ID ENTP5_HUMAN Reviewed; 428 AA. AC O75356; A1L4C5; Q96RX0; DT 29-AUG-2001, integrated into UniProtKB/Swiss-Prot. DT 01-NOV-1998, sequence version 1. DT 13-FEB-2019, entry version 163. DE RecName: Full=Ectonucleoside triphosphate diphosphohydrolase 5; DE Short=NTPDase 5; DE EC=3.6.1.6; DE AltName: Full=CD39 antigen-like 4; DE AltName: Full=ER-UDPase; DE AltName: Full=Guanosine-diphosphatase ENTPD5; DE Short=GDPase ENTPD5; DE EC=3.6.1.42; DE AltName: Full=Nucleoside diphosphatase; DE AltName: Full=Uridine-diphosphatase ENTPD5; DE Short=UDPase ENTPD5; DE Flags: Precursor; GN Name=ENTPD5; Synonyms=CD39L4, PCPH; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY. RC TISSUE=Leukemia; RX PubMed=9676430; DOI=10.1006/geno.1998.5317; RA Chadwick B.P., Frischauf A.-M.; RT "The CD39-like gene family: identification of three new human members RT (CD39L2, CD39L3, and CD39L4), their murine homologues, and a member of RT the gene family from Drosophila melanogaster."; RL Genomics 50:357-367(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA]. RX PubMed=10708485; RX DOI=10.1002/(SICI)1098-2744(200003)27:3<229::AID-MC10>3.0.CO;2-Z; RA Recio J.A., Zambrano N., Pena L., Reig J.A., Rhoads A., Rouzaut A., RA Notario V.; RT "The human PCPH proto-oncogene: cDNA identification, primary RT structure, chromosomal mapping, and expression in normal and tumor RT cells."; RL Mol. Carcinog. 27:229-236(2000). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA], SUBSTRATE PREFERENCE, COFACTOR, AND RP MUTAGENESIS OF CYS-39. RC TISSUE=Hippocampus; RX PubMed=15698960; DOI=10.1016/j.bbapap.2004.11.017; RA Murphy-Piedmonte D.M., Crawford P.A., Kirley T.L.; RT "Bacterial expression, folding, purification and characterization of RT soluble NTPDase5 (CD39L4) ecto-nucleotidase."; RL Biochim. Biophys. Acta 1747:251-259(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=12508121; DOI=10.1038/nature01348; RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C., RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A., RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., RA Sun H., Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., RA Bruels T., Jaillon O., Friedlander L., Samson G., Brottier P., RA Cure S., Segurens B., Aniere F., Samain S., Crespeau H., Abbasi N., RA Aiach N., Boscus D., Dickhoff R., Dors M., Dubois I., Friedman C., RA Gouyvenoux M., James R., Madan A., Mairey-Estrada B., Mangenot S., RA Martins N., Menard M., Oztas S., Ratcliffe A., Shaffer T., Trask B., RA Vacherie B., Bellemere C., Belser C., Besnard-Gonnet M., RA Bartol-Mavel D., Boutard M., Briez-Silla S., Combette S., RA Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C., Muselet D., RA Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P., Trybou A., RA Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M., RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V., RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., RA Verdier J., Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., RA Matsuda F., Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., RA Quetier F., Waterston R., Hood L., Weissenbach J.; RT "The DNA sequence and analysis of human chromosome 14."; RL Nature 421:601-607(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RX PubMed=15489334; DOI=10.1101/gr.2596504; RG The MGC Project Team; RT "The status, quality, and expansion of the NIH full-length cDNA RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP FUNCTION, COFACTOR, AND SUBCELLULAR LOCATION. RX PubMed=10400613; DOI=10.1074/jbc.274.29.20064; RA Mulero J.J., Yeung G., Nelken S.T., Ford J.E.; RT "CD39-L4 is a secreted human apyrase, specific for the hydrolysis of RT nucleoside diphosphates."; RL J. Biol. Chem. 274:20064-20067(1999). RN [8] RP GLYCOSYLATION, AND SUBUNIT. RX PubMed=11041857; DOI=10.1021/bi000960y; RA Mulero J.J., Yeung G., Nelken S.T., Bright J.M., McGowan D.W., RA Ford J.E.; RT "Biochemical characterization of CD39L4."; RL Biochemistry 39:12924-12928(2000). RN [9] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-232. RC TISSUE=Plasma; RX PubMed=16335952; DOI=10.1021/pr0502065; RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E., RA Moore R.J., Smith R.D.; RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction, RT hydrazide chemistry, and mass spectrometry."; RL J. Proteome Res. 4:2070-2080(2005). RN [10] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-232. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of RT multiple enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [11] RP INDUCTION. RX PubMed=21074248; DOI=10.1016/j.cell.2010.10.010; RA Fang M., Shen Z., Huang S., Zhao L., Chen S., Mak T.W., Wang X.; RT "The ER UDPase ENTPD5 promotes protein N-glycosylation, the Warburg RT effect, and proliferation in the PTEN pathway."; RL Cell 143:711-724(2010). RN [12] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). CC -!- FUNCTION: Uridine diphosphatase (UDPase) that promotes protein N- CC glycosylation and ATP level regulation. UDP hydrolysis promotes CC protein N-glycosylation and folding in the endoplasmic reticulum, CC as well as elevated ATP consumption in the cytosol via an ATP CC hydrolysis cycle. Together with CMPK1 and AK1, constitutes an ATP CC hydrolysis cycle that converts ATP to AMP and results in a CC compensatory increase in aerobic glycolysis. The nucleotide CC hydrolyzing preference is GDP > IDP > UDP, but not any other CC nucleoside di-, mono- or triphosphates, nor thiamine CC pyrophosphate. Plays a key role in the AKT1-PTEN signaling pathway CC by promoting glycolysis in proliferating cells in response to CC phosphoinositide 3-kinase (PI3K) signaling. CC {ECO:0000269|PubMed:10400613}. CC -!- CATALYTIC ACTIVITY: CC Reaction=GDP + H2O = GMP + H(+) + phosphate; Xref=Rhea:RHEA:22156, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:58115, ChEBI:CHEBI:58189; EC=3.6.1.42; CC -!- CATALYTIC ACTIVITY: CC Reaction=a ribonucleoside 5'-diphosphate + H2O = a ribonucleoside CC 5'-phosphate + H(+) + phosphate; Xref=Rhea:RHEA:36799, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, CC ChEBI:CHEBI:57930, ChEBI:CHEBI:58043; EC=3.6.1.6; CC -!- COFACTOR: CC Name=Ca(2+); Xref=ChEBI:CHEBI:29108; CC Evidence={ECO:0000269|PubMed:10400613, CC ECO:0000269|PubMed:15698960}; CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:10400613, CC ECO:0000269|PubMed:15698960}; CC -!- PATHWAY: Protein modification; protein glycosylation. CC -!- SUBUNIT: Exists both as a monomer and a disulfide-linked CC homodimer, the dimers are enzymatically inactive. CC {ECO:0000269|PubMed:11041857}. CC -!- INTERACTION: CC P50539:MXI1; NbExp=3; IntAct=EBI-7416931, EBI-752241; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000250}. CC Secreted {ECO:0000269|PubMed:10400613}. CC -!- TISSUE SPECIFICITY: Expressed in adult liver, kidney, prostate, CC testis and colon. Much weaker expression in other tissues. CC {ECO:0000269|PubMed:9676430}. CC -!- INDUCTION: Up-regulated in cell lines and primary tumor samples CC with active AKT1. {ECO:0000269|PubMed:21074248}. CC -!- PTM: N-glycosylated; high-mannose type (By similarity). CC Glycosylation is not essential for enzymatic activity. CC {ECO:0000250, ECO:0000269|PubMed:11041857, CC ECO:0000269|PubMed:16335952, ECO:0000269|PubMed:19159218}. CC -!- MISCELLANEOUS: May mediate some of the cancer-related phenotypes CC associated with AKT1 activation: its up-regulation by AKT1 leads CC to the elevation of aerobic glycolysis seen in tumor cells, a CC phenomenon known as the Warburg effect. CC {ECO:0000305|PubMed:21074248}. CC -!- SIMILARITY: Belongs to the GDA1/CD39 NTPase family. {ECO:0000305}. CC ----------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC ----------------------------------------------------------------------- DR EMBL; AF039918; AAC39885.1; -; mRNA. DR EMBL; AF136572; AAK82950.1; -; mRNA. DR EMBL; AY430094; AAR06666.1; -; mRNA. DR EMBL; AC005480; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471061; EAW81153.1; -; Genomic_DNA. DR EMBL; BC130485; AAI30486.1; -; mRNA. DR EMBL; BC130487; AAI30488.1; -; mRNA. DR CCDS; CCDS9825.1; -. DR RefSeq; NP_001240.1; NM_001249.3. DR RefSeq; NP_001308914.1; NM_001321985.1. DR