Full text data of ITPA
ITPA
(C20orf37)
[Confidence: low (only semi-automatic identification from reviews)]
Inosine triphosphate pyrophosphatase; ITPase; Inosine triphosphatase; 3.6.1.19 (Non-canonical purine NTP pyrophosphatase; Non-standard purine NTP pyrophosphatase; Nucleoside-triphosphate diphosphatase; Nucleoside-triphosphate pyrophosphatase; NTPase; Putative oncogene protein hlc14-06-p)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Inosine triphosphate pyrophosphatase; ITPase; Inosine triphosphatase; 3.6.1.19 (Non-canonical purine NTP pyrophosphatase; Non-standard purine NTP pyrophosphatase; Nucleoside-triphosphate diphosphatase; Nucleoside-triphosphate pyrophosphatase; NTPase; Putative oncogene protein hlc14-06-p)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9BY32
ID ITPA_HUMAN Reviewed; 194 AA.
AC Q9BY32; A2A2N2; A4UIM5; B2BCH7; O14878; Q5JWH4; Q9BYN1; Q9BYX0;
read moreAC Q9H3H8;
DT 23-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 23-APR-2003, sequence version 2.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Inosine triphosphate pyrophosphatase;
DE Short=ITPase;
DE Short=Inosine triphosphatase;
DE EC=3.6.1.19;
DE AltName: Full=Non-canonical purine NTP pyrophosphatase;
DE AltName: Full=Non-standard purine NTP pyrophosphatase;
DE AltName: Full=Nucleoside-triphosphate diphosphatase;
DE AltName: Full=Nucleoside-triphosphate pyrophosphatase;
DE Short=NTPase;
DE AltName: Full=Putative oncogene protein hlc14-06-p;
GN Name=ITPA; Synonyms=C20orf37; ORFNames=My049, OK/SW-cl.9;
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] (ISOFORM 1), SUBUNIT, SUBCELLULAR LOCATION,
RP AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Fetal brain;
RX PubMed=11278832; DOI=10.1074/jbc.M011084200;
RA Lin S., McLennan A.G., Ying K., Wang Z., Gu S., Jin H., Wu C., Lu W.,
RA Yuan Y., Tang R., Xie Y., Mao Y.;
RT "Cloning, expression, and characterization of a human inosine
RT triphosphate pyrophosphatase encoded by the ITPA gene.";
RL J. Biol. Chem. 276:18695-18701(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ITPAD
RP THR-32.
RC TISSUE=Fetal brain;
RA Mao Y.M., Xie Y., Zheng Z.H.;
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lung carcinoma;
RA Fan M.-Z., Chen Z., Cao Z.-M.;
RT "Molecular cloning of cDNA associated with human lung cancer antigen
RT and study on its functions.";
RL Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RA Danaei Y., Behmanesh M., Sadeghi Zadeh M.;
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-
RT reactive CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Lung carcinoma, and Neuroblastoma;
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 [9]
RP PROTEIN SEQUENCE OF 2-9; 40-56; 95-110 AND 181-194, CLEAVAGE OF
RP INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [10]
RP PROTEIN SEQUENCE OF 10-56 AND 95-130, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [11]
RP SUBSTRATE SPECIFICITY, FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=17090528; DOI=10.1074/jbc.M608708200;
RA Burgis N.E., Cunningham R.P.;
RT "Substrate specificity of RdgB protein, a deoxyribonucleoside
RT triphosphate pyrophosphohydrolase.";
RL J. Biol. Chem. 282:3531-3538(2007).
RN [12]
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.,
RA Buerckstuemmer T., 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 [13]
RP X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS).
RX PubMed=17077483; DOI=10.1107/S1744309106041790;
RA Porta J., Kolar C., Kozmin S.G., Pavlov Y.I., Borgstahl G.E.;
RT "Structure of the orthorhombic form of human inosine triphosphate
RT pyrophosphatase.";
RL Acta Crystallogr. F 62:1076-1081(2006).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS) ALONE AND IN COMPLEX WITH ITP,
RP COFACTOR, MAGNESIUM-BINDING SITES, AND SUBSTRATE-BINDING SITES.
RX PubMed=17138556; DOI=10.1074/jbc.M609838200;
RA Stenmark P., Kursula P., Flodin S., Graslund S., Landry R.,
RA Nordlund P., Schueler H.;
RT "Crystal structure of human inosine triphosphatase. Substrate binding
RT and implication of the inosine triphosphatase deficiency mutation
RT P32T.";
RL J. Biol. Chem. 282:3182-3187(2007).
RN [15]
RP VARIANT ITPAD THR-32.
RX PubMed=12384777; DOI=10.1007/s00439-002-0798-z;
RA Sumi S., Marinaki A.M., Arenas M., Fairbanks L., Shobowale-Bakre M.,
RA Rees D.C., Thein S.L., Ansari A., Sanderson J., De Abreu R.A.,
RA Simmonds H.A., Duley J.A.;
RT "Genetic basis of inosine triphosphate pyrophosphohydrolase
RT deficiency.";
RL Hum. Genet. 111:360-367(2002).
RN [16]
RP VARIANT ITPAD THR-32.
RX PubMed=12436200; DOI=10.1007/s100380200095;
RA Cao H., Hegele R.A.;
RT "DNA polymorphisms in ITPA including basis of inosine triphosphatase
RT deficiency.";
RL J. Hum. Genet. 47:620-622(2002).
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 triposphate
CC (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective
CC monophosphate derivatives. The enzyme does not distinguish between
CC the deoxy- and ribose forms. Probably excludes non-canonical
CC purines from RNA and DNA precursor pools, thus preventing their
CC incorporation into RNA and DNA and avoiding chromosomal lesions.
CC -!- CATALYTIC ACTIVITY: A nucleoside triphosphate + H(2)O = a
CC nucleotide + diphosphate.
CC -!- COFACTOR: Binds 1 magnesium ion per subunit.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.51 mM for ITP;
CC KM=0.31 mM for dITP;
CC KM=0.57 mM for XTP;
CC KM=40.7 uM for dHAPTP;
CC KM=933 uM for dGTP;
CC Vmax=1520 umol/min/mg enzyme for ITP;
CC Vmax=940 umol/min/mg enzyme for dITP;
CC Vmax=1680 umol/min/mg enzyme for XTP;
CC Note=Vmax values are similar for dITP, dHAPTP and dGTP;
CC pH dependence:
CC Optimum pH is 10;
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9BY32-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BY32-2; Sequence=VSP_042548;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9BY32-3; Sequence=VSP_045545;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in heart, liver,
CC sex glands, thyroid and adrenal gland.
CC -!- DISEASE: Inosine triphosphate pyrophosphohydrolase deficiency
CC (ITPAD) [MIM:613850]: A common inherited condition characterized
CC by the abnormal accumulation of inosine triphosphate in
CC erythrocytes. It might have pharmacogenomic implications and be
CC related to increased drug toxicity of purine analog drugs.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry. Three different human populations have
CC been reported with respect to their ITPase activity: high, mean
CC (25% of high) and low activity. The variant Thr-32 is associated
CC with complete loss of enzyme activity, may be by altering the
CC local secondary structure of the protein. Heterozygotes for this
CC polymorphism have 22.5% of the control activity: this is
CC consistent with a dimeric structure of the enzyme.
