ID NUDT3_HUMAN Reviewed; 172 AA. AC O95989; B2R8N4; DT 05-JUL-2005, integrated into UniProtKB/Swiss-Prot. DT 01-MAY-1999, sequence version 1. DT 27-MAR-2024, entry version 195. DE RecName: Full=Diphosphoinositol polyphosphate phosphohydrolase 1 {ECO:0000305}; DE Short=DIPP-1; DE EC=3.6.1.52 {ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, ECO:0000269|PubMed:34788624, ECO:0000269|PubMed:9822604}; DE AltName: Full=Diadenosine hexaphosphate hydrolase; DE Short=Ap6A hydrolase; DE EC=3.6.1.61 {ECO:0000269|PubMed:10419486, ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, ECO:0000269|PubMed:34788624}; DE AltName: Full=Endopolyphosphatase; DE EC=3.6.1.10 {ECO:0000269|PubMed:34788624}; DE AltName: Full=Nucleoside diphosphate-linked moiety X motif 3; DE Short=Nudix motif 3; DE AltName: Full=m7GpppN-mRNA hydrolase; DE EC=3.6.1.62 {ECO:0000269|PubMed:34788624}; DE AltName: Full=m7GpppX diphosphatase; DE EC=3.6.1.59 {ECO:0000269|PubMed:34788624}; GN Name=NUDT3 {ECO:0000312|HGNC:HGNC:8050}; Synonyms=DIPP, DIPP1; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, CATALYTIC ACTIVITY, RP BIOPHYSICOCHEMICAL PROPERTIES, TISSUE SPECIFICITY, AND MUTAGENESIS OF RP GLU-70. RC TISSUE=Uterus; RX PubMed=9822604; DOI=10.1093/emboj/17.22.6599; RA Safrany S.T., Caffrey J.J., Yang X., Bembenek M.E., Moyer M.B., RA Burkhart W.A., Shears S.B.; RT "A novel context for the 'MutT' module, a guardian of cell integrity, in a RT diphosphoinositol polyphosphate phosphohydrolase."; RL EMBO J. 17:6599-6607(1998). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., RA Phelan M., Farmer A.; RT "Cloning of human full-length CDSs in BD Creator(TM) system donor vector."; RL Submitted (OCT-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Amygdala; RX PubMed=14702039; DOI=10.1038/ng1285; RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S., RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA Isogai T., Sugano S.; RT "Complete sequencing and characterization of 21,243 full-length human RT cDNAs."; RL Nat. Genet. 36:40-45(2004). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=14574404; DOI=10.1038/nature02055; RA Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., RA Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., RA Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., RA Andrews T.D., Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., RA Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., RA Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., RA Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., RA Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., RA Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., RA Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., RA Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., RA French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., RA Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., RA Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., RA Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., RA Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., RA Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., RA Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., RA Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., RA Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., RA Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., RA Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., RA Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., RA Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., RA Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., RA Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., RA Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., RA West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., RA Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., RA Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., RA Rogers J., Beck S.; RT "The DNA sequence and analysis of human chromosome 6."; RL Nature 425:805-811(2003). