindingi249 – 2513NADUniRule annotation
    Nucleotide bindingi275 – 2773NADUniRule annotation

    GO - Molecular functioni

    1. NAD+ binding Source: UniProtKB-HAMAP
    2. protein binding Source: IntAct
    3. protein-malonyllysine demalonylase activity Source: UniProtKB
    4. protein-succinyllysine desuccinylase activity Source: UniProtKB
    5. zinc ion binding Source: UniProtKB-HAMAP

    GO - Biological processi

    1. negative regulation of reactive oxygen species metabolic process Source: Ensembl
    2. peptidyl-lysine demalonylation Source: UniProtKB
    3. peptidyl-lysine desuccinylation Source: UniProtKB
    4. protein deacetylation Source: UniProtKB
    5. protein desuccinylation Source: UniProtKB

    Keywords - Molecular functioni

    Hydrolase

    Keywords - Ligandi

    Metal-binding, NAD, Zinc

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    NAD-dependent protein deacylase sirtuin-5, mitochondrialUniRule annotation (EC:3.5.1.-UniRule annotation)
    Alternative name(s):
    Regulatory protein SIR2 homolog 5UniRule annotation
    SIR2-like protein 5UniRule annotation
    Gene namesi
    Name:Sirt5
    Synonyms:Sir2l5
    OrganismiMus musculus (Mouse)
    Taxonomic identifieri10090 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
    ProteomesiUP000000589: Chromosome 13

    Organism-specific databases

    MGIiMGI:1915596. Sirt5.

    Subcellular locationi

    Mitochondrion. Cytoplasmcytosol. Nucleus
    Note: Mainly mitochondrial. Also present extramitochondrially: a fraction is present in the cytosol and very small amounts are also detected in the nucleus.

    GO - Cellular componenti

    1. cytosol Source: UniProtKB
    2. mitochondrial intermembrane space Source: UniProtKB
    3. mitochondrial matrix Source: UniProtKB
    4. mitochondrion Source: UniProtKB
    5. nucleus Source: UniProtKB

    Keywords - Cellular componenti

    Cytoplasm, Mitochondrion, Nucleus

    Pathology & Biotechi

    Disruption phenotypei

    Mice are born at an abnormal Mendelian ratio with the number of live-born pups reduced by 40% (PubMed:24076663). Surviving mice display a global protein hypersuccinylation in both liver and skeletal muscle, while global lysine acetylation is not significantly impacted (PubMed:22076378, PubMed:23806337). Mice display elevated levels of blood ammonia during fasting, but otherwise are metabolically similar to wild-type (PubMed:24076663). No overt phenotype observed in mice on chow or high fat diet, suggesting that Sirt5 may be dispensable for basal homeostasis under these conditions (PubMed:24076663). After 48 hours of fasting, the absence of Cps1 activation leads to elevated blood ammonia levels, possibly due to the presence of succinylation at 'Lys-1291' in Cps1 (PubMed:22076378).5 Publications

    Mutagenesis

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Mutagenesisi158 – 1581H → Y: Loss of enzyme activity. 1 Publication

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Transit peptidei1 – 3636Mitochondrion1 PublicationUniRule annotationAdd
    BLAST
    Chaini37 – 310274NAD-dependent protein deacylase sirtuin-5, mitochondrialPRO_0000110267Add
    BLAST

    Proteomic databases

    MaxQBiQ8K2C6.
    PaxDbiQ8K2C6.
    PRIDEiQ8K2C6.

    PTM databases

    PhosphoSiteiQ8K2C6.

    Expressioni

    Tissue specificityi

    Detected in brain, liver, heart, kidney, lung, thymus, spleen, skeletal muscle, intestine, pancreas and testis (at protein level).1 Publication

    Gene expression databases

    ArrayExpressiQ8K2C6.
    BgeeiQ8K2C6.
    GenevestigatoriQ8K2C6.

    Interactioni

    Subunit structurei

    Monomer. Homodimer. Interacts with CPS1.1 PublicationUniRule annotation

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    Cps1Q8C1962EBI-2348809,EBI-2348828

    Protein-protein interaction databases

    IntActiQ8K2C6. 5 interactions.
    MINTiMINT-4134742.