CC -!- SIMILARITY: Belongs to the HAM1 NTPase family.
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DR EMBL; AF219116; AAK21848.1; -; mRNA.
DR EMBL; AF063607; AAG43165.1; -; mRNA.
DR EMBL; AF026816; AAB82608.2; -; mRNA.
DR EMBL; EF199841; ABP01354.1; -; mRNA.
DR EMBL; EF213026; ABO70316.1; -; mRNA.
DR EMBL; AB062127; BAB93459.1; -; mRNA.
DR EMBL; AL109976; CAC16798.3; -; Genomic_DNA.
DR EMBL; AL121891; CAI19399.1; -; Genomic_DNA.
DR EMBL; AL109976; CAI19399.1; JOINED; Genomic_DNA.
DR EMBL; AL121891; CAM27676.1; -; Genomic_DNA.
DR EMBL; AL109976; CAM27676.1; JOINED; Genomic_DNA.
DR EMBL; AL109976; CAM28311.1; -; Genomic_DNA.
DR EMBL; AL121891; CAM28311.1; JOINED; Genomic_DNA.
DR EMBL; CH471133; EAX10541.1; -; Genomic_DNA.
DR EMBL; BC010138; AAH10138.1; -; mRNA.
DR EMBL; BI115811; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_001254552.1; NM_001267623.1.
DR RefSeq; NP_258412.1; NM_033453.3.
DR RefSeq; NP_852470.1; NM_181493.2.
DR UniGene; Hs.415299; -.
DR PDB; 2CAR; X-ray; 1.09 A; A/B=1-194.
DR PDB; 2I5D; X-ray; 1.63 A; A=1-194.
DR PDB; 2J4E; X-ray; 2.80 A; A/B/C/D/E/F/G/H=1-194.
DR PDB; 4F95; X-ray; 2.07 A; A=1-194.
DR PDBsum; 2CAR; -.
DR PDBsum; 2I5D; -.
DR PDBsum; 2J4E; -.
DR PDBsum; 4F95; -.
DR ProteinModelPortal; Q9BY32; -.
DR SMR; Q9BY32; 1-194.
DR IntAct; Q9BY32; 1.
DR MINT; MINT-5006578; -.
DR STRING; 9606.ENSP00000369456; -.
DR PhosphoSite; Q9BY32; -.
DR DMDM; 30173120; -.
DR PaxDb; Q9BY32; -.
DR PeptideAtlas; Q9BY32; -.
DR PRIDE; Q9BY32; -.
DR DNASU; 3704; -.
DR Ensembl; ENST00000380113; ENSP00000369456; ENSG00000125877.
DR Ensembl; ENST00000399838; ENSP00000382732; ENSG00000125877.
DR Ensembl; ENST00000455664; ENSP00000413282; ENSG00000125877.
DR GeneID; 3704; -.
DR KEGG; hsa:3704; -.
DR UCSC; uc002wid.4; human.
DR CTD; 3704; -.
DR GeneCards; GC20P003189; -.
DR HGNC; HGNC:6176; ITPA.
DR HPA; HPA022824; -.
DR MIM; 147520; gene.
DR MIM; 613850; phenotype.
DR neXtProt; NX_Q9BY32; -.
DR Orphanet; 319684; Inosine triphosphatase deficiency.
DR Orphanet; 284113; Susceptibility to adverse reaction due to mercaptopurine.
DR PharmGKB; PA29973; -.
DR eggNOG; COG0127; -.
DR HOGENOM; HOG000293320; -.
DR HOVERGEN; HBG039521; -.
DR InParanoid; Q9BY32; -.
DR KO; K01519; -.
DR OMA; FATGNQN; -.
DR OrthoDB; EOG7X0VJG; -.
DR PhylomeDB; Q9BY32; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; Q9BY32; -.
DR EvolutionaryTrace; Q9BY32; -.
DR GeneWiki; ITPA; -.
DR GenomeRNAi; 3704; -.
DR NextBio; 14515; -.
DR PRO; PR:Q9BY32; -.
DR ArrayExpress; Q9BY32; -.
DR Bgee; Q9BY32; -.
DR CleanEx; HS_ITPA; -.
DR Genevestigator; Q9BY32; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0035870; F:dITP diphosphatase activity; EXP:Reactome.
DR GO; GO:0036220; F:ITP diphosphatase activity; EXP:Reactome.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0036222; F:XTP diphosphatase activity; EXP:Reactome.
DR GO; GO:0051276; P:chromosome organization; IEA:Ensembl.
DR GO; GO:0009204; P:deoxyribonucleoside triphosphate catabolic process; IEA:UniProtKB-HAMAP.
DR GO; GO:0006193; P:ITP catabolic process; IEA:Ensembl.
DR GO; GO:0055086; P:nucleobase-containing small molecule metabolic process; TAS:Reactome.
DR HAMAP; MF_03148; HAM1_NTPase; 1; -.
DR InterPro; IPR002637; Ham1p-like.
DR InterPro; IPR027502; ITPase.
DR PANTHER; PTHR11067; PTHR11067; 1.
DR Pfam; PF01725; Ham1p_like; 1.
DR TIGRFAMs; TIGR00042; TIGR00042; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation; Hydrolase;
KW Magnesium; Metal-binding; Nucleotide metabolism; Nucleotide-binding;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 194 Inosine triphosphate pyrophosphatase.
FT /FTId=PRO_0000178280.
FT REGION 14 19 Substrate binding.
FT REGION 72 73 Substrate binding.
FT REGION 149 152 Substrate binding.
FT REGION 177 178 Substrate binding.
FT METAL 44 44 Magnesium.
FT METAL 72 72 Magnesium (By similarity).
FT BINDING 56 56 Substrate.
FT BINDING 172 172 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 7 23 Missing (in isoform 2).
FT /FTId=VSP_042548.
FT VAR_SEQ 23 63 Missing (in isoform 3).
FT /FTId=VSP_045545.
FT VARIANT 32 32 P -> T (in ITPAD; complete loss of
FT enzymatic activity at homozygosity;
FT partial loss of activity without ITP
FT accumulation in heterozygous individuals;
FT dbSNP:rs1127354).
FT /FTId=VAR_015576.
FT CONFLICT 33 33 C -> R (in Ref. 1; AAK21848).
FT CONFLICT 41 41 D -> G (in Ref. 2; AAG43165).