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Uterus; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [7] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=10419486; DOI=10.1074/jbc.274.31.21735; RA Safrany S.T., Ingram S.W., Cartwright J.L., Falck J.R., McLennan A.G., RA Barnes L.D., Shears S.B.; RT "The diadenosine hexaphosphate hydrolases from Schizosaccharomyces pombe RT and Saccharomyces cerevisiae are homologues of the human diphosphoinositol RT polyphosphate phosphohydrolase. Overlapping substrate specificities in a RT MutT-type protein."; RL J. Biol. Chem. 274:21735-21740(1999). RN [8] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF GLY-50; GLY-51; GLY-52; RP GLU-66; GLY-72; GLY-75; GLY-78; GLY-82; PHE-84 AND HIS-91. RX PubMed=10585413; DOI=10.1074/jbc.274.50.35434; RA Yang X., Safrany S.T., Shears S.B.; RT "Site-directed mutagenesis of diphosphoinositol polyphosphate RT phosphohydrolase, a dual specificity NUDT enzyme that attacks diadenosine RT polyphosphates and diphosphoinositol polyphosphates."; RL J. Biol. Chem. 274:35434-35440(1999). RN [9] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=12370170; DOI=10.1074/jbc.m209795200; RA Fisher D.I., Safrany S.T., Strike P., McLennan A.G., Cartwright J.L.; RT "Nudix hydrolases that degrade dinucleoside and diphosphoinositol RT polyphosphates also have 5-phosphoribosyl 1-pyrophosphate (PRPP) RT pyrophosphatase activity that generates the glycolytic activator ribose RT 1,5-bisphosphate."; RL J. Biol. Chem. 277:47313-47317(2002). RN [10] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [11] RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=22814378; DOI=10.1073/pnas.1210303109; RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A., RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E., Timmerman E., RA Prieto J., Arnesen T., Sherman F., Gevaert K., Aldabe R.; RT "N-terminal acetylome analyses and functional insights of the N-terminal RT acetyltransferase NatB."; RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012). RN [12] RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF 69-GLU--GLU-70. RX PubMed=26932476; DOI=10.1261/rna.055699.115; RA Grudzien-Nogalska E., Jiao X., Song M.G., Hart R.P., Kiledjian M.; RT "Nudt3 is an mRNA decapping enzyme that modulates cell migration."; RL RNA 22:773-781(2016). RN [13] RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION. RX PubMed=32727897; DOI=10.1073/pnas.1922284117; RA Sahu S., Wang Z., Jiao X., Gu C., Jork N., Wittwer C., Li X., Hostachy S., RA Fiedler D., Wang H., Jessen H.J., Kiledjian M., Shears S.B.; RT "InsP7 is a small-molecule regulator of NUDT3-mediated mRNA decapping and RT processing-body dynamics."; RL Proc. Natl. Acad. Sci. U.S.A. 117:19245-19253(2020). RN [14] RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, BIOPHYSICOCHEMICAL RP PROPERTIES, COFACTOR, SUBCELLULAR LOCATION, AND MUTAGENESIS OF GLU-70. RX PubMed=34788624; DOI=10.1016/j.celrep.2021.110004; RA Samper-Martin B., Sarrias A., Lazaro B., Perez-Montero M., RA Rodriguez-Rodriguez R., Ribeiro M.P.C., Banon A., Wolfgeher