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Protein

NAD-dependent protein deacylase sirtuin-5, mitochondrial

Gene

SIRT5

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

NAD-dependent lysine demalonylase, desuccinylase and deglutarylase that specifically removes malonyl, succinyl and glutaryl groups on target proteins (PubMed:21908771, PubMed:22076378, PubMed:24703693, PubMed:29180469). Activates CPS1 and contributes to the regulation of blood ammonia levels during prolonged fasting: acts by mediating desuccinylation and deglutarylation of CPS1, thereby increasing CPS1 activity in response to elevated NAD levels during fasting (PubMed:22076378, PubMed:24703693). Activates SOD1 by mediating its desuccinylation, leading to reduced reactive oxygen species (PubMed:24140062). Activates SHMT2 by mediating its desuccinylation (PubMed:29180469). Modulates ketogenesis through the desuccinylation and activation of HMGCS2 (By similarity). 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.By similarity6 Publications

Miscellaneous

The mechanism of demalonylation and desuccinylation involves the presence of a 1',2'-cyclic intermediate, suggesting that sirtuins use the ADP-ribose-peptidylamidate mechanism to remove acyl groups from substrate lysine residues.1 Publication

Catalytic activityi

NAD+ + a malonylprotein = nicotinamide + O-malonyl-ADP-ribose + a protein.UniRule annotation1 Publication
NAD+ + a succinylprotein = nicotinamide + O-succinyl-ADP-ribose + a protein.UniRule annotation2 Publications
NAD+ + a glutarylprotein = nicotinamide + O-glutaryl-ADP-ribose + a protein.UniRule annotation1 Publication

Cofactori

Zn2+UniRule annotation1 PublicationNote: Binds 1 zinc ion per subunit.UniRule annotation1 Publication

Activity regulationi

Inhibited by suramin. NAD-dependent lysine desuccinylase activity is inhibited by physiological nicotinamide concentrations, while deacetylase activity is not. In contrast, resveratrol activates deacetylase activity, while inhibiting desuccinylase activity.3 Publications

Kineticsi

  1. KM=6.1 µM for a synthetic histone H3K9 malonyllysine peptide1 Publication
  2. KM=5.8 µM for a synthetic histone H3K9 succinyllysine peptide1 Publication
  3. KM=8.7 µM for a synthetic GLUD1 peptide malonylated at 'Lys-503'1 Publication
  4. KM=14 µM for a synthetic GLUD1 peptide succinylated at 'Lys-503'1 Publication
  5. KM=150 µM for a synthetic ACSS1 peptide malonylated at 'Lys-628'1 Publication
  6. KM=450 µM for a synthetic ACSS1 peptide succinylated at 'Lys-628'1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei102SubstrateUniRule annotation1
    Binding sitei105SubstrateUniRule annotation1
    Active sitei158Proton acceptorUniRule annotation2 Publications1
    Metal bindingi166ZincUniRule annotation1
    Metal bindingi169ZincUniRule annotation1
    Metal bindingi207ZincUniRule annotation1
    Metal bindingi212ZincUniRule annotation1
    Binding sitei293NAD; via amide nitrogenUniRule annotation3 Publications1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi58 – 77NADUniRule annotation3 PublicationsAdd BLAST20
    Nucleotide bindingi140 – 143NADUniRule annotation3 Publications4
    Nucleotide bindingi249 – 251NADUniRule annotation3 Publications3
    Nucleotide bindingi275 – 277NADUniRule annotation3 Publications3

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase
    LigandMetal-binding, NAD, Zinc

    Enzyme and pathway databases

    ReactomeiR-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
    SABIO-RKiQ9NXA8

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    NAD-dependent protein deacylase sirtuin-5, mitochondrialUniRule annotation (EC:3.5.1.-UniRule annotation3 Publications)
    Alternative name(s):
    Regulatory protein SIR2 homolog 5UniRule annotation
    SIR2-like protein 5UniRule annotation
    Gene namesi
    Name:SIRT5UniRule annotation
    Synonyms:SIR2L5
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 6