FT HELIX 2 5
FT STRAND 9 13
FT HELIX 17 27
FT STRAND 33 38
FT STRAND 45 47
FT HELIX 49 64
FT STRAND 68 77
FT HELIX 78 80
FT HELIX 88 102
FT TURN 103 106
FT STRAND 111 121
FT STRAND 130 140
FT HELIX 152 154
FT STRAND 155 157
FT TURN 164 166
FT HELIX 169 175
FT HELIX 177 189
SQ SEQUENCE 194 AA; 21446 MW; F0EC6A523722DF05 CRC64;
MAASLVGKKI VFVTGNAKKL EEVVQILGDK FPCTLVAQKI DLPEYQGEPD EISIQKCQEA
VRQVQGPVLV EDTCLCFNAL GGLPGPYIKW FLEKLKPEGL HQLLAGFEDK SAYALCTFAL
STGDPSQPVR LFRGRTSGRI VAPRGCQDFG WDPCFQPDGY EQTYAEMPKA EKNAVSHRFR
ALLELQEYFG SLAA
//
ID ITPA_HUMAN Reviewed; 194 AA.
AC Q9BY32; A2A2N2; A4UIM5; B2BCH7; O14878; Q5JWH4; Q9BYN1; Q9BYX0;
read moreAC Q9H3H8;
DT 23-APR-2003, integrated into UniProtKB/Swiss-Prot.
DT 23-APR-2003, sequence version 2.
DT 22-JAN-2014, entry version 124.
DE RecName: Full=Inosine triphosphate pyrophosphatase;
DE Short=ITPase;
DE Short=Inosine triphosphatase;
DE EC=3.6.1.19;
DE AltName: Full=Non-canonical purine NTP pyrophosphatase;
DE AltName: Full=Non-standard purine NTP pyrophosphatase;
DE AltName: Full=Nucleoside-triphosphate diphosphatase;
DE AltName: Full=Nucleoside-triphosphate pyrophosphatase;
DE Short=NTPase;
DE AltName: Full=Putative oncogene protein hlc14-06-p;
GN Name=ITPA; Synonyms=C20orf37; ORFNames=My049, OK/SW-cl.9;
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] (ISOFORM 1), SUBUNIT, SUBCELLULAR LOCATION,
RP AND BIOPHYSICOCHEMICAL PROPERTIES.
RC TISSUE=Fetal brain;
RX PubMed=11278832; DOI=10.1074/jbc.M011084200;
RA Lin S., McLennan A.G., Ying K., Wang Z., Gu S., Jin H., Wu C., Lu W.,
RA Yuan Y., Tang R., Xie Y., Mao Y.;
RT "Cloning, expression, and characterization of a human inosine
RT triphosphate pyrophosphatase encoded by the ITPA gene.";
RL J. Biol. Chem. 276:18695-18701(2001).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ITPAD
RP THR-32.
RC TISSUE=Fetal brain;
RA Mao Y.M., Xie Y., Zheng Z.H.;
RL Submitted (MAY-1998) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Lung carcinoma;
RA Fan M.-Z., Chen Z., Cao Z.-M.;
RT "Molecular cloning of cDNA associated with human lung cancer antigen
RT and study on its functions.";
RL Submitted (JAN-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RA Danaei Y., Behmanesh M., Sadeghi Zadeh M.;
RL Submitted (DEC-2006) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Colon adenocarcinoma;
RA Shichijo S., Itoh K.;
RT "Identification of immuno-peptidmics that are recognized by tumor-
RT reactive CTL generated from TIL of colon cancer patients.";
RL Submitted (MAY-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 3).
RC TISSUE=Lung carcinoma, and Neuroblastoma;
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 [9]
RP PROTEIN SEQUENCE OF 2-9; 40-56; 95-110 AND 181-194, CLEAVAGE OF
RP INITIATOR METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Embryonic kidney;
RA Bienvenut W.V., Waridel P., Quadroni M.;
RL Submitted (MAR-2009) to UniProtKB.
RN [10]
RP PROTEIN SEQUENCE OF 10-56 AND 95-130, AND MASS SPECTROMETRY.
RC TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [11]
RP SUBSTRATE SPECIFICITY, FUNCTION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=17090528; DOI=10.1074/jbc.M608708200;
RA Burgis N.E., Cunningham R.P.;
RT "Substrate specificity of RdgB protein, a deoxyribonucleoside
RT triphosphate pyrophosphohydrolase.";
RL J. Biol. Chem. 282:3531-3538(2007).
RN [12]
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.,
RA Buerckstuemmer T., 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 [13]
RP X-RAY CRYSTALLOGRAPHY (1.63 ANGSTROMS).
RX PubMed=17077483; DOI=10.1107/S1744309106041790;
RA Porta J., Kolar C., Kozmin S.G., Pavlov Y.I., Borgstahl G.E.;
RT "Structure of the orthorhombic form of human inosine triphosphate
RT pyrophosphatase.";
RL Acta Crystallogr. F 62:1076-1081(2006).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (1.1 ANGSTROMS) ALONE AND IN COMPLEX WITH ITP,
RP COFACTOR, MAGNESIUM-BINDING SITES, AND SUBSTRATE-BINDING SITES.
RX PubMed=17138556; DOI=10.1074/jbc.M609838200;
RA Stenmark P., Kursula P., Flodin S., Graslund S., Landry R.,
RA Nordlund P., Schueler H.;
RT "Crystal structure of human inosine triphosphatase. Substrate binding
RT and implication of the inosine triphosphatase deficiency mutation
RT P32T.";
RL J. Biol. Chem. 282:3182-3187(2007).
RN [15]
RP VARIANT ITPAD THR-32.
RX PubMed=12384777; DOI=10.1007/s00439-002-0798-z;
RA Sumi S., Marinaki A.M., Arenas M., Fairbanks L., Shobowale-Bakre M.,
RA Rees D.C., Thein S.L., Ansari A., Sanderson J., De Abreu R.A.,
RA Simmonds H.A., Duley J.A.;
RT "Genetic basis of inosine triphosphate pyrophosphohydrolase
RT deficiency.";
RL Hum. Genet. 111:360-367(2002).
RN [16]
RP VARIANT ITPAD THR-32.
RX PubMed=12436200; DOI=10.1007/s100380200095;
RA Cao H., Hegele R.A.;
RT "DNA polymorphisms in ITPA including basis of inosine triphosphatase
RT deficiency.";
RL J. Hum. Genet. 47:620-622(2002).
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 triposphate
CC (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective
CC monophosphate derivatives. The enzyme does not distinguish between
CC the deoxy- and ribose forms. Probably excludes non-canonical
CC purines from RNA and DNA precursor pools, thus preventing their
CC incorporation into RNA and DNA and avoiding chromosomal lesions.
CC -!- CATALYTIC ACTIVITY: A nucleoside triphosphate + H(2)O = a
CC nucleotide + diphosphate.
CC -!- COFACTOR: Binds 1 magnesium ion per subunit.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.51 mM for ITP;
CC KM=0.31 mM for dITP;
CC KM=0.57 mM for XTP;
CC KM=40.7 uM for dHAPTP;
CC KM=933 uM for dGTP;
CC Vmax=1520 umol/min/mg enzyme for ITP;
CC Vmax=940 umol/min/mg enzyme for dITP;
CC Vmax=1680 umol/min/mg enzyme for XTP;
CC Note=Vmax values are similar for dITP, dHAPTP and dGTP;
CC pH dependence:
CC Optimum pH is 10;
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Cytoplasm.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q9BY32-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q9BY32-2; Sequence=VSP_042548;
CC Note=No experimental confirmation available;
CC Name=3;
CC IsoId=Q9BY32-3; Sequence=VSP_045545;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Ubiquitous. Highly expressed in heart, liver,
CC sex glands, thyroid and adrenal gland.