D., RA Jessen H.J., Alsina B., Clotet J., Kron S.J., Saiardi A., Jimenez J., RA Bru S.; RT "Polyphosphate degradation by Nudt3-Zn2+ mediates oxidative stress RT response."; RL Cell Rep. 37:110004-110004(2021). RN [15] RP X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) IN COMPLEX WITH MAGNESIUM IONS; RP FLUORIDE AND INOSITOL HEXAKISPHOSPHATE, AND COFACTOR. RX PubMed=19585659; DOI=10.1002/prot.22489; RA Thorsell A.G., Persson C., Graslund S., Hammarstrom M., Busam R.D., RA Hallberg B.M.; RT "Crystal structure of human diphosphoinositol phosphatase 1."; RL Proteins 77:242-246(2009). CC -!- FUNCTION: Cleaves a beta-phosphate from the diphosphate groups in PP- CC InsP5 (diphosphoinositol pentakisphosphate) and [PP]2-InsP4 CC (bisdiphosphoinositol tetrakisphosphate), suggesting that it may play a CC role in signal transduction (PubMed:12370170, PubMed:9822604, CC PubMed:10585413). InsP6 (inositol hexakisphosphate) is not a substrate CC (PubMed:9822604). Acts as a negative regulator of the ERK1/2 pathway CC (By similarity). Also able to catalyze the hydrolysis of dinucleoside CC oligophosphates, with diadenosine 5',5'''-P1,P6-hexaphosphate (Ap6A) CC and diadenosine 5',5'''- P1,P5-pentaphosphate (Ap5A) being the CC preferred substrates (PubMed:12370170, PubMed:10419486). The major CC reaction products are ADP and p4a from Ap6A and ADP and ATP from Ap5A CC (PubMed:12370170). Also able to hydrolyze 5-phosphoribose 1-diphosphate CC (PubMed:12370170). Acts as a decapping enzyme that modulates the CC stability of a subset of mRNAs implicated in cell motility CC (PubMed:26932476). Hydrolyzes monomethylated capped RNA after both the CC alpha- and beta-phosphates generating m7GMP + ppRNA and m7GDP + pRNA CC (PubMed:32727897). Can hydrolyze unmethylated capped RNAs (By CC similarity). Divalent cations zinc, magnesium and manganese determine CC its substrate specificity (PubMed:34788624). Exhibits diphosphoinositol CC polyphosphate phosphohydrolase in the presence of magnesium ions, CC diadenosine hexaphosphate hydrolase activity in the presence of CC manganese ions and endopolyphosphatase activity in the presence of zinc CC ions (PubMed:34788624). Plays an important role in limiting DNA damage CC and maintaining cell survival upon oxidative stress via its CC endopolyphosphatase activity (PubMed:34788624). CC {ECO:0000250|UniProtKB:Q9JI46, ECO:0000269|PubMed:10419486, CC ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, CC ECO:0000269|PubMed:34788624, ECO:0000269|PubMed:9822604, CC ECO:0000305|PubMed:26932476}. CC -!- CATALYTIC ACTIVITY: CC Reaction=diphospho-myo-inositol polyphosphate + H2O = myo-inositol CC polyphosphate + phosphate.; EC=3.6.1.52; CC Evidence={ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, CC ECO:0000269|PubMed:34788624, ECO:0000269|PubMed:9822604}; CC -!- CATALYTIC ACTIVITY: CC Reaction=5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate + H2O CC = 1D-myo-inositol hexakisphosphate + H(+) + phosphate; CC Xref=Rhea:RHEA:22384, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:43474, ChEBI:CHEBI:58130, ChEBI:CHEBI:58628; EC=3.6.1.52; CC Evidence={ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, CC ECO:0000269|PubMed:34788624, ECO:0000269|PubMed:9822604}; CC -!- CATALYTIC ACTIVITY: CC Reaction=3,5-bis(diphospho)-1D-myo-inositol 1,2,4,6-tetrakisphosphate + CC H2O = 3-diphospho-1D-myo-inositol 1,2,4,5,6-pentakisphosphate + 2 CC H(+) + phosphate; Xref=Rhea:RHEA:56312, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:43474, ChEBI:CHEBI:140372, CC ChEBI:CHEBI:140374; EC=3.6.1.52; CC Evidence={ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, CC ECO:0000269|PubMed:34788624, ECO:0000269|PubMed:9822604}; CC -!