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000124523.14
    HGNCiHGNC:14933 SIRT5
    MIMi604483 gene
    neXtProtiNX_Q9NXA8

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cytoplasm, Mitochondrion, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi69T → A: Abolishes enzyme activity. 1 Publication1
    Mutagenesisi102Y → F: Increases the KM for desuccinylation. 1 Publication1
    Mutagenesisi105R → M: Increases the KM for desuccinylation. Does not affect deacetylase activity. 2 Publications1
    Mutagenesisi158H → A: Abolishes desuccinylation and deglutarylation activity. 4 Publications1

    Organism-specific databases

    DisGeNETi23408
    OpenTargetsiENSG00000124523
    PharmGKBiPA37938

    Chemistry databases

    ChEMBLiCHEMBL2163183
    DrugBankiDB03478 2'-O-Acetyl Adenosine-5-Diphosphoribose
    DB02059 Adenosine-5-Diphosphoribose
    DB02701 Nicotinamide
    DB04786 Suramin
    GuidetoPHARMACOLOGYi2711

    Polymorphism and mutation databases

    BioMutaiSIRT5
    DMDMi38258652

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 36MitochondrionUniRule annotationAdd BLAST36
    ChainiPRO_000011026637 – 310NAD-dependent protein deacylase sirtuin-5, mitochondrialAdd BLAST274

    Proteomic databases

    EPDiQ9NXA8
    MaxQBiQ9NXA8
    PaxDbiQ9NXA8
    PeptideAtlasiQ9NXA8
    PRIDEiQ9NXA8
    ProteomicsDBi83064
    83065 [Q9NXA8-2]
    83066 [Q9NXA8-3]
    83067 [Q9NXA8-4]

    PTM databases

    iPTMnetiQ9NXA8
    PhosphoSitePlusiQ9NXA8

    Expressioni

    Tissue specificityi

    Widely expressed.1 Publication

    Gene expression databases

    BgeeiENSG00000124523 Expressed in 218 organ(s), highest expression level in myocardium
    CleanExiHS_SIRT5
    ExpressionAtlasiQ9NXA8 baseline and differential
    GenevisibleiQ9NXA8 HS

    Organism-specific databases

    HPAiHPA021798
    HPA022002
    HPA022992

    Interactioni

    Subunit structurei

    Interacts with CPS1 (By similarity). Interacts with PCCA (PubMed:23438705). Monomer (PubMed:17355872). Homodimer (PubMed:17355872). Forms homodimers upon suramin binding (PubMed:17355872).By similarity7 Publications

    Protein-protein interaction databases

    BioGridi116980, 26 interactors
    IntActiQ9NXA8, 5 interactors
    STRINGi9606.ENSP00000368552

    Chemistry databases

    BindingDBiQ9NXA8

    Structurei

    Secondary structure

    1310
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliQ9NXA8
    SMRiQ9NXA8
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiQ9NXA8

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini41 – 309Deacetylase sirtuin-typeUniRule annotationAdd BLAST269

    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 (PubMed:22076378).1 Publication

    Sequence similaritiesi

    Belongs to the sirtuin family. Class III subfamily.UniRule annotation

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2684 Eukaryota
    COG0846 LUCA
    GeneTreeiENSGT00870000136443
    HOGENOMiHOG000085950
    HOVERGENiHBG056009
    InParanoidiQ9NXA8
    KOiK11415
    OMAiSMQVYPA
    OrthoDBiEOG091G0KF2
    PhylomeDBiQ9NXA8
    TreeFamiTF106183

    Family and domain databases

    CDDicd01412 SIRT5_Af1_CobB, 1 hit
    Gene3Di3.30.1600.10, 1 hit
    HAMAPiMF_01121 Sirtuin_ClassIII, 1 hit
    InterProiView protein in InterPro
    IPR029035 DHS-like_NAD/FAD-binding_dom
    IPR003000 Sirtuin
    IPR026591 Sirtuin_cat_small_dom_sf
    IPR027546 Sirtuin_class_III
    IPR026590 Ssirtuin_cat_dom
    PfamiView protein in Pfam
    PF02146 SIR2, 1 hit
    SUPFAMiSSF52467 SSF52467, 1 hit
    PROSITEiView protein in PROSITE
    PS50305 SIRTUIN, 1 hit

    Sequences (4+)i

    Sequence statusi: Complete.

