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Protein

Nucleotide triphosphate diphosphatase NUDT15

Gene

NUDT15

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein leveli

Functioni

May catalyze the hydrolysis of nucleoside triphosphates including dGTP, dTTP, dCTP, their oxidized forms like 8-oxo-dGTP and the prodrug thiopurine derivatives 6-thio-dGTP and 6-thio-GTP (PubMed:26238318). Could also catalyze the hydrolysis of some nucleoside diphosphate derivatives (PubMed:22556419, PubMed:26238318). Hydrolyzes oxidized nucleosides triphosphates like 8-oxo-dGTP in vitro, but the specificity and efficiency towards these substrates are low. Therefore, the potential in vivo sanitizing role of this enzyme, that would consist in removing oxidatively damaged forms of nucleosides to prevent their incorporation into DNA, is unclear (PubMed:26238318, PubMed:22556419). Through the hydrolysis of thioguanosine triphosphates may participate in the catabolism of thiopurine drugs (PubMed:26238318, PubMed:25108385). May also have a role in DNA synthesis and cell cycle progression by stabilizing PCNA (PubMed:19419956).4 Publications

Catalytic activityi

A nucleoside triphosphate + H2O = a nucleotide + diphosphate.1 Publication

Cofactori

Mg2+By similarity, Mn2+By similarityNote: Magnesium may be the real cofactor in vivo.By similarity

Kineticsi

Has a 10-fold higher catalytic efficiency toward dGTP compared to 8-oxo-dGTP.1 Publication

Manual assertion based on experiment ini

  1. KM=42 µM for dGTP (at pH 7.5)1 Publication
  2. KM=110 µM for 8-oxo-dGTP (at pH 7.5)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi63Magnesium or manganeseBy similarity1
    Metal bindingi67Magnesium or manganeseBy similarity1

    GO - Molecular functioni

    GO - Biological processi

    • dGTP catabolic process Source: UniProtKB
    • DNA protection Source: UniProtKB
    • exogenous drug catabolic process Source: UniProtKB
    • mitotic cell cycle Source: UniProtKB
    • nucleobase-containing small molecule catabolic process Source: Reactome
    • nucleoside phosphate catabolic process Source: UniProtKB
    • purine nucleotide catabolic process Source: UniProtKB
    • regulation of proteasomal protein catabolic process Source: UniProtKB
    Complete GO annotation...

    Keywords - Molecular functioni

    Hydrolase

    Keywords - Ligandi

    Magnesium, Manganese, Metal-binding

    Enzyme and pathway databases

    BioCyciZFISH:ENSG00000136159-MONOMER.
    ReactomeiR-HSA-2393930. Phosphate bond hydrolysis by NUDT proteins.

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Nucleotide triphosphate diphosphatase NUDT15Curated (EC:3.6.1.93 Publications)
    Alternative name(s):
    MutT homolog 21 Publication
    Short name:
    MTH21 Publication
    Nucleoside diphosphate-linked moiety X motif 15Curated
    Short name:
    Nudix motif 15Curated
    Nucleoside diphosphate-linked to another moiety X hydrolase 151 Publication
    Short name:
    Nudix hydrolase 15Imported
    Gene namesi
    Name:NUDT15Imported
    Synonyms:MTH21 Publication
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 13

    Organism-specific databases

    HGNCiHGNC:23063. NUDT15.

    Subcellular locationi

    GO - Cellular componenti

    Complete GO annotation...

    Pathology & Biotechi

    Organism-specific databases

    DisGeNETi55270.
    MIMi616903. phenotype.
    OpenTargetsiENSG00000136159.
    PharmGKBiPA134963132.

    Polymorphism and mutation databases

    BioMutaiNUDT15.
    DMDMi68565944.

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000571151 – 164Nucleotide triphosphate diphosphatase NUDT15Add BLAST164

    Proteomic databases

    EPDiQ9NV35.
    MaxQBiQ9NV35.
    PaxDbiQ9NV35.
    PeptideAtlasiQ9NV35.
    PRIDEiQ9NV35.

    PTM databases

    iPTMnetiQ9NV35.
    PhosphoSitePlusiQ9NV35.

    Expressioni

    Gene expression databases

    BgeeiENSG00000136159.
    CleanExiHS_NUDT15.
    GenevisibleiQ9NV35. HS.

    Organism-specific databases

    HPAiHPA038968.
    HPA038969.

    Interactioni

    Subunit structurei

    Homodimer (PubMed:26238318). Interacts with PCNA; interaction is disrupted in response to UV irradiation (PubMed:19419956).2 Publications

    Protein-protein interaction databases

    BioGridi120559. 5 interactors.
    IntActiQ9NV35. 1 interactor.
    MINTiMINT-4657900.
    STRINGi9606.ENSP00000258662.

