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Protein

NAD-dependent protein lipoamidase sirtuin-4, mitochondrial

Gene

SIRT4

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

Functioni

Acts as NAD-dependent protein lipoamidase, ADP-ribosyl transferase and deacetylase. Catalyzes more efficiently removal of lipoyl- and biotinyl- than acetyl-lysine modifications. Inhibits the pyruvate dehydrogenase complex (PDH) activity via the enzymatic hydrolysis of the lipoamide cofactor from the E2 component, DLAT, in a phosphorylation-independent manner (PubMed:25525879). Catalyzes the transfer of ADP-ribosyl groups onto target proteins, including mitochondrial GLUD1, inhibiting GLUD1 enzyme activity. Acts as a negative regulator of mitochondrial glutamine metabolism by mediating mono ADP-ribosylation of GLUD1: expressed in response to DNA damage and negatively regulates anaplerosis by inhibiting GLUD1, leading to block metabolism of glutamine into tricarboxylic acid cycle and promoting cell cycle arrest (PubMed:16959573, PubMed:17715127). In response to mTORC1 signal, SIRT4 expression is repressed, promoting anaplerosis and cell proliferation. Acts as a tumor suppressor (PubMed:23562301, PubMed:23663782). Also acts as a NAD-dependent protein deacetylase: mediates deacetylation of 'Lys-471' of MLYCD, inhibiting its activity, thereby acting as a regulator of lipid homeostasis (By similarity). Does not seem to deacetylate PC (PubMed:23438705). Controls fatty acid oxidation by inhibiting PPARA transcriptional activation. Impairs SIRT1:PPARA interaction probably through the regulation of NAD+ levels (PubMed:24043310). Down-regulates insulin secretion.UniRule annotation7 Publications

Miscellaneous

Expression is down-regulated in a number of cancers, while overexpression reduces cell proliferation, transformation, and tumor development (PubMed:23562301, PubMed:23663782).2 Publications
According to some authors, ADP-ribosyltransferase activity of sirtuins may be an inefficient side reaction of the deacetylase activity and may not be physiologically relevant.UniRule annotation

Catalytic activityi

NAD+ + a protein = nicotinamide + an N-(ADP-D-ribosyl)-protein.UniRule annotation
NAD+ + an acetylprotein = nicotinamide + O-acetyl-ADP-ribose + a protein.UniRule annotation

Cofactori

Zn2+UniRule annotationNote: Binds 1 zinc ion per subunit.UniRule annotation

Kineticsi

kcat is 0.0019 sec(-1) for the delipoylation of H3 'Lys-9'. kcat is 0.0005 sec(-1) for the debiotinylation of H3 'Lys-9'. kcat is 0.0018 sec(-1) for the delipoylation of DLAT 'Lys-259'.1 Publication
  1. KM=719 µM for a peptide of H3 biotinylated at 'Lys-9'1 Publication
  2. KM=814 µM for a peptide of H3 lipoylated at 'Lys-9'1 Publication
  3. KM=239 µM for a peptide of DLAT lipoylated at 'Lys-259'1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Active sitei161Proton acceptorUniRule annotation1
    Metal bindingi169ZincUniRule annotation1
    Metal bindingi172ZincUniRule annotation1
    Metal bindingi220ZincUniRule annotation1
    Metal bindingi223ZincUniRule annotation1
    Binding sitei304NAD; via amide nitrogenUniRule annotation1

    Regions

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Nucleotide bindingi62 – 82NADUniRule annotationAdd BLAST21
    Nucleotide bindingi143 – 146NADUniRule annotation4
    Nucleotide bindingi260 – 262NADUniRule annotation3
    Nucleotide bindingi286 – 288NADUniRule annotation3

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase, Transferase
    Biological processDNA damage
    LigandMetal-binding, NAD, Zinc

    Enzyme and pathway databases

    ReactomeiR-HSA-2151201 Transcriptional activation of mitochondrial biogenesis

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    NAD-dependent protein lipoamidase sirtuin-4, mitochondrial1 PublicationUniRule annotation (EC:3.5.1.-UniRule annotation1 Publication)
    Alternative name(s):
    NAD-dependent ADP-ribosyltransferase sirtuin-4UniRule annotation (EC:2.4.2.-UniRule annotation)
    NAD-dependent protein deacetylase sirtuin-4UniRule annotation (EC:3.5.1.-UniRule annotation)
    Regulatory protein SIR2 homolog 4UniRule annotation
    SIR2-like protein 4UniRule annotation
    Gene namesi
    Name:SIRT4UniRule annotationImported
    Synonyms:SIR2L4
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 12

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000089163.4
    HGNCiHGNC:14932 SIRT4
    MIMi604482 gene
    neXtProtiNX_Q9Y6E7