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

    This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 4 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

    Isoform 1 (identifier: Q9NXA8-1) [UniParc]FASTAAdd to basket

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MRPLQIVPSR LISQLYCGLK PPASTRNQIC LKMARPSSSM ADFRKFFAKA
    60 70 80 90 100
    KHIVIISGAG VSAESGVPTF RGAGGYWRKW QAQDLATPLA FAHNPSRVWE
    110 120 130 140 150
    FYHYRREVMG SKEPNAGHRA IAECETRLGK QGRRVVVITQ NIDELHRKAG
    160 170 180 190 200
    TKNLLEIHGS LFKTRCTSCG VVAENYKSPI CPALSGKGAP EPGTQDASIP
    210 220 230 240 250
    VEKLPRCEEA GCGGLLRPHV VWFGENLDPA ILEEVDRELA HCDLCLVVGT
    260 270 280 290 300
    SSVVYPAAMF APQVAARGVP VAEFNTETTP ATNRFRFHFQ GPCGTTLPEA
    310
    LACHENETVS
    Length:310
    Mass (Da):33,881
    Last modified:October 31, 2003 - v2
    Checksum:i022DA32CDB43AC3A
    GO
    Isoform 2 (identifier: Q9NXA8-2) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         286-299: RFHFQGPCGTTLPE → SHLISISSLIIIKN
         300-310: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:299
    Mass (Da):32,674
    Checksum:i2EE7C311AAA34CBA
    GO
    Isoform 3 (identifier: Q9NXA8-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         189-206: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:292
    Mass (Da):31,994
    Checksum:iD89A65C251224735
    GO
    Isoform 4 (identifier: Q9NXA8-4) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         1-108: Missing.

    Note: No experimental confirmation available.
    Show »
    Length:202
    Mass (Da):21,689
    Checksum:i051C7D4BE508D66B
    GO

    Computationally mapped potential isoform sequencesi

    There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    Q7Z3A0Q7Z3A0_HUMAN
    NAD-dependent protein deacylase sir...
    SIRT5 DKFZp686L2375
    79Annotation score:
    U3KQT8U3KQT8_HUMAN
    NAD-dependent protein deacylase sir...
    SIRT5
    41Annotation score:

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti53I → M in BAG63757 (PubMed:14702039).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_029042285F → L. Corresponds to variant dbSNP:rs9464003Ensembl.1
    Natural variantiVAR_051980305E → G. Corresponds to variant dbSNP:rs34162626Ensembl.1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_0422911 – 108Missing in isoform 4. 1 PublicationAdd BLAST108
    Alternative sequenceiVSP_042292189 – 206Missing in isoform 3. 1 PublicationAdd BLAST18
    Alternative sequenceiVSP_008730286 – 299RFHFQ…TTLPE → SHLISISSLIIIKN in isoform 2. 1 PublicationAdd BLAST14
    Alternative sequenceiVSP_008731300 – 310Missing in isoform 2. 1 PublicationAdd BLAST11