    Structurei

    Secondary structure

    1164
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details
    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Beta strandi13 – 21Combined sources9
    Beta strandi28 – 34Combined sources7
    Beta strandi36 – 39Combined sources4
    Beta strandi42 – 44Combined sources3
    Beta strandi46 – 49Combined sources4
    Helixi56 – 68Combined sources13
    Beta strandi72 – 85Combined sources14
    Helixi86 – 88Combined sources3
    Beta strandi90 – 101Combined sources12
    Turni114 – 116Combined sources3
    Beta strandi117 – 124Combined sources8
    Helixi125 – 127Combined sources3
    Helixi131 – 133Combined sources3
    Helixi136 – 143Combined sources8
    Helixi154 – 156Combined sources3

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5BONX-ray1.80A/B/C/D/E/F/G/H1-164[»]
    5LPGX-ray1.70A/B1-164[»]
    ProteinModelPortaliQ9NV35.
    SMRiQ9NV35.
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini9 – 145Nudix hydrolasePROSITE-ProRule annotationAdd BLAST137

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni76 – 164Interaction with PCNA1 PublicationAdd BLAST89

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi48 – 69Nudix boxAdd BLAST22

    Sequence similaritiesi

    Belongs to the Nudix hydrolase family.Curated
    Contains 1 nudix hydrolase domain.PROSITE-ProRule annotation

    Phylogenomic databases

    eggNOGiENOG410J0G8. Eukaryota.
    COG1051. LUCA.
    GeneTreeiENSGT00390000003338.
    HOGENOMiHOG000261967.
    HOVERGENiHBG061816.
    InParanoidiQ9NV35.
    KOiK03574.
    OMAiIMEPEKC.
    OrthoDBiEOG091G0QNG.
    PhylomeDBiQ9NV35.
    TreeFamiTF106353.

    Family and domain databases

    Gene3Di3.90.79.10. 1 hit.
    InterProiIPR000086. NUDIX_hydrolase_dom.
    IPR015797. NUDIX_hydrolase_dom-like.
    [Graphical view]
    PfamiPF00293. NUDIX. 1 hit.
    [Graphical view]
    SUPFAMiSSF55811. SSF55811. 1 hit.
    PROSITEiPS51462. NUDIX. 1 hit.
    [Graphical view]

    Sequencei

    Sequence statusi: Complete.

    Q9NV35-1 [UniParc]FASTAAdd to basket

    « Hide

            10         20         30         40         50
    MTASAQPRGR RPGVGVGVVV TSCKHPRCVL LGKRKGSVGA GSFQLPGGHL
    60 70 80 90 100
    EFGETWEECA QRETWEEAAL HLKNVHFASV VNSFIEKENY HYVTILMKGE
    110 120 130 140 150
    VDVTHDSEPK NVEPEKNESW EWVPWEELPP LDQLFWGLRC LKEQGYDPFK
    160
    EDLNHLVGYK GNHL
    Length:164
    Mass (Da):18,609
    Last modified:October 1, 2000 - v1
    Checksum:i9FF20DA411C9E9C7
    GO

    Polymorphismi

    Polymorphic NUDT15 variants define the poor metabolism of thiopurines 2 genetic locus (THPM2) [MIMi:616903]. Thiopurines are used as immunosuppressants or cytotoxic drugs and are prescribed for a variety of clinical conditions including leukemia, autoimmune disease and organ transplantation. Patients with low NUDT15 activities have an increased risk for toxic effects after receiving standard doses of thiopurine drugs.2 Publications

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_07680618V → I Polymorphism; associated with increased risk for thiopurines toxicity; decreased thermostability; decreased diphosphatase activity towards 6-thio-dGTP and 6-thio-GTP. 1 Publication1
    Natural variantiVAR_07680718V → VG Polymorphism; associated with increased risk for thiopurines toxicity; decreased thermostability; decreased diphosphatase activity towards 6-thio-dGTP and 6-thio-GTP. 1 Publication1
    Natural variantiVAR_076808139R → C Polymorphism; associated with increased risk for thiopurines toxicity; decreased thermostability; loss of diphosphatase activity towards 6-thio-dGTP and 6-thio-GTP. 2 PublicationsCorresponds to variant rs116855232dbSNPEnsembl.1
    Natural variantiVAR_076809139R → H Polymorphism; associated with increased risk for thiopurines toxicity; decreased thermostability; decreased diphosphatase activity towards 6-thio-dGTP and 6-thio-GTP. 1 PublicationCorresponds to variant rs147390019dbSNPEnsembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK001818 mRNA. Translation: BAA91925.1.
    AL158196 Genomic DNA. Translation: CAI17017.1.
    CH471075 Genomic DNA. Translation: EAX08782.1.
    BC064607 mRNA. Translation: AAH64607.1.
    BC107875 mRNA. Translation: AAI07876.1.
    BC133015 mRNA. Translation: AAI33016.1.
    BC133017 mRNA. Translation: AAI33018.1.
    CCDSiCCDS9407.1.
    RefSeqiNP_001291674.1. NM_001304745.1.
    NP_060753.1. NM_018283.3.
    UniGeneiHs.144407.