CC -!- DISEASE: Inosine triphosphate pyrophosphohydrolase deficiency
CC (ITPAD) [MIM:613850]: A common inherited condition characterized
CC by the abnormal accumulation of inosine triphosphate in
CC erythrocytes. It might have pharmacogenomic implications and be
CC related to increased drug toxicity of purine analog drugs.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry. Three different human populations have
CC been reported with respect to their ITPase activity: high, mean
CC (25% of high) and low activity. The variant Thr-32 is associated
CC with complete loss of enzyme activity, may be by altering the
CC local secondary structure of the protein. Heterozygotes for this
CC polymorphism have 22.5% of the control activity: this is
CC consistent with a dimeric structure of the enzyme.
CC -!- SIMILARITY: Belongs to the HAM1 NTPase family.
CC -----------------------------------------------------------------------
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DR EMBL; AF219116; AAK21848.1; -; mRNA.
DR EMBL; AF063607; AAG43165.1; -; mRNA.
DR EMBL; AF026816; AAB82608.2; -; mRNA.
DR EMBL; EF199841; ABP01354.1; -; mRNA.
DR EMBL; EF213026; ABO70316.1; -; mRNA.
DR EMBL; AB062127; BAB93459.1; -; mRNA.
DR EMBL; AL109976; CAC16798.3; -; Genomic_DNA.
DR EMBL; AL121891; CAI19399.1; -; Genomic_DNA.
DR EMBL; AL109976; CAI19399.1; JOINED; Genomic_DNA.
DR EMBL; AL121891; CAM27676.1; -; Genomic_DNA.
DR EMBL; AL109976; CAM27676.1; JOINED; Genomic_DNA.
DR EMBL; AL109976; CAM28311.1; -; Genomic_DNA.
DR EMBL; AL121891; CAM28311.1; JOINED; Genomic_DNA.
DR EMBL; CH471133; EAX10541.1; -; Genomic_DNA.
DR EMBL; BC010138; AAH10138.1; -; mRNA.
DR EMBL; BI115811; -; NOT_ANNOTATED_CDS; mRNA.
DR RefSeq; NP_001254552.1; NM_001267623.1.
DR RefSeq; NP_258412.1; NM_033453.3.
DR RefSeq; NP_852470.1; NM_181493.2.
DR UniGene; Hs.415299; -.
DR PDB; 2CAR; X-ray; 1.09 A; A/B=1-194.
DR PDB; 2I5D; X-ray; 1.63 A; A=1-194.
DR PDB; 2J4E; X-ray; 2.80 A; A/B/C/D/E/F/G/H=1-194.
DR PDB; 4F95; X-ray; 2.07 A; A=1-194.
DR PDBsum; 2CAR; -.
DR PDBsum; 2I5D; -.
DR PDBsum; 2J4E; -.
DR PDBsum; 4F95; -.
DR ProteinModelPortal; Q9BY32; -.
DR SMR; Q9BY32; 1-194.
DR IntAct; Q9BY32; 1.
DR MINT; MINT-5006578; -.
DR STRING; 9606.ENSP00000369456; -.
DR PhosphoSite; Q9BY32; -.
DR DMDM; 30173120; -.
DR PaxDb; Q9BY32; -.
DR PeptideAtlas; Q9BY32; -.
DR PRIDE; Q9BY32; -.
DR DNASU; 3704; -.
DR Ensembl; ENST00000380113; ENSP00000369456; ENSG00000125877.
DR Ensembl; ENST00000399838; ENSP00000382732; ENSG00000125877.
DR Ensembl; ENST00000455664; ENSP00000413282; ENSG00000125877.
DR GeneID; 3704; -.
DR KEGG; hsa:3704; -.
DR UCSC; uc002wid.4; human.
DR CTD; 3704; -.
DR GeneCards; GC20P003189; -.
DR HGNC; HGNC:6176; ITPA.
DR HPA; HPA022824; -.
DR MIM; 147520; gene.
DR MIM; 613850; phenotype.
DR neXtProt; NX_Q9BY32; -.
DR Orphanet; 319684; Inosine triphosphatase deficiency.
DR Orphanet; 284113; Susceptibility to adverse reaction due to mercaptopurine.
DR PharmGKB; PA29973; -.
DR eggNOG; COG0127; -.
DR HOGENOM; HOG000293320; -.
DR HOVERGEN; HBG039521; -.
DR InParanoid; Q9BY32; -.
DR KO; K01519; -.
DR OMA; FATGNQN; -.
DR OrthoDB; EOG7X0VJG; -.
DR PhylomeDB; Q9BY32; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; Q9BY32; -.
DR EvolutionaryTrace; Q9BY32; -.
DR GeneWiki; ITPA; -.
DR GenomeRNAi; 3704; -.
DR NextBio; 14515; -.
DR PRO; PR:Q9BY32; -.
DR ArrayExpress; Q9BY32; -.
DR Bgee; Q9BY32; -.
DR CleanEx; HS_ITPA; -.
DR Genevestigator; Q9BY32; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0035870; F:dITP diphosphatase activity; EXP:Reactome.
DR GO; GO:0036220; F:ITP diphosphatase activity; EXP:Reactome.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0036222; F:XTP diphosphatase activity; EXP:Reactome.
DR GO; GO:0051276; P:chromosome organization; IEA:Ensembl.
DR GO; GO:0009204; P:deoxyribonucleoside triphosphate catabolic process; IEA:UniProtKB-HAMAP.
DR GO; GO:0006193; P:ITP catabolic process; IEA:Ensembl.
DR GO; GO:0055086; P:nucleobase-containing small molecule metabolic process; TAS:Reactome.
DR HAMAP; MF_03148; HAM1_NTPase; 1; -.
DR InterPro; IPR002637; Ham1p-like.
DR InterPro; IPR027502; ITPase.
DR PANTHER; PTHR11067; PTHR11067; 1.
DR Pfam; PF01725; Ham1p_like; 1.
DR TIGRFAMs; TIGR00042; TIGR00042; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; Complete proteome;
KW Cytoplasm; Direct protein sequencing; Disease mutation; Hydrolase;
KW Magnesium; Metal-binding; Nucleotide metabolism; Nucleotide-binding;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 194 Inosine triphosphate pyrophosphatase.
FT /FTId=PRO_0000178280.
FT REGION 14 19 Substrate binding.
FT REGION 72 73 Substrate binding.
FT REGION 149 152 Substrate binding.
FT REGION 177 178 Substrate binding.
FT METAL 44 44 Magnesium.
FT METAL 72 72 Magnesium (By similarity).
FT BINDING 56 56 Substrate.