    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

    Mitochondrion

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi161H → Y: Abolishes inhibition of PDH complex activity. 1 Publication1

    Keywords - Diseasei

    Tumor suppressor

    Organism-specific databases

    DisGeNETi23409
    OpenTargetsiENSG00000089163
    PharmGKBiPA37937

    Chemistry databases

    ChEMBLiCHEMBL2163185

    Polymorphism and mutation databases

    BioMutaiSIRT4
    DMDMi38258657

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Transit peptidei1 – 28MitochondrionUniRule annotation2 PublicationsAdd BLAST28
    ChainiPRO_000011026429 – 314NAD-dependent protein lipoamidase sirtuin-4, mitochondrialAdd BLAST286

    Proteomic databases

    PaxDbiQ9Y6E7
    PeptideAtlasiQ9Y6E7
    PRIDEiQ9Y6E7
    ProteomicsDBi86660

    PTM databases

    iPTMnetiQ9Y6E7
    PhosphoSitePlusiQ9Y6E7

    Expressioni

    Tissue specificityi

    Detected in vascular smooth muscle and striated muscle. Detected in insulin-producing beta-cells in pancreas islets of Langerhans (at protein level). Widely expressed. Weakly expressed in leukocytes and fetal thymus.1 Publication

    Inductioni

    Induced by glutamine (at protein level).1 Publication

    Gene expression databases

    BgeeiENSG00000089163 Expressed in 140 organ(s), highest expression level in muscle of leg
    CleanExiHS_SIRT4
    ExpressionAtlasiQ9Y6E7 baseline and differential
    GenevisibleiQ9Y6E7 HS

    Organism-specific databases

    HPAiHPA029691
    HPA029692

    Interactioni

    Subunit structurei

    Interacts with GLUD1, IDE and SLC25A5 (PubMed:16959573, PubMed:17715127). Interacts with DLAT and PDHX (PubMed:25525879). Interacts with MCCC1 (via the biotin carboxylation domain) (PubMed:23438705). Interacts with PCCA and PC (PubMed:23438705).UniRule annotation4 Publications

    Binary interactionsi

    Protein-protein interaction databases

    BioGridi116981, 10 interactors
    IntActiQ9Y6E7, 109 interactors
    STRINGi9606.ENSP00000202967

    Structurei

    3D structure databases

    ProteinModelPortaliQ9Y6E7
    SMRiQ9Y6E7
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini45 – 314Deacetylase sirtuin-typeUniRule annotationAdd BLAST270

    Sequence similaritiesi

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

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2683 Eukaryota
    COG0846 LUCA
    GeneTreeiENSGT00870000136443
    HOGENOMiHOG000085953
    HOVERGENiHBG059577
    InParanoidiQ9Y6E7
    KOiK11414
    OMAiRRHYWAR
    OrthoDBiEOG091G0DTB
    PhylomeDBiQ9Y6E7
    TreeFamiTF106182

    Family and domain databases

    Gene3Di3.30.1600.10, 1 hit
    HAMAPiMF_01967 Sirtuin_ClassII, 1 hit
    InterProiView protein in InterPro
    IPR029035 DHS-like_NAD/FAD-binding_dom
    IPR003000 Sirtuin
    IPR026591 Sirtuin_cat_small_dom_sf
    IPR026587 Sirtuin_class_II
    IPR026590 Ssirtuin_cat_dom
    PfamiView protein in Pfam
    PF02146 SIR2, 1 hit
    SUPFAMiSSF52467 SSF52467, 1 hit
    PROSITEiView protein in PROSITE
    PS50305 SIRTUIN, 1 hit

    Sequence (1+)i

    Sequence statusi: Complete.

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

    This entry has 1 described isoform and 1 potential isoform that is computationally mapped.Show allAlign All

    Q9Y6E7-1 [UniParc]FASTAAdd to basket
    « Hide
            10         20         30         40         50
    MKMSFALTFR SAKGRWIANP SQPCSKASIG LFVPASPPLD PEKVKELQRF
    60 70 80 90 100
    ITLSKRLLVM TGAGISTESG IPDYRSEKVG LYARTDRRPI QHGDFVRSAP
    110 120 130 140 150
    IRQRYWARNF VGWPQFSSHQ PNPAHWALST WEKLGKLYWL VTQNVDALHT
    160 170 180 190 200
    KAGSRRLTEL HGCMDRVLCL DCGEQTPRGV LQERFQVLNP TWSAEAHGLA
    210 220 230 240 250
    PDGDVFLSEE QVRSFQVPTC VQCGGHLKPD VVFFGDTVNP DKVDFVHKRV
    260 270 280 290 300
    KEADSLLVVG SSLQVYSGYR FILTAWEKKL PIAILNIGPT RSDDLACLKL
    310
    NSRCGELLPL IDPC
    Length:314
    Mass (Da):35,188
    Last modified:November 1, 1999 - v1
    Checksum:i2B76963AD2C3B354
    GO

