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Protein

Ectonucleotide pyrophosphatase/phosphodiesterase family member 3

Gene

ENPP3

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

Functioni

Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP (PubMed:29717535). Limits mast cell and basophil responses during inflammation and during the chronic phases of allergic responses by eliminating the extracellular ATP that functions as signaling molecule and activates basophils and mast cells and induces the release of inflammatory cytokines. Metabolizes extracellular ATP in the lumen of the small intestine, and thereby prevents ATP-induced apoptosis of intestinal plasmacytoid dendritic cells (By similarity). Has also alkaline phosphodiesterase activity (PubMed:11342463).By similarity2 Publications

Catalytic activityi

Hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides.1 Publication
A nucleoside triphosphate + H2O = a nucleotide + diphosphate.1 Publication

Cofactori

Zn2+1 PublicationNote: Binds 2 zinc ions per subunit.1 Publication

Kineticsi

  1. KM=61.5 µM for ATP
  2. KM=120.3 µM for UTP
  3. KM=120.2 µM for CTP
  4. KM=123.7 µM for GTP

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Metal bindingi167Zinc 1; catalyticCombined sources1 Publication1
    Binding sitei204SubstrateCombined sources1 Publication1
    Active sitei205Nucleophile1 Publication1
    Metal bindingi205Zinc 1; catalyticCombined sources1 Publication1
    Binding sitei226SubstrateCombined sources1 Publication1
    Binding sitei275SubstrateCombined sources1 Publication1
    Binding sitei289SubstrateCombined sources1 Publication1
    Metal bindingi325Zinc 2; catalyticCombined sources1 Publication1
    Metal bindingi329Zinc 2; via tele nitrogen; catalyticCombined sources1 Publication1
    Metal bindingi372Zinc 1; catalyticCombined sources1 Publication1
    Metal bindingi373Zinc 1; via tele nitrogen; catalyticCombined sources1 Publication1
    Metal bindingi483Zinc 2; via tele nitrogen; catalyticCombined sources1 Publication1
    Metal bindingi752CalciumCombined sources1 Publication1
    Metal bindingi754CalciumCombined sources1 Publication1
    Metal bindingi756CalciumCombined sources1 Publication1
    Metal bindingi758Calcium; via carbonyl oxygenCombined sources1 Publication1
    Metal bindingi760CalciumCombined sources1 Publication1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase
    LigandCalcium, Metal-binding, Zinc

    Enzyme and pathway databases

    BRENDAi3.6.1.9 2681
    ReactomeiR-HSA-199220 Vitamin B5 (pantothenate) metabolism

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Ectonucleotide pyrophosphatase/phosphodiesterase family member 3
    Short name:
    E-NPP 3
    Short name:
    NPP31 Publication
    Alternative name(s):
    Phosphodiesterase I beta1 Publication
    Short name:
    PD-Ibeta1 Publication
    Phosphodiesterase I/nucleotide pyrophosphatase 3
    CD_antigen: CD203c2 Publications
    Including the following 2 domains:
    Alkaline phosphodiesterase I (EC:3.1.4.11 Publication)
    Nucleotide pyrophosphatase (EC:3.6.1.91 Publication)
    Short name:
    NPPase
    Alternative name(s):
    Nucleotide diphosphataseCurated
    Gene namesi
    Name:ENPP3
    Synonyms:PDNP31 Publication
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 6

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000154269.14
    HGNCiHGNC:3358 ENPP3
    MIMi602182 gene
    neXtProtiNX_O14638

    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

    Topology

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Topological domaini1 – 11CytoplasmicSequence analysisAdd BLAST11
    Transmembranei12 – 30Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST19
    Topological domaini31 – 875ExtracellularSequence analysisAdd BLAST845