FT BINDING 172 172 Substrate.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 7 23 Missing (in isoform 2).
FT /FTId=VSP_042548.
FT VAR_SEQ 23 63 Missing (in isoform 3).
FT /FTId=VSP_045545.
FT VARIANT 32 32 P -> T (in ITPAD; complete loss of
FT enzymatic activity at homozygosity;
FT partial loss of activity without ITP
FT accumulation in heterozygous individuals;
FT dbSNP:rs1127354).
FT /FTId=VAR_015576.
FT CONFLICT 33 33 C -> R (in Ref. 1; AAK21848).
FT CONFLICT 41 41 D -> G (in Ref. 2; AAG43165).
FT HELIX 2 5
FT STRAND 9 13
FT HELIX 17 27
FT STRAND 33 38
FT STRAND 45 47
FT HELIX 49 64
FT STRAND 68 77
FT HELIX 78 80
FT HELIX 88 102
FT TURN 103 106
FT STRAND 111 121
FT STRAND 130 140
FT HELIX 152 154
FT STRAND 155 157
FT TURN 164 166
FT HELIX 169 175
FT HELIX 177 189
SQ SEQUENCE 194 AA; 21446 MW; F0EC6A523722DF05 CRC64;
MAASLVGKKI VFVTGNAKKL EEVVQILGDK FPCTLVAQKI DLPEYQGEPD EISIQKCQEA
VRQVQGPVLV EDTCLCFNAL GGLPGPYIKW FLEKLKPEGL HQLLAGFEDK SAYALCTFAL
STGDPSQPVR LFRGRTSGRI VAPRGCQDFG WDPCFQPDGY EQTYAEMPKA EKNAVSHRFR
ALLELQEYFG SLAA
//
MIM
147520
*RECORD*
*FIELD* NO
147520
*FIELD* TI
*147520 INOSINE TRIPHOSPHATASE; ITPA
;;INOSINE TRIPHOSPHATE PYROPHOSPHOHYDROLASE
*FIELD* TX
read more
DESCRIPTION
Inosine triphosphate pyrophosphohydrolase (ITPase; EC 3.6.1.19)
catalyzes the pyrophosphohydrolysis of inosine triphosphate (ITP) to
inosine monophosphate (IMP) (Sumi et al., 2002).
CLONING
Lin et al. (2001) isolated and expressed a full-length cDNA clone
encoding human ITPase. The 1,085-basepair cDNA contained an open reading
frame of 585 nucleotides encoding a protein of 194 amino acids. Lin et
al. (2001) showed that ITPase is present not only in red blood cells,
but also in many tissues.
GENE STRUCTURE
Sumi et al. (2002) showed that the ITPA gene contains 8 exons.
MAPPING
From cell hybrid studies, the ITPA structural gene was shown to be on
chromosome 20 (Meera Khan et al., 1976; Hopkinson et al., 1976). Gene
dosage studies of adenosine deaminase (ADA; 608958) and ITPA provided
corroboration of partial trisomy 20 diagnosed cytogenetically (Rudd et
al., 1979).
The human ITPA gene is on 20p; the gene for ADA, a functionally related
enzyme, is on 20q (Mohandas et al., 1980). Using linkage methods, Taylor
et al. (1987) assigned the mouse Itp locus to chromosome 2.
GENE FUNCTION
Sumi et al. (2002) stated that the putative role of ITPase is to recycle
purines trapped in the form of ITP and to protect the cell from the
accumulation of 'rogue' nucleotides such as ITP, dITP, or xanthosine
triphosphate (XTP) that may be incorporated into RNA and DNA.
MOLECULAR GENETICS
Harris et al. (1974) found no genetic variants at the inosine
triphosphatase locus by electrophoretic means.
Sumi et al. (2002) identified 2 mutations in the ITPA gene (147520.0001,
147520.0002) associated with deficient ITPase enzyme activity (613850).
Sumi et al. (2002) suggested that the possibility of thiopurine drug
toxicity consequent to ITPase deficiency warrants further investigation.
Chronic hepatitis C virus infection is treated with a combination of
pegylated interferon-alpha (147660) and ribavirin. One of the most
important side effects is ribavirin-induced hemolytic anemia, which
affects most patients and is severe enough to require dose modification
in up to 15% of patients. Fellay et al. (2010) showed that genetic
variants leading to inosine triphosphatase deficiency, a condition not
thought to be clinically important, protect against hemolytic anemia in
hepatitis C-infected patients receiving ribavirin. The association
between the ITPA gene variants with protection against anemia was
identified by an association between the SNP dbSNP rs6051702 with a
genomewide P value of 1.1 x 10(-45) among European Americans. This SNP
was in linkage disequilibrium with 2 less common alleles within ITPA, a
P32T mutation (dbSNP rs1127354, 147520.0001) and a splice site variant
(dbSNP rs7270101, 147520.0002).
*FIELD* AV
.0001
INOSINE TRIPHOSPHATASE DEFICIENCY
ITPA, PRO32THR (dbSNP rs1127354)
In patients with ITPase deficiency (613850), Sumi et al. (2002) found a
94C-A transversion in exon 2 of the ITPA gene that resulted in a
pro32-to-thr (P32T) substitution. The proline residue is conserved in
mouse and Drosophila. All 6 individuals who were homozygous for the
94C-A mutation had completely deficient erythrocyte ITPase activity,
accompanied by the abnormal accumulation of ITP and red blood cells. In
addition, ITPase activity was decreased in all 13 heterozygotes,
providing further evidence of the association between the 94C-A mutation
and an ITPase-deficient phenotype. Heterozygotes showed a mean ITPase
activity of 22.5% of the control value, consistent with a dimeric
structure of ITPase. In heterozygotes, only 1 of the 4 possible dimers
would be composed of wildtype subunits.
Cao and Hegele (2002) sequenced genomic DNA for the ITPA gene in a
Caucasian subject with complete ITPase deficiency and found homozygosity
for the P32T mutation. The authors referred to the transversion as
198C-A because they included 104 bp of untranslated region and 66 bp of
translated region. The P32T allele frequency of 0.07 in Caucasians was
similar to the estimates derived from earlier biochemical studies
(0.05). P32T was found to be present at varying frequency in other
ethnic groups. Cao and Hegele (2002) concluded that the P32T allele
appears to be more prevalent in subjects of Chinese and East Indian
origin. Thus, homozygous ITPase deficiency may be higher in these
populations than in Caucasians. They also noted that P32T is
evolutionarily conserved in species ranging from human to mouse (Lin et
al., 2001), supporting the functionality of this residue.
.0002
INOSINE TRIPHOSPHATASE DEFICIENCY
ITPA, IVS2, A-C, +21 (dbSNP rs7270101)
In patients with ITPase deficiency, Sumi et al. (2002) found a SNP in
intron 2, IVS2+21A-C. ITPase activity of heterozygotes was 60% that of
the normal control mean; in individuals compound heterozygous for
IVS2+21A-C and P32T (147520.0001), activity was 10%.