RefSeq; NP_001308915.1; NM_001321986.1. DR RefSeq; NP_001308916.1; NM_001321987.1. DR RefSeq; NP_001308917.1; NM_001321988.1. DR RefSeq; XP_005268281.1; XM_005268224.3. DR RefSeq; XP_016877302.1; XM_017021813.1. DR UniGene; Hs.655070; -. DR UniGene; Hs.656955; -. DR UniGene; Hs.720540; -. DR ProteinModelPortal; O75356; -. DR SMR; O75356; -. DR BioGrid; 107395; 5. DR IntAct; O75356; 3. DR MINT; O75356; -. DR STRING; 9606.ENSP00000335246; -. DR GlyConnect; 1194; -. DR iPTMnet; O75356; -. DR PhosphoSitePlus; O75356; -. DR BioMuta; ENTPD5; -. DR EPD; O75356; -. DR jPOST; O75356; -. DR MaxQB; O75356; -. DR PaxDb; O75356; -. DR PeptideAtlas; O75356; -. DR PRIDE; O75356; -. DR ProteomicsDB; 49923; -. DR DNASU; 957; -. DR Ensembl; ENST00000334696; ENSP00000335246; ENSG00000187097. DR GeneID; 957; -. DR KEGG; hsa:957; -. DR UCSC; uc010tuo.3; human. DR CTD; 957; -. DR DisGeNET; 957; -. DR EuPathDB; HostDB:ENSG00000187097.12; -. DR GeneCards; ENTPD5; -. DR HGNC; HGNC:3367; ENTPD5. DR HPA; HPA002927; -. DR MIM; 603162; gene. DR neXtProt; NX_O75356; -. DR OpenTargets; ENSG00000187097; -. DR PharmGKB; PA27802; -. DR eggNOG; KOG1385; Eukaryota. DR eggNOG; COG5371; LUCA. DR GeneTree; ENSGT00940000156312; -. DR HOGENOM; HOG000220904; -. DR HOVERGEN; HBG018208; -. DR InParanoid; O75356; -. DR KO; K01511; -. DR OMA; YEMPIDR; -. DR OrthoDB; 1337265at2759; -. DR PhylomeDB; O75356; -. DR TreeFam; TF315029; -. DR Reactome; R-HSA-8850843; Phosphate bond hydrolysis by NTPDase proteins. DR UniPathway; UPA00378; -. DR ChiTaRS; ENTPD5; human. DR GeneWiki; ENTPD5; -. DR GenomeRNAi; 957; -. DR PRO; PR:O75356; -. DR Proteomes; UP000005640; Chromosome 14. DR Bgee; ENSG00000187097; Expressed in 195 organ(s), highest expression level in colon. DR ExpressionAtlas; O75356; baseline and differential. DR Genevisible; O75356; HS. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0004382; F:guanosine-diphosphatase activity; ISS:UniProtKB. DR GO; GO:0017110; F:nucleoside-diphosphatase activity; EXP:Reactome. DR GO; GO:0045134; F:uridine-diphosphatase activity; ISS:UniProtKB. DR GO; GO:0051084; P:'de novo' posttranslational protein folding; ISS:UniProtKB. DR GO; GO:0046034; P:ATP metabolic process; ISS:UniProtKB. DR GO; GO:0008283; P:cell population proliferation; ISS:UniProtKB. DR GO; GO:0034656; P:nucleobase-containing small molecule catabolic process; TAS:Reactome. DR GO; GO:0045821; P:positive regulation of glycolytic process; ISS:UniProtKB. DR GO; GO:0006487; P:protein N-linked glycosylation; ISS:UniProtKB. DR GO; GO:0014066; P:regulation of phosphatidylinositol 3-kinase signaling; ISS:UniProtKB. DR InterPro; IPR000407; GDA1_CD39_NTPase. DR PANTHER; PTHR11782; PTHR11782; 1. DR Pfam; PF01150; GDA1_CD39; 1. DR PROSITE; PS01238; GDA1_CD39_NTPASE; 1. PE 1: Evidence at protein level; KW Calcium; Complete proteome; Disulfide bond; Endoplasmic reticulum; KW Glycoprotein; Hydrolase; Magnesium; Polymorphism; Proto-oncogene; KW Reference proteome; Secreted; Signal. FT SIGNAL 1 24 {ECO:0000255}. FT CHAIN 25 428 Ectonucleoside triphosphate FT diphosphohydrolase 5. FT /FTId=PRO_0000019908. FT ACT_SITE 172 172 Proton acceptor. {ECO:0000250}. FT CARBOHYD 232 232 N-linked (GlcNAc...) asparagine. FT {ECO:0000269|PubMed:16335952, FT ECO:0000269|PubMed:19159218}. FT CARBOHYD 368 368 N-linked (GlcNAc...) asparagine. FT {ECO:0000255}. FT DISULFID 272 303 {ECO:0000250}. FT DISULFID 363 377 {ECO:0000250}. FT VARIANT 314 314 K -> R (in dbSNP:rs17094434). FT /FTId=VAR_050308. FT MUTAGEN 39 39 C->S: No change in quaternary structure FT nor enzymatic activity. FT {ECO:0000269|PubMed:15698960}. SQ SEQUENCE 428 AA; 47517 MW; 830437A155DE4DDD CRC64; MATSWGTVFF MLVVSCVCSA VSHRNQQTWF EGIFLSSMCP INVSASTLYG IMFDAGSTGT RIHVYTFVQK MPGQLPILEG EVFDSVKPGL SAFVDQPKQG AETVQGLLEV AKDSIPRSHW KKTPVVLKAT AGLRLLPEHK AKALLFEVKE IFRKSPFLVP KGSVSIMDGS DEGILAWVTV NFLTGQLHGH RQETVGTLDL GGASTQITFL PQFEKTLEQT PRGYLTSFEM FNSTYKLYTH SYLGFGLKAA RLATLGALET EGTDGHTFRS ACLPRWLEAE WIFGGVKYQY GGNQEGEVGF EPCYAEVLRV VRGKLHQPEE VQRGSFYAFS YYYDRAVDTD MIDYEKGGIL KVEDFERKAR EVCDNLENFT SGSPFLCMDL SYITALLKDG FGFADSTVLQ LTKKVNNIET GWALGATFHL LQSLGISH //