ITPA_MOUSE
ID ITPA_MOUSE Reviewed; 198 AA.
AC Q9D892; Q8R0Q8;
DT 23-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 23-APR-2003, sequence version 2.
DT 03-AUG-2022, entry version 148.
DE RecName: Full=Inosine triphosphate pyrophosphatase {ECO:0000255|HAMAP-Rule:MF_03148};
DE Short=ITPase {ECO:0000255|HAMAP-Rule:MF_03148};
DE Short=Inosine triphosphatase {ECO:0000255|HAMAP-Rule:MF_03148};
DE EC=3.6.1.9 {ECO:0000255|HAMAP-Rule:MF_03148, ECO:0000269|PubMed:17090528, ECO:0000269|PubMed:20081199};
DE AltName: Full=Non-canonical purine NTP pyrophosphatase {ECO:0000255|HAMAP-Rule:MF_03148};
DE AltName: Full=Non-standard purine NTP pyrophosphatase {ECO:0000255|HAMAP-Rule:MF_03148};
DE AltName: Full=Nucleoside-triphosphate diphosphatase {ECO:0000255|HAMAP-Rule:MF_03148};
DE AltName: Full=Nucleoside-triphosphate pyrophosphatase {ECO:0000255|HAMAP-Rule:MF_03148};
DE Short=NTPase {ECO:0000255|HAMAP-Rule:MF_03148};
GN Name=Itpa;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Small intestine;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Eye;
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 [3]
RP SUBSTRATE SPECIFICITY, FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL
RP PROPERTIES.
RX PubMed=17090528; DOI=10.1074/jbc.m608708200;
RA Burgis N.E., Cunningham R.P.;
RT "Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate
RT pyrophosphohydrolase.";
RL J. Biol. Chem. 282:3531-3538(2007).
RN [4]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-146, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Heart, Kidney, Liver, Lung, Pancreas,
RC Spleen, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=20601097; DOI=10.1016/j.mrgentox.2010.06.009;
RA Sakumi K., Abolhassani N., Behmanesh M., Iyama T., Tsuchimoto D.,
RA Nakabeppu Y.;
RT "ITPA protein, an enzyme that eliminates deaminated purine nucleoside
RT triphosphates in cells.";
RL Mutat. Res. 703:43-50(2010).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, AND DISRUPTION PHENOTYPE.
RX PubMed=20081199; DOI=10.1093/nar/gkp1250;
RA Abolhassani N., Iyama T., Tsuchimoto D., Sakumi K., Ohno M., Behmanesh M.,
RA Nakabeppu Y.;
RT "NUDT16 and ITPA play a dual protective role in maintaining chromosome
RT stability and cell growth by eliminating dIDP/IDP and dITP/ITP from
RT nucleotide pools in mammals.";
RL Nucleic Acids Res. 38:2891-2903(2010).
CC -!- FUNCTION: Pyrophosphatase that hydrolyzes the non-canonical purine
CC nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate
CC (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triphosphate
CC (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective
CC monophosphate derivatives. The enzyme does not distinguish between the
CC deoxy- and ribose forms. Probably excludes non-canonical purines from
CC RNA and DNA precursor pools, thus preventing their incorporation into
CC RNA and DNA and avoiding chromosomal lesions. {ECO:0000255|HAMAP-
CC Rule:MF_03148, ECO:0000269|PubMed:17090528,
CC ECO:0000269|PubMed:20081199, ECO:0000269|PubMed:20601097}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a ribonucleoside 5'-triphosphate + H2O = a ribonucleoside 5'-
CC phosphate + diphosphate + H(+); Xref=Rhea:RHEA:23996,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58043, ChEBI:CHEBI:61557; EC=3.6.1.9;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000269|PubMed:20081199};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:23997;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000269|PubMed:20081199};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 2'-deoxyribonucleoside 5'-triphosphate + H2O = a 2'-
CC deoxyribonucleoside 5'-phosphate + diphosphate + H(+);