*FIELD* SA
Holmes et al. (1979)
*FIELD* RF
1. Cao, H.; Hegele, R. A.: DNA polymorphisms in ITPA including basis
of inosine triphosphatase deficiency. J. Hum. Genet. 47: 620-622,
2002.
2. Fellay, J.; Thompson, A. J.; Ge, D.; Gumbs, C. E.; Urban, T. J.;
Shianna, K. V.; Little, L. D.; Qiu, P.; Bertelsen, A. H.; Watson,
M.; Warner, A.; Muir, A. J.; Brass, C.; Albrecht, J.; Sulkowski, M.;
McHutchison, J. G.; Goldstein, D. B.: ITPA gene variants protect
against anaemia in patients treated for chronic hepatitis C. Nature 464:
405-408, 2010.
3. Harris, H.; Hopkinson, D. A.; Robson, E. B.: The incidence of
rare alleles determining electrophoretic variants: data on 43 enzyme
loci in man. Ann. Hum. Genet. 37: 237-253, 1974.
4. Holmes, S. L.; Turner, B. M.; Hirschhorn, K.: Human inosine triphophatase:
catalytic properties and population studies. Clin. Chim. Acta 97:
143-153, 1979.
5. Hopkinson, D. A.; Povey, S.; Solomon, E.; Bobrow, M.; Gormley,
I. P.: Confirmation of the assignment of the locus determining ADA
to chromosome 20 in man: data on possible synteny of ADA and ITP in
human-Chinese hamster somatic cell hybrids. Birth Defects Orig. Art.
Ser. XII(7): 159-160, 1976. Note: Alternate: Cytogenet. Cell Genet.
16: 159-160, 1976.
6. Lin, S.; McLennan, A. G.; Ying, K.; Wang, Z.; Gu, S.; Jin, H.;
Wu, C.; Liu, W.; Yuan, Y.; Tang, R.; Xie, Y.; Mao, Y.: Cloning, expression,
and characterization of a human inosine triphosphate pyrophosphatase
encoded by the ITPA gene. J. Biol. Chem. 276: 18695-18701, 2001.
7. Meera Khan, P.; Pearson, P. L.; Wijnen, L. L. L.; Doppert, B. A.;
Westerveld, A.; Bootsma, D.: Assignment of inosine triphosphatase
gene to gorilla chromosome 13 and to human chromosome 20 in primate-rodent
somatic cell hybrids. Birth Defects Orig. Art. Ser. XII(7): 420-421,
1976. Note: Alternate: Cytogenet. Cell Genet. 16: 420-421, 1976.
8. Mohandas, T.; Sparkes, R. S.; Passage, M. B.; Sparkes, M. C.; Miles,
J. H.; Kaback, M. M.: Regional mapping of ADA and ITP on human chromosome
20: cytogenetic and somatic cell studies in an X/20 translocation. Cytogenet.
Cell Genet. 26: 28-35, 1980.
9. Rudd, N. L.; Bain, H. W.; Giblett, E.; Chen, S.-H.; Worton, R.
G.: Partial trisomy 20 confirmed by gene dosage studies. Am. J.
Med. Genet. 4: 357-364, 1979.
10. Sumi, S.; Marinaki, A. M.; Arenas, M.; Fairbanks, L.; Shobowale-Bakre,
M.; Rees, D. C.; Thein, S. L.; Ansari, A.; Sanderson, J.; De Abreu,
R. A.; Simmonds, H. A.; Duley, J. A.: Genetic basis of inosine triphosphate
pyrophosphohydrolase deficiency. Hum. Genet. 111: 360-367, 2002.
11. Taylor, B. A.; Walls, D. M.; Wimsatt, M. J.: Localization of
inosine triphosphatase locus (Itp) on chromosome 2 of the mouse. Biochem.
Genet. 25: 267-274, 1987.
*FIELD* CN
Ada Hamosh - updated: 4/15/2010
Victor A. McKusick - updated: 12/31/2002
Victor A. McKusick - updated: 11/13/2002
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 03/30/2011
alopez: 4/15/2010
terry: 4/15/2010
carol: 6/15/2005
ckniffin: 10/28/2004
mgross: 3/17/2004
terry: 5/15/2003
cwells: 1/7/2003
terry: 12/31/2002
tkritzer: 11/25/2002
tkritzer: 11/15/2002
terry: 11/13/2002
warfield: 4/12/1994
carol: 11/30/1992
carol: 4/1/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
*RECORD*
*FIELD* NO
147520
*FIELD* TI
*147520 INOSINE TRIPHOSPHATASE; ITPA
;;INOSINE TRIPHOSPHATE PYROPHOSPHOHYDROLASE
*FIELD* TX
read more
DESCRIPTION
Inosine triphosphate pyrophosphohydrolase (ITPase; EC 3.6.1.19)
catalyzes the pyrophosphohydrolysis of inosine triphosphate (ITP) to
inosine monophosphate (IMP) (Sumi et al., 2002).
CLONING
Lin et al. (2001) isolated and expressed a full-length cDNA clone
encoding human ITPase. The 1,085-basepair cDNA contained an open reading
frame of 585 nucleotides encoding a protein of 194 amino acids. Lin et
al. (2001) showed that ITPase is present not only in red blood cells,
but also in many tissues.
GENE STRUCTURE
Sumi et al. (2002) showed that the ITPA gene contains 8 exons.
MAPPING
From cell hybrid studies, the ITPA structural gene was shown to be on
chromosome 20 (Meera Khan et al., 1976; Hopkinson et al., 1976). Gene
dosage studies of adenosine deaminase (ADA; 608958) and ITPA provided
corroboration of partial trisomy 20 diagnosed cytogenetically (Rudd et
al., 1979).
The human ITPA gene is on 20p; the gene for ADA, a functionally related
enzyme, is on 20q (Mohandas et al., 1980). Using linkage methods, Taylor
et al. (1987) assigned the mouse Itp locus to chromosome 2.
GENE FUNCTION
Sumi et al. (2002) stated that the putative role of ITPase is to recycle
purines trapped in the form of ITP and to protect the cell from the
accumulation of 'rogue' nucleotides such as ITP, dITP, or xanthosine
triphosphate (XTP) that may be incorporated into RNA and DNA.
MOLECULAR GENETICS
Harris et al. (1974) found no genetic variants at the inosine
triphosphatase locus by electrophoretic means.
Sumi et al. (2002) identified 2 mutations in the ITPA gene (147520.0001,
147520.0002) associated with deficient ITPase enzyme activity (613850).
Sumi et al. (2002) suggested that the possibility of thiopurine drug
toxicity consequent to ITPase deficiency warrants further investigation.