    Keywords - Cellular componenti

    Cell membrane, Membrane, Secreted

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi179T → C: Causes the formation of covalently linked homodimers in solution; when associated with C-336. 1 Publication1
    Mutagenesisi204K → A: Strongly decreases affinity for nucleotides and slows their hydrolysis. 1 Publication1
    Mutagenesisi227N → A: No effect on affinity for nucleotides and enzyme activity. 1 Publication1
    Mutagenesisi275E → A: No effect on substrate specificity. Increases affinity for nucleotides and slows their hydrolysis. 1 Publication1
    Mutagenesisi336A → C: Causes the formation of covalently linked homodimers in solution; when associated with C-179. 1 Publication1

    Organism-specific databases

    DisGeNETi5169
    OpenTargetsiENSG00000154269
    PharmGKBiPA27793

    Chemistry databases

    ChEMBLiCHEMBL5580

    Polymorphism and mutation databases

    BioMutaiENPP3

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00001885701 – 875Ectonucleotide pyrophosphatase/phosphodiesterase family member 3Add BLAST875

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Disulfide bondi54 ↔ 71PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi58 ↔ 89PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi69 ↔ 82PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi75 ↔ 81PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi98 ↔ 115PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi103 ↔ 133PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi113 ↔ 126PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi119 ↔ 125PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi144 ↔ 190PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi152 ↔ 364PROSITE-ProRule annotationCombined sources1 Publication
    Glycosylationi236N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Glycosylationi279N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Glycosylationi290N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Disulfide bondi380 ↔ 478PROSITE-ProRule annotationCombined sources1 Publication
    Glycosylationi426N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Disulfide bondi429 ↔ 818PROSITE-ProRule annotationCombined sources1 Publication
    Glycosylationi533N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Disulfide bondi562 ↔ 623Combined sources1 Publication
    Disulfide bondi575 ↔ 679PROSITE-ProRule annotationCombined sources1 Publication
    Disulfide bondi577 ↔ 664PROSITE-ProRule annotationCombined sources1 Publication
    Glycosylationi582N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Glycosylationi594N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Glycosylationi687N-linked (GlcNAc...) asparagine1 Publication1
    Glycosylationi699N-linked (GlcNAc...) asparagineCombined sources1 Publication1
    Disulfide bondi787 ↔ 797PROSITE-ProRule annotationCombined sources1 Publication
    Glycosylationi789N-linked (GlcNAc...) asparagineCombined sources1 Publication1

    Post-translational modificationi

    N-glycosylated. N-glycosylation is necessary for normal transport to the cell membrane, but is not the apical targeting signal.By similarity

    Keywords - PTMi

    Disulfide bond, Glycoprotein

    Proteomic databases

    MaxQBiO14638
    PaxDbiO14638
    PeptideAtlasiO14638
    PRIDEiO14638
    ProteomicsDBi48132

    PTM databases

    iPTMnetiO14638
    PhosphoSitePlusiO14638

    Expressioni

    Tissue specificityi

    Detected on bile ducts in liver, and in blood serum (at protein level) (PubMed:15072822). Detected in prostate and uterus (PubMed:9344668). Detected on basophils, but not neutrophils (PubMed:11342463).3 Publications

    Inductioni

    Up-regulated by stimulation by allergen or by cross-linking with IgE. The IgE-mediated activation is enhanced by tetradecanoyl phorbol acetate (TPA), a stimulator of the PKC pathway, and inhibited by the P13 kinase inhibitors, LY294002 and wortmannin. Up-regulated in invasive bile duct cancers.1 Publication

    Gene expression databases

    BgeeiENSG00000154269 Expressed in 118 organ(s), highest expression level in jejunal mucosa
    CleanExiHS_ENPP3
    ExpressionAtlasiO14638 baseline and differential
    GenevisibleiO14638 HS

    Organism-specific databases

    HPAiHPA043772

    Interactioni

    Subunit structurei

    Monomer and homodimer.1 Publication

    Protein-protein interaction databases

    BioGridi111195, 1 interactor
    IntActiO14638, 1 interactor
    MINTiO14638
    STRINGi9606.ENSP00000350265

    Chemistry databases

    BindingDBiO14638

    Structurei

    Secondary structure

    1875
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliO14638
    SMRiO14638
    ModBaseiSearch...
    MobiDBiSearch...