CC Xref=Rhea:RHEA:44644, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:61560, ChEBI:CHEBI:65317; EC=3.6.1.9;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000269|PubMed:17090528};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:44645;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000305|PubMed:17090528};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + ITP = diphosphate + H(+) + IMP; Xref=Rhea:RHEA:29399,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:58053, ChEBI:CHEBI:61402; EC=3.6.1.9;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000269|PubMed:20081199};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:29400;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000269|PubMed:20081199};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=dITP + H2O = dIMP + diphosphate + H(+); Xref=Rhea:RHEA:28342,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:61194, ChEBI:CHEBI:61382; EC=3.6.1.9;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000269|PubMed:17090528};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28343;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148,
CC ECO:0000305|PubMed:17090528};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + XTP = diphosphate + H(+) + XMP; Xref=Rhea:RHEA:28610,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57464, ChEBI:CHEBI:61314; EC=3.6.1.9;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:28611;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148};
CC Name=Mn(2+); Xref=ChEBI:CHEBI:29035;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03148};
CC Note=Binds 1 divalent metal cation per subunit; can use either Mg(2+)
CC or Mn(2+). {ECO:0000255|HAMAP-Rule:MF_03148};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=24.9 uM for dITP {ECO:0000269|PubMed:17090528};
CC KM=38.4 uM for dHAPTP {ECO:0000269|PubMed:17090528};
CC KM=667 uM for dGTP {ECO:0000269|PubMed:17090528};
CC Note=kcat is 84 sec(-1) with dITP as substrate (PubMed:17090528).
CC kcat is 115 sec(-1) with dHAPTP as substrate (PubMed:17090528). kcat
CC is 12.4 sec(-1) with dGTP as substrate (PubMed:17090528).
CC {ECO:0000269|PubMed:17090528};
CC -!- SUBUNIT: Homodimer. {ECO:0000255|HAMAP-Rule:MF_03148}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000255|HAMAP-Rule:MF_03148}.
CC -!- DISRUPTION PHENOTYPE: Pups die about 2 weeks after birth with growth
CC retardation and heart failure. Accumulates ITP in erythrocytes.
CC Accumulates inosine in RNA and deoxyinosine in DNA.
CC {ECO:0000269|PubMed:20081199, ECO:0000269|PubMed:20601097}.
CC -!- SIMILARITY: Belongs to the HAM1 NTPase family. {ECO:0000255|HAMAP-
CC Rule:MF_03148}.
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DR EMBL; AK008279; BAB25571.1; -; mRNA.
DR EMBL; BC026508; AAH26508.1; -; mRNA.
DR CCDS; CCDS16748.1; -.
DR RefSeq; NP_080198.2; NM_025922.2.
DR RefSeq; XP_017171220.1; XM_017315731.1.
DR AlphaFoldDB; Q9D892; -.
DR SMR; Q9D892; -.
DR BioGRID; 200846; 1.
DR IntAct; Q9D892; 1.
DR STRING; 10090.ENSMUSP00000099482; -.
DR iPTMnet; Q9D892; -.
DR PhosphoSitePlus; Q9D892; -.
DR SwissPalm; Q9D892; -.
DR REPRODUCTION-2DPAGE; Q9D892; -.
DR CPTAC; non-CPTAC-3829; -.
DR EPD; Q9D892; -.
DR jPOST; Q9D892; -.
DR MaxQB; Q9D892; -.
DR PaxDb; Q9D892; -.
DR PRIDE; Q9D892; -.
DR ProteomicsDB; 269412; -.
DR Antibodypedia; 7322; 293 antibodies from 31 providers.
DR DNASU; 16434; -.
DR Ensembl; ENSMUST00000103193; ENSMUSP00000099482; ENSMUSG00000074797.
DR GeneID; 16434; -.
DR KEGG; mmu:16434; -.
DR UCSC; uc008mju.1; mouse.
DR CTD; 3704; -.
DR MGI; MGI:96622; Itpa.
DR VEuPathDB; HostDB:ENSMUSG00000074797; -.
DR eggNOG; KOG3222; Eukaryota.
DR GeneTree; ENSGT00390000015399; -.