Chronic hepatitis C virus infection is treated with a combination of
pegylated interferon-alpha (147660) and ribavirin. One of the most
important side effects is ribavirin-induced hemolytic anemia, which
affects most patients and is severe enough to require dose modification
in up to 15% of patients. Fellay et al. (2010) showed that genetic
variants leading to inosine triphosphatase deficiency, a condition not
thought to be clinically important, protect against hemolytic anemia in
hepatitis C-infected patients receiving ribavirin. The association
between the ITPA gene variants with protection against anemia was
identified by an association between the SNP dbSNP rs6051702 with a
genomewide P value of 1.1 x 10(-45) among European Americans. This SNP
was in linkage disequilibrium with 2 less common alleles within ITPA, a
P32T mutation (dbSNP rs1127354, 147520.0001) and a splice site variant
(dbSNP rs7270101, 147520.0002).
*FIELD* AV
.0001
INOSINE TRIPHOSPHATASE DEFICIENCY
ITPA, PRO32THR (dbSNP rs1127354)
In patients with ITPase deficiency (613850), Sumi et al. (2002) found a
94C-A transversion in exon 2 of the ITPA gene that resulted in a
pro32-to-thr (P32T) substitution. The proline residue is conserved in
mouse and Drosophila. All 6 individuals who were homozygous for the
94C-A mutation had completely deficient erythrocyte ITPase activity,
accompanied by the abnormal accumulation of ITP and red blood cells. In
addition, ITPase activity was decreased in all 13 heterozygotes,
providing further evidence of the association between the 94C-A mutation
and an ITPase-deficient phenotype. Heterozygotes showed a mean ITPase
activity of 22.5% of the control value, consistent with a dimeric
structure of ITPase. In heterozygotes, only 1 of the 4 possible dimers
would be composed of wildtype subunits.
Cao and Hegele (2002) sequenced genomic DNA for the ITPA gene in a
Caucasian subject with complete ITPase deficiency and found homozygosity
for the P32T mutation. The authors referred to the transversion as
198C-A because they included 104 bp of untranslated region and 66 bp of
translated region. The P32T allele frequency of 0.07 in Caucasians was
similar to the estimates derived from earlier biochemical studies
(0.05). P32T was found to be present at varying frequency in other
ethnic groups. Cao and Hegele (2002) concluded that the P32T allele
appears to be more prevalent in subjects of Chinese and East Indian
origin. Thus, homozygous ITPase deficiency may be higher in these
populations than in Caucasians. They also noted that P32T is
evolutionarily conserved in species ranging from human to mouse (Lin et
al., 2001), supporting the functionality of this residue.
.0002
INOSINE TRIPHOSPHATASE DEFICIENCY
ITPA, IVS2, A-C, +21 (dbSNP rs7270101)
In patients with ITPase deficiency, Sumi et al. (2002) found a SNP in
intron 2, IVS2+21A-C. ITPase activity of heterozygotes was 60% that of
the normal control mean; in individuals compound heterozygous for
IVS2+21A-C and P32T (147520.0001), activity was 10%.
*FIELD* SA
Holmes et al. (1979)
*FIELD* RF
1. Cao, H.; Hegele, R. A.: DNA polymorphisms in ITPA including basis
of inosine triphosphatase deficiency. J. Hum. Genet. 47: 620-622,
2002.
2. Fellay, J.; Thompson, A. J.; Ge, D.; Gumbs, C. E.; Urban, T. J.;
Shianna, K. V.; Little, L. D.; Qiu, P.; Bertelsen, A. H.; Watson,
M.; Warner, A.; Muir, A. J.; Brass, C.; Albrecht, J.; Sulkowski, M.;
McHutchison, J. G.; Goldstein, D. B.: ITPA gene variants protect
against anaemia in patients treated for chronic hepatitis C. Nature 464:
405-408, 2010.
3. Harris, H.; Hopkinson, D. A.; Robson, E. B.: The incidence of
rare alleles determining electrophoretic variants: data on 43 enzyme
loci in man. Ann. Hum. Genet. 37: 237-253, 1974.
4. Holmes, S. L.; Turner, B. M.; Hirschhorn, K.: Human inosine triphophatase:
catalytic properties and population studies. Clin. Chim. Acta 97:
143-153, 1979.
5. Hopkinson, D. A.; Povey, S.; Solomon, E.; Bobrow, M.; Gormley,
I. P.: Confirmation of the assignment of the locus determining ADA
to chromosome 20 in man: data on possible synteny of ADA and ITP in
human-Chinese hamster somatic cell hybrids. Birth Defects Orig. Art.
Ser. XII(7): 159-160, 1976. Note: Alternate: Cytogenet. Cell Genet.
16: 159-160, 1976.
6. Lin, S.; McLennan, A. G.; Ying, K.; Wang, Z.; Gu, S.; Jin, H.;
Wu, C.; Liu, W.; Yuan, Y.; Tang, R.; Xie, Y.; Mao, Y.: Cloning, expression,
and characterization of a human inosine triphosphate pyrophosphatase
encoded by the ITPA gene. J. Biol. Chem. 276: 18695-18701, 2001.
7. Meera Khan, P.; Pearson, P. L.; Wijnen, L. L. L.; Doppert, B. A.;
Westerveld, A.; Bootsma, D.: Assignment of inosine triphosphatase
gene to gorilla chromosome 13 and to human chromosome 20 in primate-rodent
somatic cell hybrids. Birth Defects Orig. Art. Ser. XII(7): 420-421,
1976. Note: Alternate: Cytogenet. Cell Genet. 16: 420-421, 1976.
8. Mohandas, T.; Sparkes, R. S.; Passage, M. B.; Sparkes, M. C.; Miles,
J. H.; Kaback, M. M.: Regional mapping of ADA and ITP on human chromosome
20: cytogenetic and somatic cell studies in an X/20 translocation. Cytogenet.
Cell Genet. 26: 28-35, 1980.
9. Rudd, N. L.; Bain, H. W.; Giblett, E.; Chen, S.-H.; Worton, R.
G.: Partial trisomy 20 confirmed by gene dosage studies. Am. J.
Med. Genet. 4: 357-364, 1979.
10. Sumi, S.; Marinaki, A. M.; Arenas, M.; Fairbanks, L.; Shobowale-Bakre,
M.; Rees, D. C.; Thein, S. L.; Ansari, A.; Sanderson, J.; De Abreu,
R. A.; Simmonds, H. A.; Duley, J. A.: Genetic basis of inosine triphosphate
pyrophosphohydrolase deficiency. Hum. Genet. 111: 360-367, 2002.
11. Taylor, B. A.; Walls, D. M.; Wimsatt, M. J.: Localization of
inosine triphosphatase locus (Itp) on chromosome 2 of the mouse. Biochem.
Genet. 25: 267-274, 1987.
*FIELD* CN
Ada Hamosh - updated: 4/15/2010
Victor A. McKusick - updated: 12/31/2002
Victor A. McKusick - updated: 11/13/2002
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
carol: 03/30/2011
alopez: 4/15/2010
terry: 4/15/2010
carol: 6/15/2005
ckniffin: 10/28/2004
mgross: 3/17/2004
terry: 5/15/2003
cwells: 1/7/2003
terry: 12/31/2002
tkritzer: 11/25/2002
tkritzer: 11/15/2002
terry: 11/13/2002
warfield: 4/12/1994
carol: 11/30/1992
carol: 4/1/1992
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
MIM
613850
*RECORD*
*FIELD* NO
613850
*FIELD* TI
#613850 INOSINE TRIPHOSPHATASE DEFICIENCY
;;INOSINE TRIPHOSPHATE PYROPHOSPHOHYDROLASE DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because inosine triphosphatase
deficiency can be caused by mutation in the ITPA gene (147520) on
chromosome 20p.