- CATALYTIC ACTIVITY: CC Reaction=[phosphate](n+1) + n H2O = n H(+) + (n+1) phosphate; CC Xref=Rhea:RHEA:22452, Rhea:RHEA-COMP:14280, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16838, ChEBI:CHEBI:43474; EC=3.6.1.10; CC Evidence={ECO:0000269|PubMed:34788624}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + P(1),P(5)-bis(5'-adenosyl) pentaphosphate = ADP + ATP + CC 2 H(+); Xref=Rhea:RHEA:30527, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:62041, ChEBI:CHEBI:456216; CC EC=3.6.1.61; Evidence={ECO:0000269|PubMed:10419486, CC ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170, CC ECO:0000269|PubMed:34788624}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + P(1),P(6)-bis(5'-adenosyl) hexaphosphate = 2 ATP + 2 CC H(+); Xref=Rhea:RHEA:32043, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:63740; EC=3.6.1.61; CC Evidence={ECO:0000269|PubMed:10419486, ECO:0000269|PubMed:10585413, CC ECO:0000269|PubMed:12370170}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + P(1),P(4)-bis(5'-adenosyl) tetraphosphate = AMP + ATP + CC 2 H(+); Xref=Rhea:RHEA:32039, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:30616, ChEBI:CHEBI:58141, ChEBI:CHEBI:456215; CC EC=3.6.1.61; Evidence={ECO:0000269|PubMed:10419486, CC ECO:0000269|PubMed:10585413, ECO:0000269|PubMed:12370170}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside CC in mRNA + H2O = a 5'-end diphospho-ribonucleoside in mRNA + 2 H(+) + CC N(7)-methyl-GMP; Xref=Rhea:RHEA:65388, Rhea:RHEA-COMP:17165, CC Rhea:RHEA-COMP:17167, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:58285, ChEBI:CHEBI:156461, ChEBI:CHEBI:167616; CC EC=3.6.1.59; Evidence={ECO:0000269|PubMed:32727897}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a 5'-end (N(7)-methyl 5'-triphosphoguanosine)-ribonucleoside CC in mRNA + H2O = a 5'-end phospho-ribonucleoside in mRNA + 2 H(+) + CC N(7)-methyl-GDP; Xref=Rhea:RHEA:67484, Rhea:RHEA-COMP:15692, CC Rhea:RHEA-COMP:17167, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:63714, ChEBI:CHEBI:138282, ChEBI:CHEBI:156461; CC EC=3.6.1.62; Evidence={ECO:0000269|PubMed:32727897}; CC -!- COFACTOR: CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420; CC Evidence={ECO:0000269|PubMed:19585659, ECO:0000269|PubMed:34788624}; CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035; CC Evidence={ECO:0000269|PubMed:34788624}; CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105; CC Evidence={ECO:0000269|PubMed:34788624}; CC Note=Binds 3 Mg(2+) ions per subunit. {ECO:0000269|PubMed:19585659}; CC -!- ACTIVITY REGULATION: Endopolyphospahatase activity is inhibited by NaF, CC NaPPi, beta-glycerol phosphate and heparin (PubMed:34788624). 5- CC diphosphoinositol pentakisphosphate (5-InsP7) inhibits its mRNA CC decapping activity (PubMed:32727897). {ECO:0000269|PubMed:32727897, CC ECO:0000269|PubMed:34788624}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=5.9 uM for Ap6A {ECO:0000269|PubMed:10419486, CC ECO:0000269|PubMed:12370170}; CC KM=7.7 uM for Ap5A {ECO:0000269|PubMed:10419486}; CC KM=38 mM for 5-phosphoribose 1-diphosphate CC {ECO:0000269|PubMed:12370170}; CC KM=4.2 nM for PP-InsP5 {ECO:0000269|PubMed:12370170}; CC pH dependence: CC Optimum pH is 7.0-7.5 for PP-InsP5 hydrolysis. Displays strong CC endopolyphosphatase activity at pH 6.8 and 7.4. CC {ECO:0000269|PubMed:34788624, ECO:0000269|PubMed:9822604}; CC -!