    Genome annotation databases

    EnsembliENST00000258662; ENSP00000258662; ENSG00000136159.
    GeneIDi55270.
    KEGGihsa:55270.
    UCSCiuc001vbw.2. human.

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AK001818 mRNA. Translation: BAA91925.1.
    AL158196 Genomic DNA. Translation: CAI17017.1.
    CH471075 Genomic DNA. Translation: EAX08782.1.
    BC064607 mRNA. Translation: AAH64607.1.
    BC107875 mRNA. Translation: AAI07876.1.
    BC133015 mRNA. Translation: AAI33016.1.
    BC133017 mRNA. Translation: AAI33018.1.
    CCDSiCCDS9407.1.
    RefSeqiNP_001291674.1. NM_001304745.1.
    NP_060753.1. NM_018283.3.
    UniGeneiHs.144407.

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    5BONX-ray1.80A/B/C/D/E/F/G/H1-164[»]
    5LPGX-ray1.70A/B1-164[»]
    ProteinModelPortaliQ9NV35.
    SMRiQ9NV35.
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi120559. 5 interactors.
    IntActiQ9NV35. 1 interactor.
    MINTiMINT-4657900.
    STRINGi9606.ENSP00000258662.

    PTM databases

    iPTMnetiQ9NV35.
    PhosphoSitePlusiQ9NV35.

    Polymorphism and mutation databases

    BioMutaiNUDT15.
    DMDMi68565944.

    Proteomic databases

    EPDiQ9NV35.
    MaxQBiQ9NV35.
    PaxDbiQ9NV35.
    PeptideAtlasiQ9NV35.
    PRIDEiQ9NV35.

    Protocols and materials databases

    DNASUi55270.
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000258662; ENSP00000258662; ENSG00000136159.
    GeneIDi55270.
    KEGGihsa:55270.
    UCSCiuc001vbw.2. human.

    Organism-specific databases

    CTDi55270.
    DisGeNETi55270.
    GeneCardsiNUDT15.
    HGNCiHGNC:23063. NUDT15.
    HPAiHPA038968.
    HPA038969.
    MIMi615792. gene.
    616903. phenotype.
    neXtProtiNX_Q9NV35.
    OpenTargetsiENSG00000136159.
    PharmGKBiPA134963132.
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiENOG410J0G8. Eukaryota.
    COG1051. LUCA.
    GeneTreeiENSGT00390000003338.
    HOGENOMiHOG000261967.
    HOVERGENiHBG061816.
    InParanoidiQ9NV35.
    KOiK03574.
    OMAiIMEPEKC.
    OrthoDBiEOG091G0QNG.
    PhylomeDBiQ9NV35.
    TreeFamiTF106353.

    Enzyme and pathway databases

    BioCyciZFISH:ENSG00000136159-MONOMER.
    ReactomeiR-HSA-2393930. Phosphate bond hydrolysis by NUDT proteins.

    Miscellaneous databases

    GenomeRNAii55270.
    PROiQ9NV35.
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000136159.
    CleanExiHS_NUDT15.
    GenevisibleiQ9NV35. HS.

    Family and domain databases

    Gene3Di3.90.79.10. 1 hit.
    InterProiIPR000086. NUDIX_hydrolase_dom.
    IPR015797. NUDIX_hydrolase_dom-like.
    [Graphical view]
    PfamiPF00293. NUDIX. 1 hit.
    [Graphical view]
    SUPFAMiSSF55811. SSF55811. 1 hit.
    PROSITEiPS51462. NUDIX. 1 hit.
    [Graphical view]
    ProtoNetiSearch...

    Entry informationi

    Entry nameiNUD15_HUMAN
    AccessioniPrimary (citable) accession number: Q9NV35
    Secondary accession number(s): A2RUR6, Q32Q27, Q6P2C9
    Entry historyi
    Integrated into UniProtKB/Swiss-Prot: July 5, 2005
    Last sequence update: October 1, 2000
    Last modified: November 30, 2016
    This is version 121 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

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome

    Documents

    1. Human chromosome 13
      Human chromosome 13: entries, gene names and cross-references to MIM
    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. 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.