DESCRIPTION
Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a
common inherited condition characterized by the abnormal accumulation of
inosine triphosphate (ITP) in erythrocytes (Sumi et al., 2002).
CLINICAL FEATURES
Vanderheiden (1969) found relatively high levels of inosine triphosphate
in the red cells of 2 sibs and suggested that this resulted from
deficiency of inosine triphosphatase activity. In a follow-up study, a
high level of ITP was found in 7 of over 6,000 samples from mainly
unrelated persons. Persons with very low enzyme levels were apparently
homozygous. The enzyme is a cytosolic nucleoside triphosphate
pyrophosphohydrolase specific for ITP (Vanderheiden, 1975).
ITPase deficiency is not associated with any defined pathology other
than the characteristic and abnormal accumulation of ITP in red blood
cells. Nevertheless, ITPase deficiency may have pharmacogenomic
implications, and the abnormal metabolism of 6-mercaptopurine in
ITPase-deficient patients may lead to thiopurine drug toxicity (Fraser
et al., 1975; Sumi et al., 2002).
Greene (1986) stated that the Camden Cell Bank has lymphoblastoid cells
and skin fibroblasts supplied by Vanderheiden from a 29-year-old woman
(GM1619) with ITPase deficiency. The lymphoblastoid cells had only 20%
normal ITPA activity after recovery from storage in liquid nitrogen. The
possibility that ITP deficiency has some clinical significance, perhaps
under conditions of stress, should be considered.
POPULATION GENETICS
The frequency of heterozygosity for ITPase deficiency in Caucasian
populations is estimated to be 5 per 100 (Fraser et al., 1975; Sumi et
al., 2002).
MOLECULAR GENETICS
Sumi et al. (2002) identified 2 mutations in the ITPA gene
(147520.0001-147520.0002) associated with deficient ITPase enzyme
activity.
*FIELD* RF
1. Fraser, J. H.; Meyers, H.; Henderson, J. F.; Brox, L. W.; McCoy,
E. E.: Individual variation in inosine triphosphate accumulation
in human erythrocytes. Clin. Biochem. 8: 353-364, 1975.
2. Greene, A. E.: Personal Communication. Camden, N. J. 3/4/1986.
3. Sumi, S.; Marinaki, A. M.; Arenas, M.; Fairbanks, L.; Shobowale-Bakre,
M.; Rees, D. C.; Thein, S. L.; Ansari, A.; Sanderson, J.; De Abreu,
R. A.; Simmonds, H. A.; Duley, J. A.: Genetic basis of inosine triphosphate
pyrophosphohydrolase deficiency. Hum. Genet. 111: 360-367, 2002.
4. Vanderheiden, B. S.: ITP pyrophosphohydrolase and IDP phosphohydrolase
in rat tissue. J. Cell. Physiol. 86: 167-176, 1975.
5. Vanderheiden, B. S.: Genetic studies of human erythrocyte inosine
triphosphatase. Biochem. Genet. 3: 289-297, 1969.
*FIELD* CD
Carol A. Bocchini: 3/30/2011
*FIELD* ED
carol: 03/30/2011
*RECORD*
*FIELD* NO
613850
*FIELD* TI
#613850 INOSINE TRIPHOSPHATASE DEFICIENCY
;;INOSINE TRIPHOSPHATE PYROPHOSPHOHYDROLASE DEFICIENCY
read more*FIELD* TX
A number sign (#) is used with this entry because inosine triphosphatase
deficiency can be caused by mutation in the ITPA gene (147520) on
chromosome 20p.
DESCRIPTION
Inosine triphosphate pyrophosphohydrolase (ITPase) deficiency is a
common inherited condition characterized by the abnormal accumulation of
inosine triphosphate (ITP) in erythrocytes (Sumi et al., 2002).
CLINICAL FEATURES
Vanderheiden (1969) found relatively high levels of inosine triphosphate
in the red cells of 2 sibs and suggested that this resulted from
deficiency of inosine triphosphatase activity. In a follow-up study, a
high level of ITP was found in 7 of over 6,000 samples from mainly
unrelated persons. Persons with very low enzyme levels were apparently
homozygous. The enzyme is a cytosolic nucleoside triphosphate
pyrophosphohydrolase specific for ITP (Vanderheiden, 1975).
ITPase deficiency is not associated with any defined pathology other
than the characteristic and abnormal accumulation of ITP in red blood
cells. Nevertheless, ITPase deficiency may have pharmacogenomic
implications, and the abnormal metabolism of 6-mercaptopurine in
ITPase-deficient patients may lead to thiopurine drug toxicity (Fraser
et al., 1975; Sumi et al., 2002).
Greene (1986) stated that the Camden Cell Bank has lymphoblastoid cells
and skin fibroblasts supplied by Vanderheiden from a 29-year-old woman
(GM1619) with ITPase deficiency. The lymphoblastoid cells had only 20%
normal ITPA activity after recovery from storage in liquid nitrogen. The
possibility that ITP deficiency has some clinical significance, perhaps
under conditions of stress, should be considered.
POPULATION GENETICS
The frequency of heterozygosity for ITPase deficiency in Caucasian
populations is estimated to be 5 per 100 (Fraser et al., 1975; Sumi et
al., 2002).
MOLECULAR GENETICS
Sumi et al. (2002) identified 2 mutations in the ITPA gene
(147520.0001-147520.0002) associated with deficient ITPase enzyme
activity.
*FIELD* RF
1. Fraser, J. H.; Meyers, H.; Henderson, J. F.; Brox, L. W.; McCoy,
E. E.: Individual variation in inosine triphosphate accumulation
in human erythrocytes. Clin. Biochem. 8: 353-364, 1975.
2. Greene, A. E.: Personal Communication. Camden, N. J. 3/4/1986.
3. Sumi, S.; Marinaki, A. M.; Arenas, M.; Fairbanks, L.; Shobowale-Bakre,
M.; Rees, D. C.; Thein, S. L.; Ansari, A.; Sanderson, J.; De Abreu,
R. A.; Simmonds, H. A.; Duley, J. A.: Genetic basis of inosine triphosphate
pyrophosphohydrolase deficiency. Hum. Genet. 111: 360-367, 2002.
4. Vanderheiden, B. S.: ITP pyrophosphohydrolase and IDP phosphohydrolase
in rat tissue. J. Cell. Physiol. 86: 167-176, 1975.
5. Vanderheiden, B. S.: Genetic studies of human erythrocyte inosine
triphosphatase. Biochem. Genet. 3: 289-297, 1969.
*FIELD* CD
Carol A. Bocchini: 3/30/2011
*FIELD* ED
carol: 03/30/2011