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini50 – 93SMB 1PROSITE-ProRule annotationAdd BLAST44
    Domaini94 – 138SMB 2PROSITE-ProRule annotationAdd BLAST45

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni140 – 510PhosphodiesteraseAdd BLAST371
    Regioni605 – 875NucleaseAdd BLAST271

    Motif

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Motifi78 – 80Cell attachment siteSequence analysis3

    Sequence similaritiesi

    Keywords - Domaini

    Repeat, Signal-anchor, Transmembrane, Transmembrane helix

    Phylogenomic databases

    eggNOGiKOG2645 Eukaryota
    COG1524 LUCA
    GeneTreeiENSGT00760000119157
    HOGENOMiHOG000037439
    HOVERGENiHBG051484
    InParanoidiO14638
    KOiK01513
    OMAiTRIWTCN
    OrthoDBiEOG091G017X
    PhylomeDBiO14638
    TreeFamiTF330032

    Family and domain databases

    Gene3Di3.40.720.10, 1 hit
    InterProiView protein in InterPro
    IPR017849 Alkaline_Pase-like_a/b/a
    IPR017850 Alkaline_phosphatase_core_sf
    IPR001604 DNA/RNA_non-sp_Endonuclease
    IPR020821 Extracellular_endonuc_su_A
    IPR002591 Phosphodiest/P_Trfase
    IPR036024 Somatomedin_B-like_dom_sf
    IPR001212 Somatomedin_B_dom
    PfamiView protein in Pfam
    PF01223 Endonuclease_NS, 1 hit
    PF01663 Phosphodiest, 1 hit
    PF01033 Somatomedin_B, 2 hits
    SMARTiView protein in SMART
    SM00892 Endonuclease_NS, 1 hit
    SM00477 NUC, 1 hit
    SM00201 SO, 2 hits
    SUPFAMiSSF53649 SSF53649, 1 hit
    SSF90188 SSF90188, 2 hits
    PROSITEiView protein in PROSITE
    PS00524 SMB_1, 2 hits
    PS50958 SMB_2, 2 hits

    Sequence (1+)i

    Sequence statusi: Complete.

    This entry has 1 described isoform and 3 potential isoforms that are computationally mapped.Show allAlign All

    O14638-1 [UniParc]FASTAAdd to basket
    « Hide
            10         20         30         40         50
    MESTLTLATE QPVKKNTLKK YKIACIVLLA LLVIMSLGLG LGLGLRKLEK
    60 70 80 90 100
    QGSCRKKCFD ASFRGLENCR CDVACKDRGD CCWDFEDTCV ESTRIWMCNK
    110 120 130 140 150
    FRCGETRLEA SLCSCSDDCL QRKDCCADYK SVCQGETSWL EENCDTAQQS
    160 170 180 190 200
    QCPEGFDLPP VILFSMDGFR AEYLYTWDTL MPNINKLKTC GIHSKYMRAM
    210 220 230 240 250
    YPTKTFPNHY TIVTGLYPES HGIIDNNMYD VNLNKNFSLS SKEQNNPAWW
    260 270 280 290 300
    HGQPMWLTAM YQGLKAATYF WPGSEVAING SFPSIYMPYN GSVPFEERIS
    310 320 330 340 350
    TLLKWLDLPK AERPRFYTMY FEEPDSSGHA GGPVSARVIK ALQVVDHAFG
    360 370 380 390 400
    MLMEGLKQRN LHNCVNIILL ADHGMDQTYC NKMEYMTDYF PRINFFYMYE
    410 420 430 440 450
    GPAPRIRAHN IPHDFFSFNS EEIVRNLSCR KPDQHFKPYL TPDLPKRLHY
    460 470 480 490 500
    AKNVRIDKVH LFVDQQWLAV RSKSNTNCGG GNHGYNNEFR SMEAIFLAHG
    510 520 530 540 550
    PSFKEKTEVE PFENIEVYNL MCDLLRIQPA PNNGTHGSLN HLLKVPFYEP
    560 570 580 590 600
    SHAEEVSKFS VCGFANPLPT ESLDCFCPHL QNSTQLEQVN QMLNLTQEEI
    610 620 630 640 650
    TATVKVNLPF GRPRVLQKNV DHCLLYHREY VSGFGKAMRM PMWSSYTVPQ
    660 670 680 690 700
    LGDTSPLPPT VPDCLRADVR VPPSESQKCS FYLADKNITH GFLYPPASNR
    710 720 730 740 750
    TSDSQYDALI TSNLVPMYEE FRKMWDYFHS VLLIKHATER NGVNVVSGPI
    760 770 780 790 800
    FDYNYDGHFD APDEITKHLA NTDVPIPTHY FVVLTSCKNK SHTPENCPGW
    810 820 830 840 850
    LDVLPFIIPH RPTNVESCPE GKPEALWVEE RFTAHIARVR DVELLTGLDF
    860 870
    YQDKVQPVSE ILQLKTYLPT FETTI
    Length:875
    Mass (Da):100,124
    Last modified:September 23, 2008 - v2
    Checksum:i629D2E33B4C45196
    GO