- SUBUNIT: Monomer. {ECO:0000250|UniProtKB:Q566C7}. CC -!- INTERACTION: CC O95989; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-713708, EBI-742054; CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:34788624}. Nucleus CC {ECO:0000269|PubMed:34788624}. CC -!- TISSUE SPECIFICITY: Widely expressed. Expressed at higher level in CC brain, heart, pancreas and liver. Also expressed in placenta, lung and CC kidney. {ECO:0000269|PubMed:9822604}. CC -!- SIMILARITY: Belongs to the Nudix hydrolase family. DIPP subfamily. CC {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; AF062529; AAC83224.1; -; mRNA. DR EMBL; AF062530; AAC83225.1; -; mRNA. DR EMBL; BT019984; AAV38787.1; -; mRNA. DR EMBL; BT019985; AAV38788.1; -; mRNA. DR EMBL; AK313440; BAG36231.1; -; mRNA. DR EMBL; Z98036; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; AL355855; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471081; EAX03781.1; -; Genomic_DNA. DR EMBL; BC007727; AAH07727.1; -; mRNA. DR CCDS; CCDS4791.1; -. DR RefSeq; NP_006694.1; NM_006703.3. DR PDB; 2FVV; X-ray; 1.25 A; A=1-172. DR PDB; 2Q9P; X-ray; 1.65 A; A=1-172. DR PDB; 6PCK; X-ray; 1.20 A; A=1-148. DR PDB; 6PCL; X-ray; 1.30 A; A=1-148. DR PDB; 6WO7; X-ray; 1.40 A; A=1-148. DR PDB; 6WO8; X-ray; 1.70 A; A=1-148. DR PDB; 6WO9; X-ray; 2.00 A; A=1-148. DR PDB; 6WOA; X-ray; 1.50 A; A=1-148. DR PDB; 6WOB; X-ray; 1.45 A; A=1-148. DR PDB; 6WOC; X-ray; 1.35 A; A=1-148. DR PDB; 6WOD; X-ray; 1.35 A; A=1-148. DR PDB; 6WOE; X-ray; 1.40 A; A=1-148. DR PDB; 6WOF; X-ray; 1.60 A; A=1-148. DR PDB; 6WOG; X-ray; 1.50 A; A=1-148. DR PDB; 6WOH; X-ray; 1.70 A; A=1-148. DR PDB; 6WOI; X-ray; 1.50 A; A=1-148. DR PDB; 7TN4; X-ray; 1.85 A; A=1-172. DR PDB; 8T98; X-ray; 1.30 A; A=1-148. DR PDB; 8T99; X-ray; 1.50 A; A=1-148. DR PDB; 8TF9; X-ray; 1.55 A; A=1-148. DR PDB; 8TFA; X-ray; 1.40 A; A=1-148. DR PDBsum; 2FVV; -. DR PDBsum; 2Q9P; -. DR PDBsum; 6PCK; -. DR PDBsum; 6PCL; -. DR PDBsum; 6WO7; -. DR PDBsum; 6WO8; -. DR PDBsum; 6WO9; -. DR PDBsum; 6WOA; -. DR PDBsum; 6WOB; -. DR PDBsum; 6WOC; -. DR PDBsum; 6WOD; -. DR PDBsum; 6WOE; -. DR PDBsum; 6WOF; -. DR PDBsum; 6WOG; -. DR PDBsum; 6WOH; -. DR PDBsum; 6WOI; -. DR PDBsum; 7TN4; -. DR PDBsum; 8T98; -. DR PDBsum; 8T99; -. DR PDBsum; 8TF9; -. DR PDBsum; 8TFA; -. DR AlphaFoldDB; O95989; -. DR SMR; O95989; -. DR BioGRID; 116336; 98. DR IntAct; O95989; 43. DR MINT; O95989; -. DR STRING; 9606.ENSP00000476119; -. DR ChEMBL; CHEMBL4295689; -. DR iPTMnet; O95989; -. DR PhosphoSitePlus; O95989; -. DR SwissPalm; O95989; -. DR BioMuta; NUDT3; -. DR EPD; O95989; -. DR jPOST; O95989; -. DR MassIVE; O95989; -. DR MaxQB; O95989; -. DR PaxDb; 9606-ENSP00000476119; -. DR PeptideAtlas; O95989; -. DR ProteomicsDB; 51165; -. DR Pumba; O95989; -. DR Antibodypedia; 69618; 61 antibodies from 21 providers. DR DNASU; 11165; -. DR Ensembl; ENST00000607016.2; ENSP00000476119.1; ENSG00000272325.2. DR GeneID; 11165; -. DR KEGG; hsa:11165; -. DR MANE-Select; ENST00000607016.2; ENSP00000476119.1; NM_006703.4; NP_006694.1. DR UCSC; uc003ojl.4; human. DR AGR; HGNC:8050; -. DR CTD; 11165; -. DR DisGeNET; 11165; -. DR GeneCards; NUDT3; -. DR HGNC; HGNC:8050; NUDT3. DR HPA; ENSG00000272325; Low tissue specificity. DR MIM; 609228; gene. DR neXtProt; NX_O95989; -. DR OpenTargets; ENSG00000272325; -. DR PharmGKB; PA31834; -. DR VEuPathDB; HostDB:ENSG00000272325; -. DR eggNOG; KOG2839; Eukaryota. DR GeneTree; ENSGT00940000157882; -. DR HOGENOM; CLU_037162_1_0_1; -. DR InParanoid; O95989; -. DR OMA; WHEDKLN; -. DR OrthoDB; 154729at2759; -. DR PhylomeDB; O95989; -. DR TreeFam; TF106349; -. DR