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF083110 mRNA Translation: AAD40853.1
    AK000355 mRNA Translation: BAA91107.1
    AK294162 mRNA Translation: BAG57485.1
    AK302467 mRNA Translation: BAG63757.1
    AM393414 mRNA Translation: CAL38292.1
    AL441883 Genomic DNA No translation available.
    CH471087 Genomic DNA Translation: EAW55332.1
    BC000126 mRNA Translation: AAH00126.1
    CCDSiCCDS4526.1 [Q9NXA8-1]
    CCDS4527.1 [Q9NXA8-2]
    CCDS54966.1 [Q9NXA8-3]
    CCDS56398.1 [Q9NXA8-4]
    RefSeqiNP_001180196.1, NM_001193267.2 [Q9NXA8-3]
    NP_001229756.1, NM_001242827.1 [Q9NXA8-4]
    NP_036373.1, NM_012241.4 [Q9NXA8-1]
    NP_112534.1, NM_031244.3 [Q9NXA8-2]
    XP_005249025.1, XM_005248968.4 [Q9NXA8-1]
    UniGeneiHs.567431
    Hs.594133

    Genome annotation databases

    EnsembliENST00000359782; ENSP00000352830; ENSG00000124523 [Q9NXA8-3]
    ENST00000379262; ENSP00000368564; ENSG00000124523 [Q9NXA8-2]
    ENST00000397350; ENSP00000380509; ENSG00000124523 [Q9NXA8-4]
    ENST00000606117; ENSP00000476228; ENSG00000124523 [Q9NXA8-1]
    GeneIDi23408
    KEGGihsa:23408
    UCSCiuc003naw.4 human [Q9NXA8-1]

    Keywords - Coding sequence diversityi

    Alternative splicing, Polymorphism

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF083110 mRNA Translation: AAD40853.1
    AK000355 mRNA Translation: BAA91107.1
    AK294162 mRNA Translation: BAG57485.1
    AK302467 mRNA Translation: BAG63757.1
    AM393414 mRNA Translation: CAL38292.1
    AL441883 Genomic DNA No translation available.
    CH471087 Genomic DNA Translation: EAW55332.1
    BC000126 mRNA Translation: AAH00126.1
    CCDSiCCDS4526.1 [Q9NXA8-1]
    CCDS4527.1 [Q9NXA8-2]
    CCDS54966.1 [Q9NXA8-3]
    CCDS56398.1 [Q9NXA8-4]
    RefSeqiNP_001180196.1, NM_001193267.2 [Q9NXA8-3]
    NP_001229756.1, NM_001242827.1 [Q9NXA8-4]
    NP_036373.1, NM_012241.4 [Q9NXA8-1]
    NP_112534.1, NM_031244.3 [Q9NXA8-2]
    XP_005249025.1, XM_005248968.4 [Q9NXA8-1]
    UniGeneiHs.567431
    Hs.594133

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    2B4YX-ray1.90A/B/C/D34-302[»]
    2NYRX-ray2.06A/B34-302[»]
    3RIGX-ray2.00A/B34-302[»]
    3RIYX-ray1.55A/B34-302[»]
    4F4UX-ray2.00A/B34-302[»]
    4F56X-ray1.70A/B34-302[»]
    4G1CX-ray1.94A/B36-302[»]
    4HDAX-ray2.60A/B34-302[»]
    5BWLX-ray1.55A33-302[»]
    5XHSX-ray2.19A34-302[»]
    6EQSX-ray1.32A/B/C/D34-302[»]
    ProteinModelPortaliQ9NXA8
    SMRiQ9NXA8
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi116980, 26 interactors
    IntActiQ9NXA8, 5 interactors
    STRINGi9606.ENSP00000368552

    Chemistry databases

    BindingDBiQ9NXA8
    ChEMBLiCHEMBL2163183
    DrugBankiDB03478 2'-O-Acetyl Adenosine-5-Diphosphoribose
    DB02059 Adenosine-5-Diphosphoribose
    DB02701 Nicotinamide
    DB04786 Suramin
    GuidetoPHARMACOLOGYi2711

