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Protein

NAD-dependent protein lipoamidase sirtuin-4, mitochondrial

Gene

SIRT4

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-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). 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 annotation6 Publications

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

Manual assertion based on experiment ini

  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

    • biotinidase activity Source: UniProtKB
    • lipoamidase activity Source: UniProtKB
    • NAD+ ADP-ribosyltransferase activity Source: UniProtKB
    • NAD+ binding Source: UniProtKB-HAMAP
    • zinc ion binding Source: UniProtKB-HAMAP

    GO - Biological processi

    Complete GO annotation...

    Keywords - Molecular functioni

    Hydrolase, Transferase

    Keywords - Biological processi

    DNA damage

    Keywords - Ligandi

    Metal-binding, NAD, Zinc

    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

    HGNCiHGNC:14932. SIRT4.

    Subcellular locationi

    GO - Cellular componenti

    • mitochondrial inner membrane Source: Ensembl
    • mitochondrial matrix Source: UniProtKB
    • mitochondrion Source: UniProtKB
    Complete GO annotation...

    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.
    PRIDEiQ9Y6E7.

    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.
    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).UniRule annotation3 Publications

    Binary interactionsi

    WithEntry#Exp.IntActNotes
    DLATP105156EBI-2606540,EBI-2959723
    PDHXO003304EBI-2606540,EBI-751566
    SLC25A5P051412EBI-2606540,EBI-355133

    Protein-protein interaction databases

    BioGridi116981. 9 interactors.
    IntActiQ9Y6E7. 109 interactors.
    STRINGi9606.ENSP00000202967.

    Structurei

    3D structure databases

    ProteinModelPortaliQ9Y6E7.
    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
    Contains 1 deacetylase sirtuin-type domain.UniRule annotation

    Keywords - Domaini

    Transit peptide

    Phylogenomic databases

    eggNOGiKOG2683. Eukaryota.
    COG0846. LUCA.
    GeneTreeiENSGT00850000132288.
    HOGENOMiHOG000085953.
    HOVERGENiHBG059577.
    InParanoidiQ9Y6E7.
    KOiK11414.
    OMAiQVLNPTW.
    OrthoDBiEOG091G0DTB.
    PhylomeDBiQ9Y6E7.
    TreeFamiTF106182.

    Family and domain databases

    Gene3Di3.30.1600.10. 2 hits.
    3.40.50.1220. 3 hits.
    HAMAPiMF_01967. Sirtuin_ClassII. 1 hit.
    InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
    IPR003000. Sirtuin.
    IPR026591. Sirtuin_cat_small_dom.
    IPR026587. Sirtuin_class_II.
    IPR026590. Ssirtuin_cat_dom.
    [Graphical view]
    PANTHERiPTHR11085. PTHR11085. 2 hits.
    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.

    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

    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.

    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.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi116981. 9 interactors.
    IntActiQ9Y6E7. 109 interactors.
    STRINGi9606.ENSP00000202967.

    Chemistry databases

    ChEMBLiCHEMBL2163185.

    PTM databases

    iPTMnetiQ9Y6E7.
    PhosphoSitePlusiQ9Y6E7.

    Polymorphism and mutation databases

    BioMutaiSIRT4.
    DMDMi38258657.

    Proteomic databases

    PaxDbiQ9Y6E7.
    PRIDEiQ9Y6E7.

    Protocols and materials databases

    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

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

    Organism-specific databases

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

    Phylogenomic databases

    eggNOGiKOG2683. Eukaryota.
    COG0846. LUCA.
    GeneTreeiENSGT00850000132288.
    HOGENOMiHOG000085953.
    HOVERGENiHBG059577.
    InParanoidiQ9Y6E7.
    KOiK11414.
    OMAiQVLNPTW.
    OrthoDBiEOG091G0DTB.
    PhylomeDBiQ9Y6E7.
    TreeFamiTF106182.

    Miscellaneous databases

    GeneWikiiSIRT4.
    GenomeRNAii23409.
    PROiQ9Y6E7.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000089163.
    CleanExiHS_SIRT4.
    ExpressionAtlasiQ9Y6E7. baseline and differential.
    GenevisibleiQ9Y6E7. HS.

    Family and domain databases

    Gene3Di3.30.1600.10. 2 hits.
    3.40.50.1220. 3 hits.
    HAMAPiMF_01967. Sirtuin_ClassII. 1 hit.
    InterProiIPR029035. DHS-like_NAD/FAD-binding_dom.
    IPR003000. Sirtuin.
    IPR026591. Sirtuin_cat_small_dom.
    IPR026587. Sirtuin_class_II.
    IPR026590. Ssirtuin_cat_dom.
    [Graphical view]
    PANTHERiPTHR11085. PTHR11085. 2 hits.
    PfamiPF02146. SIR2. 1 hit.
    [Graphical view]
    SUPFAMiSSF52467. SSF52467. 1 hit.
    PROSITEiPS50305. SIRTUIN. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiSIR4_HUMAN
    AccessioniPrimary (citable) accession number: Q9Y6E7
    Secondary accession number(s): O43346, Q32M33
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: October 31, 2003
    Last sequence update: November 1, 1999
    Last modified: November 2, 2016
    This is version 131 of the entry and version 1 of the sequence. [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

    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

    Keywords - Technical termi

    Complete proteome, Direct protein sequencing, Reference proteome

    Documents

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

    Similar proteinsi

    Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
    100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
    90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
    50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.