    Computationally mapped potential isoform sequencesi

    There are 3 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    F8W6H5F8W6H5_HUMAN
    Ectonucleotide pyrophosphatase/phos...
    ENPP3
    663Annotation score:
    E9PDB4E9PDB4_HUMAN
    Ectonucleotide pyrophosphatase/phos...
    ENPP3
    53Annotation score:
    E7ETI7E7ETI7_HUMAN
    Ectonucleotide pyrophosphatase/phos...
    ENPP3
    53Annotation score:

    Sequence cautioni

    The sequence AAD05192 differs from that shown. Reason: Erroneous gene model prediction.Curated

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti122R → K in AAC51813 (PubMed:9344668).Curated1

    Natural variant

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Natural variantiVAR_018516620V → M. Corresponds to variant dbSNP:rs9321309Ensembl.1
    Natural variantiVAR_046538744N → H. Corresponds to variant dbSNP:rs36094194Ensembl.1
    Natural variantiVAR_031253786S → N. Corresponds to variant dbSNP:rs17601580Ensembl.1

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF005632 mRNA Translation: AAC51813.1
    EF560735 mRNA Translation: ABQ59045.1
    AC005587 Genomic DNA Translation: AAD05192.1 Sequence problems.
    AL121575 Genomic DNA No translation available.
    AL355150 Genomic DNA No translation available.
    CH471051 Genomic DNA Translation: EAW48045.1
    CCDSiCCDS5148.1
    RefSeqiNP_005012.2, NM_005021.4
    UniGeneiHs.486489

    Genome annotation databases

    EnsembliENST00000357639; ENSP00000350265; ENSG00000154269
    ENST00000414305; ENSP00000406261; ENSG00000154269
    GeneIDi5169
    KEGGihsa:5169
    UCSCiuc003qcu.5 human

    Keywords - Coding sequence diversityi

    Polymorphism

    Cross-referencesi

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    AF005632 mRNA Translation: AAC51813.1
    EF560735 mRNA Translation: ABQ59045.1
    AC005587 Genomic DNA Translation: AAD05192.1 Sequence problems.
    AL121575 Genomic DNA No translation available.
    AL355150 Genomic DNA No translation available.
    CH471051 Genomic DNA Translation: EAW48045.1
    CCDSiCCDS5148.1
    RefSeqiNP_005012.2, NM_005021.4
    UniGeneiHs.486489

    3D structure databases

    Select the link destinations:
    PDBei
    RCSB PDBi
    PDBji
    Links Updated
    PDB entryMethodResolution (Å)ChainPositionsPDBsum
    6C01X-ray2.30A/B48-875[»]
    6C02X-ray1.94A/B48-875[»]
    ProteinModelPortaliO14638
    SMRiO14638
    ModBaseiSearch...
    MobiDBiSearch...