    PTM databases

    iPTMnetiQ9NXA8
    PhosphoSitePlusiQ9NXA8

    Polymorphism and mutation databases

    BioMutaiSIRT5
    DMDMi38258652

    Proteomic databases

    EPDiQ9NXA8
    MaxQBiQ9NXA8
    PaxDbiQ9NXA8
    PeptideAtlasiQ9NXA8
    PRIDEiQ9NXA8
    ProteomicsDBi83064
    83065 [Q9NXA8-2]
    83066 [Q9NXA8-3]
    83067 [Q9NXA8-4]

    Protocols and materials databases

    DNASUi23408
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000359782; ENSP00000352830; ENSG00000124523 [Q9NXA8-3]
    ENST00000379262; ENSP00000368564; ENSG00000124523 [Q9NXA8-2]
    ENST00000397350; ENSP00000380509; ENSG00000124523 [Q9NXA8-4]
    ENST00000606117; ENSP00000476228; ENSG00000124523 [Q9NXA8-1]
    GeneIDi23408
    KEGGihsa:23408
    UCSCiuc003naw.4 human [Q9NXA8-1]

    Organism-specific databases

    CTDi23408
    DisGeNETi23408
    EuPathDBiHostDB:ENSG00000124523.14
    GeneCardsiSIRT5
    HGNCiHGNC:14933 SIRT5
    HPAiHPA021798
    HPA022002
    HPA022992
    MIMi604483 gene
    neXtProtiNX_Q9NXA8
    OpenTargetsiENSG00000124523
    PharmGKBiPA37938
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2684 Eukaryota
    COG0846 LUCA
    GeneTreeiENSGT00870000136443
    HOGENOMiHOG000085950
    HOVERGENiHBG056009
    InParanoidiQ9NXA8
    KOiK11415
    OMAiSMQVYPA
    OrthoDBiEOG091G0KF2
    PhylomeDBiQ9NXA8
    TreeFamiTF106183

    Enzyme and pathway databases

    ReactomeiR-HSA-2151201 Transcriptional activation of mitochondrial biogenesis
    SABIO-RKiQ9NXA8

    Miscellaneous databases

    ChiTaRSiSIRT5 human
    EvolutionaryTraceiQ9NXA8
    GeneWikiiSIRT5
    GenomeRNAii23408
    PROiPR:Q9NXA8
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000124523 Expressed in 218 organ(s), highest expression level in myocardium
    CleanExiHS_SIRT5
    ExpressionAtlasiQ9NXA8 baseline and differential
    GenevisibleiQ9NXA8 HS

    Family and domain databases

    CDDicd01412 SIRT5_Af1_CobB, 1 hit
    Gene3Di3.30.1600.10, 1 hit
    HAMAPiMF_01121 Sirtuin_ClassIII, 1 hit
    InterProiView protein in InterPro
    IPR029035 DHS-like_NAD/FAD-binding_dom
    IPR003000 Sirtuin
    IPR026591 Sirtuin_cat_small_dom_sf
    IPR027546 Sirtuin_class_III
    IPR026590 Ssirtuin_cat_dom
    PfamiView protein in Pfam
    PF02146 SIR2, 1 hit
    SUPFAMiSSF52467 SSF52467, 1 hit
    PROSITEiView protein in PROSITE
    PS50305 SIRTUIN, 1 hit
    ProtoNetiSearch...

    Entry informationi

    Entry nameiSIR5_HUMAN
    AccessioniPrimary (citable) accession number: Q9NXA8
    Secondary accession number(s): B4DFM4
    , B4DYJ5, F5H5Z9, Q5T294, Q5T295, Q9Y6E6
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2003
    Last sequence update: October 31, 2003
    Last modified: November 7, 2018
    This is version 156 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. Human entries with polymorphisms or disease mutations
      List of human entries with polymorphisms or disease mutations
    3. Human polymorphisms and disease mutations
      Index of human polymorphisms and disease mutations
    4. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    5. PDB cross-references
      Index of Protein Data Bank (PDB) cross-references
    6. Human chromosome 6
      Human chromosome 6: entries, gene names and cross-references to MIM
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