BioCyc; MetaCyc:HS03602-MONOMER; -. DR BRENDA; 3.6.1.17; 2681. DR BRENDA; 3.6.1.42; 2681. DR BRENDA; 3.6.1.52; 2681. DR BRENDA; 3.6.1.60; 2681. DR PathwayCommons; O95989; -. DR Reactome; R-HSA-1855167; Synthesis of pyrophosphates in the cytosol. DR SABIO-RK; O95989; -. DR SignaLink; O95989; -. DR SIGNOR; O95989; -. DR BioGRID-ORCS; 11165; 11 hits in 1136 CRISPR screens. DR ChiTaRS; NUDT3; human. DR EvolutionaryTrace; O95989; -. DR GeneWiki; NUDT3; -. DR GenomeRNAi; 11165; -. DR Pharos; O95989; Tbio. DR PRO; PR:O95989; -. DR Proteomes; UP000005640; Chromosome 6. DR RNAct; O95989; Protein. DR Bgee; ENSG00000272325; Expressed in dorsal motor nucleus of vagus nerve and 213 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005634; C:nucleus; IDA:UniProtKB. DR GO; GO:0140932; F:5'-(N(7)-methyl 5'-triphosphoguanosine)-[mRNA] diphosphatase activity; IDA:UniProtKB. DR GO; GO:0140933; F:5'-(N(7)-methylguanosine 5'-triphospho)-[mRNA] hydrolase activity; IDA:UniProtKB. DR GO; GO:0034431; F:bis(5'-adenosyl)-hexaphosphatase activity; IBA:GO_Central. DR GO; GO:0034432; F:bis(5'-adenosyl)-pentaphosphatase activity; IBA:GO_Central. DR GO; GO:0008486; F:diphosphoinositol-polyphosphate diphosphatase activity; IDA:UniProtKB. DR GO; GO:0000298; F:endopolyphosphatase activity; IDA:UniProtKB. DR GO; GO:0052842; F:inositol diphosphate pentakisphosphate diphosphatase activity; IDA:UniProtKB. DR GO; GO:0052840; F:inositol diphosphate tetrakisphosphate diphosphatase activity; IDA:UniProtKB. DR GO; GO:0052848; F:inositol-3,5-bisdiphosphate-2,3,4,6-tetrakisphosphate 5-diphosphatase activity; IEA:RHEA. DR GO; GO:0052845; F:inositol-5-diphosphate-1,2,3,4,6-pentakisphosphate diphosphatase activity; IEA:RHEA. DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB. DR GO; GO:0030145; F:manganese ion binding; IDA:UniProtKB. DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB. DR GO; GO:1901911; P:adenosine 5'-(hexahydrogen pentaphosphate) catabolic process; IBA:GO_Central. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:1901909; P:diadenosine hexaphosphate catabolic process; IDA:UniProtKB. DR GO; GO:1901907; P:diadenosine pentaphosphate catabolic process; IBA:GO_Central. DR GO; GO:0015961; P:diadenosine polyphosphate catabolic process; TAS:ProtInc. DR GO; GO:0071544; P:diphosphoinositol polyphosphate catabolic process; IDA:UniProtKB. DR GO; GO:0071543; P:diphosphoinositol polyphosphate metabolic process; IBA:GO_Central. DR GO; GO:0110154; P:RNA decapping; IDA:UniProtKB. DR CDD; cd04666; Nudix_Hydrolase_9; 1. DR Gene3D; 3.90.79.10; Nucleoside Triphosphate Pyrophosphohydrolase; 1. DR InterPro; IPR047198; DDP-like_NUDIX. DR InterPro; IPR015797; NUDIX_hydrolase-like_dom_sf. DR InterPro; IPR020084; NUDIX_hydrolase_CS. DR InterPro; IPR000086; NUDIX_hydrolase_dom. DR PANTHER; PTHR12629; DIPHOSPHOINOSITOL POLYPHOSPHATE PHOSPHOHYDROLASE; 1. DR PANTHER; PTHR12629:SF5; DIPHOSPHOINOSITOL POLYPHOSPHATE PHOSPHOHYDROLASE 1; 1. DR Pfam; PF00293; NUDIX; 1. DR SUPFAM; SSF55811; Nudix; 1. DR PROSITE; PS51462; NUDIX; 1. DR PROSITE; PS00893; NUDIX_BOX; 1. DR Genevisible; O95989; HS. PE 1: Evidence at protein level; KW 3D-structure; Acetylation; Cytoplasm; Hydrolase; Magnesium; Manganese; KW Metal-binding; Nucleus; Reference proteome; Zinc. FT CHAIN 1..172 FT /note="Diphosphoinositol polyphosphate phosphohydrolase 1" FT /id="PRO_0000057055" FT DOMAIN 17..142 FT /note="Nudix hydrolase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00794" FT MOTIF 51..72 FT /note="Nudix box" FT ACT_SITE 69 FT /note="Proton acceptor" FT /evidence="ECO:0000305" FT BINDING 10 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2FVV, ECO:0007744|PDB:2Q9P" FT BINDING 18..20 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2FVV, ECO:0007744|PDB:2Q9P" FT BINDING 39..41 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2FVV, ECO:0007744|PDB:2Q9P" FT BINDING 50 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2Q9P" FT BINDING 66 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="2" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2Q9P" FT BINDING 66 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="3" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2Q9P" FT BINDING 70 FT /ligand="Mg(2+)" FT /ligand_id="ChEBI:CHEBI:18420" FT /ligand_label="1" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2Q9P" FT BINDING 89..91 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2FVV, ECO:0007744|PDB:2Q9P" FT BINDING 115 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2Q9P" FT BINDING 133 FT /ligand="substrate" FT /evidence="ECO:0000269|PubMed:19585659, FT ECO:0007744|PDB:2FVV, ECO:0007744|PDB:2Q9P" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0007744|PubMed:22814378" FT MUTAGEN 50 FT /note="G->A,V: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 51 FT /note="G->A: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 52 FT /note="G->A,V: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 66 FT /note="E->Q: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 69..70 FT /note="EE->QQ: Loss of mRNA-decapping activity." FT /evidence="ECO:0000269|PubMed:26932476" FT MUTAGEN 70 FT /note="E->A: Loss of endopolyphosphatase activity." FT /evidence="ECO:0000269|PubMed:34788624" FT MUTAGEN 70 FT /note="E->Q: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:9822604" FT MUTAGEN 72 FT /note="G->A: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 75 FT /note="G->A: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 78 FT /note="G->A: No effect on diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 78 FT /note="G->V: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 82 FT /note="G->A: Loss of diphosphoinositol polyphosphate FT phosphohydrolase activity." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 84 FT /note="F->Y: Induces a strong decrease in Ap6A and FT [PP]-InsP4 hydrolysis, while it only weakly affects FT PP-InsP5 hydrolysis." FT /evidence="ECO:0000269|PubMed:10585413" FT MUTAGEN 91 FT /note="H->L: Induces a strong decrease in Ap6A and FT [PP]-InsP4 hydrolysis, while it only weakly affects FT PP-InsP5 hydrolysis." FT /evidence="ECO:0000269|PubMed:10585413" FT STRAND 18..28 FT /evidence="ECO:0007829|PDB:6PCK" FT STRAND 33..38 FT /evidence="ECO:0007829|PDB:6PCK" FT STRAND 45..47 FT /evidence="ECO:0007829|PDB:6PCK" FT STRAND 50..52 FT /evidence="ECO:0007829|PDB:6PCK" FT HELIX 59..71 FT /evidence="ECO:0007829|PDB:6PCK" FT STRAND 73..86 FT /evidence="ECO:0007829|PDB:6PCK" FT TURN 87..90 FT /evidence="ECO:0007829|PDB:6PCK" FT STRAND 91..103 FT /evidence="ECO:0007829|PDB:6PCK" FT HELIX 108..113 FT /evidence="ECO:0007829|PDB:6PCK" FT STRAND 117..121 FT /evidence="ECO:0007829|PDB:6PCK" FT HELIX 122..129 FT /evidence="ECO:0007829|PDB:6PCK" FT TURN 130..132 FT /evidence="ECO:0007829|PDB:6PCK" FT HELIX 134..138 FT /evidence="ECO:0007829|PDB:6PCK" SQ SEQUENCE 172 AA; 19471 MW; DE823FECF5C6438A CRC64; MMKLKSNQTR TYDGDGYKKR AACLCFRSES EEEVLLVSSS RHPDRWIVPG GGMEPEEEPS VAAVREVCEE AGVKGTLGRL VGIFENQERK HRTYVYVLIV TEVLEDWEDS VNIGRKREWF KIEDAIKVLQ YHKPVQASYF ETLRQGYSAN NGTPVVATTY SVSAQSSMSG IR //