    Protein-protein interaction databases

    BioGridi111195, 1 interactor
    IntActiO14638, 1 interactor
    MINTiO14638
    STRINGi9606.ENSP00000350265

    Chemistry databases

    BindingDBiO14638
    ChEMBLiCHEMBL5580

    PTM databases

    iPTMnetiO14638
    PhosphoSitePlusiO14638

    Polymorphism and mutation databases

    BioMutaiENPP3

    Proteomic databases

    MaxQBiO14638
    PaxDbiO14638
    PeptideAtlasiO14638
    PRIDEiO14638
    ProteomicsDBi48132

    Protocols and materials databases

    DNASUi5169
    Structural Biology KnowledgebaseSearch...

    Genome annotation databases

    EnsembliENST00000357639; ENSP00000350265; ENSG00000154269
    ENST00000414305; ENSP00000406261; ENSG00000154269
    GeneIDi5169
    KEGGihsa:5169
    UCSCiuc003qcu.5 human

    Organism-specific databases

    CTDi5169
    DisGeNETi5169
    EuPathDBiHostDB:ENSG00000154269.14
    GeneCardsiENPP3
    HGNCiHGNC:3358 ENPP3
    HPAiHPA043772
    MIMi602182 gene
    neXtProtiNX_O14638
    OpenTargetsiENSG00000154269
    PharmGKBiPA27793
    GenAtlasiSearch...

    Phylogenomic databases

    eggNOGiKOG2645 Eukaryota
    COG1524 LUCA
    GeneTreeiENSGT00760000119157
    HOGENOMiHOG000037439
    HOVERGENiHBG051484
    InParanoidiO14638
    KOiK01513
    OMAiTRIWTCN
    OrthoDBiEOG091G017X
    PhylomeDBiO14638
    TreeFamiTF330032

    Enzyme and pathway databases

    BRENDAi3.6.1.9 2681
    ReactomeiR-HSA-199220 Vitamin B5 (pantothenate) metabolism

    Miscellaneous databases

    ChiTaRSiENPP3 human
    GeneWikiiENPP3
    GenomeRNAii5169
    PROiPR:O14638
    SOURCEiSearch...

    Gene expression databases

    BgeeiENSG00000154269 Expressed in 118 organ(s), highest expression level in jejunal mucosa
    CleanExiHS_ENPP3
    ExpressionAtlasiO14638 baseline and differential
    GenevisibleiO14638 HS

    Family and domain databases

    Gene3Di3.40.720.10, 1 hit
    InterProiView protein in InterPro
    IPR017849 Alkaline_Pase-like_a/b/a
    IPR017850 Alkaline_phosphatase_core_sf
    IPR001604 DNA/RNA_non-sp_Endonuclease
    IPR020821 Extracellular_endonuc_su_A
    IPR002591 Phosphodiest/P_Trfase
    IPR036024 Somatomedin_B-like_dom_sf
    IPR001212 Somatomedin_B_dom
    PfamiView protein in Pfam
    PF01223 Endonuclease_NS, 1 hit
    PF01663 Phosphodiest, 1 hit
    PF01033 Somatomedin_B, 2 hits
    SMARTiView protein in SMART
    SM00892 Endonuclease_NS, 1 hit
    SM00477 NUC, 1 hit
    SM00201 SO, 2 hits
    SUPFAMiSSF53649 SSF53649, 1 hit
    SSF90188 SSF90188, 2 hits
    PROSITEiView protein in PROSITE
    PS00524 SMB_1, 2 hits
    PS50958 SMB_2, 2 hits
    ProtoNetiSearch...

    Entry informationi

    Entry nameiENPP3_HUMAN
    AccessioniPrimary (citable) accession number: O14638
    Secondary accession number(s): Q5JTL3
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: September 19, 2002
    Last sequence update: September 23, 2008
    Last modified: November 7, 2018
    This is version 163 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, Direct protein sequencing, 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
    7. Human cell differentiation molecules
      CD nomenclature of surface proteins of human leucocytes and list of entries
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