DR HOGENOM; CLU_082080_1_1_1; -.
DR InParanoid; Q9D892; -.
DR OMA; DCFADDT; -.
DR OrthoDB; 1298391at2759; -.
DR PhylomeDB; Q9D892; -.
DR TreeFam; TF105614; -.
DR Reactome; R-MMU-74259; Purine catabolism.
DR BioGRID-ORCS; 16434; 4 hits in 73 CRISPR screens.
DR ChiTaRS; Itpa; mouse.
DR PRO; PR:Q9D892; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q9D892; protein.
DR Bgee; ENSMUSG00000074797; Expressed in ectoplacental cone and 275 other tissues.
DR ExpressionAtlas; Q9D892; baseline and differential.
DR Genevisible; Q9D892; MM.
DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; ISO:MGI.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0005654; C:nucleoplasm; ISO:MGI.
DR GO; GO:0035870; F:dITP diphosphatase activity; IMP:MGI.
DR GO; GO:0036218; F:dTTP diphosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0042802; F:identical protein binding; ISO:MGI.
DR GO; GO:0036220; F:ITP diphosphatase activity; IEA:RHEA.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0035529; F:NADH pyrophosphatase activity; IEA:UniProtKB-EC.
DR GO; GO:0047429; F:nucleoside-triphosphate diphosphatase activity; IDA:MGI.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0036222; F:XTP diphosphatase activity; IEA:RHEA.
DR GO; GO:0051276; P:chromosome organization; IMP:MGI.
DR GO; GO:0009204; P:deoxyribonucleoside triphosphate catabolic process; IEA:UniProtKB-UniRule.
DR GO; GO:0006193; P:ITP catabolic process; IMP:MGI.
DR GO; GO:0009143; P:nucleoside triphosphate catabolic process; IBA:GO_Central.
DR CDD; cd00515; HAM1; 1.
DR Gene3D; 3.90.950.10; -; 1.
DR HAMAP; MF_03148; HAM1_NTPase; 1.
DR InterPro; IPR002637; Ham1p-like.
DR InterPro; IPR027502; ITPase.
DR InterPro; IPR029001; ITPase-like_fam.
DR PANTHER; PTHR11067; PTHR11067; 1.
DR Pfam; PF01725; Ham1p_like; 1.
DR SUPFAM; SSF52972; SSF52972; 1.
DR TIGRFAMs; TIGR00042; TIGR00042; 1.
PE 1: Evidence at protein level;
KW Acetylation; Cytoplasm; Hydrolase; Magnesium; Manganese; Metal-binding;
KW Nucleotide metabolism; Nucleotide-binding; Phosphoprotein;
KW Reference proteome.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT CHAIN 2..198
FT /note="Inosine triphosphate pyrophosphatase"
FT /id="PRO_0000178281"
FT BINDING 14..19
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 44
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 56
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 72..73
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 89
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 149..152
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 172
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT BINDING 177..178
FT /ligand="ITP"
FT /ligand_id="ChEBI:CHEBI:61402"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03148"
FT MOD_RES 2
FT /note="N-acetylalanine"
FT /evidence="ECO:0000250|UniProtKB:Q9BY32, ECO:0000255|HAMAP-
FT Rule:MF_03148"
FT MOD_RES 146
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21183079"
FT CONFLICT 32
FT /note="P -> Q (in Ref. 2; BAB25571)"
FT /evidence="ECO:0000305"
FT CONFLICT 54
FT /note="I -> M (in Ref. 2; BAB25571)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 198 AA; 21897 MW; D70337E3D2001A9E CRC64;
MAASLVGKKI VFVTGNAKKL EEVIQILGDN FPCTLEAQKI DLPEYQGEPD EISIQKCREA
ARQVQGPVLV EDTCLCFNAL GGLPGPYIKW FLQKLKPEGL HQLLAGFEDK SAYALCTFAL
STGDPSQPVL LFRGQTSGQI VMPRGSRDFG WDPCFQPDGY EQTYAEMPKS EKNTISHRFR
ALHKLQEYFS VAAGAGDH