    Computationally mapped potential isoform sequencesi

    There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    F5H4X9F5H4X9_HUMAN
    NAD-dependent protein lipoamidase s...
    SIRT4
    106Annotation score:

    Sequence cautioni

    The sequence AAB95634 differs from that shown. Reason: Erroneous gene model prediction.Curated

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF083109 mRNA Translation: AAD40852.1
    AC003982 Genomic DNA Translation: AAB95634.1 Sequence problems.
    BC109319 mRNA Translation: AAI09320.1
    BC109320 mRNA Translation: AAI09321.1
    CCDSiCCDS9194.1
    RefSeqiNP_036372.1, NM_012240.2
    XP_006719371.1, XM_006719308.2
    XP_006719372.1, XM_006719309.3
    UniGeneiHs.50861

    Genome annotation databases

    EnsembliENST00000202967; ENSP00000202967; ENSG00000089163
    GeneIDi23409
    KEGGihsa:23409
    UCSCiuc001tyc.4 human

    Similar proteinsi

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF083109 mRNA Translation: AAD40852.1
    AC003982 Genomic DNA Translation: AAB95634.1 Sequence problems.
    BC109319 mRNA Translation: AAI09320.1
    BC109320 mRNA Translation: AAI09321.1
    CCDSiCCDS9194.1
    RefSeqiNP_036372.1, NM_012240.2
    XP_006719371.1, XM_006719308.2
    XP_006719372.1, XM_006719309.3
    UniGeneiHs.50861

    3D structure databases

    ProteinModelPortaliQ9Y6E7
    SMRiQ9Y6E7
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi116981, 10 interactors
    IntActiQ9Y6E7, 109 interactors
    STRINGi9606.ENSP00000202967

    Chemistry databases

    ChEMBLiCHEMBL2163185

    PTM databases

    iPTMnetiQ9Y6E7
    PhosphoSitePlusiQ9Y6E7

    Polymorphism and mutation databases

    BioMutaiSIRT4
    DMDMi38258657

    Proteomic databases

    PaxDbiQ9Y6E7
    PeptideAtlasiQ9Y6E7
    PRIDEiQ9Y6E7
    ProteomicsDBi86660

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000202967; ENSP00000202967; ENSG00000089163
    GeneIDi23409
    KEGGihsa:23409
    UCSCiuc001tyc.4 human

    Organism-specific databases

    CTDi23409
    DisGeNETi23409
    EuPathDBiHostDB:ENSG00000089163.4
    GeneCardsiSIRT4
    HGNCiHGNC:14932 SIRT4
    HPAiHPA029691
    HPA029692
    MIMi604482 gene
    neXtProtiNX_Q9Y6E7
    OpenTargetsiENSG00000089163
    PharmGKBiPA37937
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2683 Eukaryota
    COG0846 LUCA
    GeneTreeiENSGT00870000136443
    HOGENOMiHOG000085953
    HOVERGENiHBG059577
    InParanoidiQ9Y6E7
    KOiK11414
    OMAiRRHYWAR
    OrthoDBiEOG091G0DTB
    PhylomeDBiQ9Y6E7
    TreeFamiTF106182

    Enzyme and pathway databases

    ReactomeiR-HSA-2151201 Transcriptional activation of mitochondrial biogenesis

    Miscellaneous databases

    GeneWikiiSIRT4
    GenomeRNAii23409
    PROiPR:Q9Y6E7
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000089163 Expressed in 140 organ(s), highest expression level in muscle of leg
    CleanExiHS_SIRT4
    ExpressionAtlasiQ9Y6E7 baseline and differential
    GenevisibleiQ9Y6E7 HS

    Family and domain databases

    Gene3Di3.30.1600.10, 1 hit
    HAMAPiMF_01967 Sirtuin_ClassII, 1 hit
    InterProiView protein in InterPro
    IPR029035 DHS-like_NAD/FAD-binding_dom
    IPR003000 Sirtuin
    IPR026591 Sirtuin_cat_small_dom_sf
    IPR026587 Sirtuin_class_II
    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 nameiSIR4_HUMAN
    AccessioniPrimary (citable) accession number: Q9Y6E7
    Secondary accession number(s): O43346, Q32M33
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: October 31, 2003
    Last sequence update: November 1, 1999
    Last modified: November 7, 2018
    This is version 144 of the entry and version 1 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

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

    1. SIMILARITY comments
      Index of protein domains and families
    2. MIM cross-references
      Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
    3. Human chromosome 12
      Human chromosome 12: entries, gene names and cross-references to MIM
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