    Structurei

    3D structure databases

    ProteinModelPortaliQ8K2C6.
    SMRiQ8K2C6. Positions 34-302.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
    Domaini41 – 309269Deacetylase sirtuin-typeUniRule annotationAdd
    BLAST

    Domaini

    In contrast to class I sirtuins, class III sirtuins have only weak deacetylase activity. Difference in substrate specificity is probably due to a larger hydrophobic pocket with 2 residues (Tyr-102 and Arg-105) that bind to malonylated and succinylated substrates and define the specificity.UniRule annotation

    Sequence similaritiesi

    Belongs to the sirtuin family. Class III subfamily.UniRule annotation
    Contains 1 deacetylase sirtuin-type domain.UniRule annotation

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiCOG0846.
    GeneTreeiENSGT00740000115330.
    HOGENOMiHOG000085950.
    HOVERGENiHBG056009.
    InParanoidiQ8K2C6.
    KOiK11415.
    OMAiVESEFEE.
    OrthoDBiEOG77Q4XG.
    PhylomeDBiQ8K2C6.
    TreeFamiTF106183.

    Family and domain databases

    Gene3Di3.30.1600.10. 2 hits.
    3.40.50.1220. 3 hits.
    HAMAPiMF_01121. Sirtuin_ClassIII.
    InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
    IPR003000. Sirtuin.
    IPR026591. Sirtuin_cat_small_dom.
    IPR027546. Sirtuin_class_III.
    IPR026590. Ssirtuin_cat_dom.
    [Graphical view]
    PANTHERiPTHR11085. PTHR11085. 1 hit.
    PfamiPF02146. SIR2. 1 hit.
    [Graphical view]
    SUPFAMiSSF52467. SSF52467. 1 hit.
    PROSITEiPS50305. SIRTUIN. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Sequence processingi: The displayed sequence is further processed into a mature form.

    Q8K2C6-1 [UniParc]FASTAAdd to Basket

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    MRPLLIAPGR FISQLCCRRK PPASPQSKIC LTMARPSSNM ADFRKCFANA    50
    KHIAIISGAG VSAESGVPTF RGAGGYWRKW QAQDLATPQA FARNPSQVWE 100
    FYHYRREVMR SKEPNPGHLA IAQCEARLRD QGRRVVVITQ NIDELHRKAG 150
    TKNLLEIHGT LFKTRCTSCG TVAENYRSPI CPALAGKGAP EPETQDARIP 200
    VDKLPRCEEA GCGGLLRPHV VWFGENLDPA ILEEVDRELA LCDLCLVVGT 250
    SSVVYPAAMF APQVASRGVP VAEFNMETTP ATDRFRFHFP GPCGKTLPEA 300
    LAPHETERTS 310
    Length:310
    Mass (Da):34,134
    Last modified:October 1, 2002 - v1
    Checksum:iA0C4962D5E6F8729
    GO

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    BC031770 mRNA. Translation: AAH31770.1.
    CCDSiCCDS26478.1.
    RefSeqiNP_849179.1. NM_178848.3.
    UniGeneiMm.35325.

    Genome annotation databases

    EnsembliENSMUST00000066804; ENSMUSP00000071048; ENSMUSG00000054021.
    GeneIDi68346.
    KEGGimmu:68346.
    UCSCiuc007qfz.1. mouse.

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBL
    GenBank
    DDBJ
    Links Updated
    BC031770 mRNA. Translation: AAH31770.1 .
    CCDSi CCDS26478.1.
    RefSeqi NP_849179.1. NM_178848.3.
    UniGenei Mm.35325.

    3D structure databases

    ProteinModelPortali Q8K2C6.
    SMRi Q8K2C6. Positions 34-302.
    ModBasei Search...
    MobiDBi Search...

    Protein-protein interaction databases

    IntActi Q8K2C6. 5 interactions.
    MINTi MINT-4134742.

    PTM databases

    PhosphoSitei Q8K2C6.

    Proteomic databases

    MaxQBi Q8K2C6.
    PaxDbi Q8K2C6.
    PRIDEi Q8K2C6.

    Protocols and materials databases

    Structural Biology Knowledgebase Search...

    Genome annotation databases

    Ensembli ENSMUST00000066804 ; ENSMUSP00000071048 ; ENSMUSG00000054021 .
    GeneIDi 68346.
    KEGGi mmu:68346.
    UCSCi uc007qfz.1. mouse.

    Organism-specific databases

    CTDi 23408.
    MGIi MGI:1915596. Sirt5.

    Phylogenomic databases

    eggNOGi COG0846.
    GeneTreei ENSGT00740000115330.
    HOGENOMi HOG000085950.
    HOVERGENi HBG056009.
    InParanoidi Q8K2C6.
    KOi K11415.
    OMAi VESEFEE.
    OrthoDBi EOG77Q4XG.
    PhylomeDBi Q8K2C6.
    TreeFami TF106183.

    Miscellaneous databases

    NextBioi 327033.
    PROi Q8K2C6.
    SOURCEi Search...

    Gene expression databases

    ArrayExpressi Q8K2C6.
    Bgeei Q8K2C6.
    Genevestigatori Q8K2C6.

    Family and domain databases

    Gene3Di 3.30.1600.10. 2 hits.
    3.40.50.1220. 3 hits.
    HAMAPi MF_01121. Sirtuin_ClassIII.
    InterProi IPR029035. DHS-like_NAD/FAD-binding_dom.
    IPR003000. Sirtuin.
    IPR026591. Sirtuin_cat_small_dom.
    IPR027546. Sirtuin_class_III.
    IPR026590. Ssirtuin_cat_dom.
    [Graphical view ]
    PANTHERi PTHR11085. PTHR11085. 1 hit.
    Pfami PF02146. SIR2. 1 hit.
    [Graphical view ]
    SUPFAMi SSF52467. SSF52467. 1 hit.
    PROSITEi PS50305. SIRTUIN. 1 hit.
    [Graphical view ]
    ProtoNeti Search...

    Publicationsi

    1. "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
      The MGC Project Team
      Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
      Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
      Tissue: Mammary tumor.
    2. "SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle."
      Nakagawa T., Lomb D.J., Haigis M.C., Guarente L.
      Cell 137:560-570(2009) [PubMed] [Europe PMC] [Abstract]
      Cited for: PROTEIN SEQUENCE OF N-TERMINUS, FUNCTION, MUTAGENESIS OF HIS-158, SUBCELLULAR LOCATION, INTERACTION WITH CPS1, DISRUPTION PHENOTYPE, TISSUE SPECIFICITY.
    3. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
    4. "Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase."
      Du J., Zhou Y., Su X., Yu J.J., Khan S., Jiang H., Kim J., Woo J., Kim J.H., Choi B.H., He B., Chen W., Zhang S., Cerione R.A., Auwerx J., Hao Q., Lin H.
      Science 334:806-809(2011) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, DISRUPTION PHENOTYPE.
    5. "SIRT5 deacetylates and activates urate oxidase in liver mitochondria of mice."
      Nakamura Y., Ogura M., Ogura K., Tanaka D., Inagaki N.
      FEBS Lett. 586:4076-4081(2012) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION.
    6. "SIRT5-mediated lysine desuccinylation impacts diverse metabolic pathways."
      Park J., Chen Y., Tishkoff D.X., Peng C., Tan M., Dai L., Xie Z., Zhang Y., Zwaans B.M., Skinner M.E., Lombard D.B., Zhao Y.
      Mol. Cell 50:919-930(2013) [PubMed] [Europe PMC] [Abstract]
      Cited for: FUNCTION, SUBCELLULAR LOCATION, DISRUPTION PHENOTYPE.
    7. Cited for: DISRUPTION PHENOTYPE.

    Entry informationi

    Entry nameiSIR5_MOUSE
    AccessioniPrimary (citable) accession number: Q8K2C6
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 31, 2003
    Last sequence update: October 1, 2002
    Last modified: October 1, 2014
    This is version 97 of the entry and version 1 of the sequence. [Complete history]
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program

    Miscellaneousi

    Caution

    The ability to deacetylate Uox in vivo is unclear. The anti-acetylated lysine antibody used in the assay is not fully specific and cross-reacts with some acylated lysines. It is therefore possible that it also recognizes N6-malonyllysine and N6-succinyllysine residues (PubMed:23085393).1 Publication

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. MGD cross-references
      Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
    2. SIMILARITY comments
      Index of protein domains and families

    External Data

    Dasty 3