Human Gene ITPA (uc002wid.4) Description and Page Index
Description: Homo sapiens inosine triphosphatase (nucleoside triphosphate pyrophosphatase) (ITPA), transcript variant 1, mRNA. RefSeq Summary (NM_033453): This gene encodes an inosine triphosphate pyrophosphohydrolase. The encoded protein hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. This protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer. Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency which causes an accumulation of ITP in red blood cells. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]. Transcript (Including UTRs) Position: hg19 chr20:3,190,006-3,204,516 Size: 14,511 Total Exon Count: 8 Strand: + Coding Region Position: hg19 chr20:3,190,198-3,204,108 Size: 13,911 Coding Exon Count: 8
ID:ITPA_HUMAN DESCRIPTION: RecName: Full=Inosine triphosphate pyrophosphatase; Short=ITPase; Short=Inosine triphosphatase; EC=184.108.40.206; AltName: Full=Non-canonical purine NTP pyrophosphatase; AltName: Full=Non-standard purine NTP pyrophosphatase; AltName: Full=Nucleoside-triphosphate diphosphatase; AltName: Full=Nucleoside-triphosphate pyrophosphatase; Short=NTPase; AltName: Full=Putative oncogene protein hlc14-06-p; FUNCTION: Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triposphate (dHAPTP) and xanthosine 5'-triphosphate (XTP) to their respective monophosphate derivatives. The enzyme does not distinguish between the deoxy- and ribose forms. Probably excludes non-canonical purines from RNA and DNA precursor pools, thus preventing their incorporation into RNA and DNA and avoiding chromosomal lesions. CATALYTIC ACTIVITY: A nucleoside triphosphate + H(2)O = a nucleotide + diphosphate. COFACTOR: Binds 1 magnesium ion per subunit. BIOPHYSICOCHEMICAL PROPERTIES: Kinetic parameters: KM=0.51 mM for ITP; KM=0.31 mM for dITP; KM=0.57 mM for XTP; KM=40.7 uM for dHAPTP; KM=933 uM for dGTP; Vmax=1520 umol/min/mg enzyme for ITP; Vmax=940 umol/min/mg enzyme for dITP; Vmax=1680 umol/min/mg enzyme for XTP; Note=Vmax values are similar for dITP, dHAPTP and dGTP; pH dependence: Optimum pH is 10; SUBUNIT: Homodimer. SUBCELLULAR LOCATION: Cytoplasm. TISSUE SPECIFICITY: Ubiquitous. Highly expressed in heart, liver, sex glands, thyroid and adrenal gland. DISEASE: Defects in ITPA are the cause of inosine triphosphate pyrophosphohydrolase deficiency (ITPAD) [MIM:613850]. It is a common inherited trait characterized by the abnormal accumulation of inosine triphosphate (ITP) in erythrocytes and also leukocytes and fibroblasts. The pathological consequences of ITPA deficiency, if any, are unknown. However, it might have pharmacogenomic implications and be related to increased drug toxicity of purine analog drugs. Note=Three different human populations have been reported with respect to their ITPase activity: high, mean (25% of high) and low activity. The variant Thr-32 is associated with complete loss of enzyme activity, may be by altering the local secondary structure of the protein. Heterozygotes for this polymorphism have 22.5% of the control activity: this is consistent with a dimeric structure of the enzyme. SIMILARITY: Belongs to the HAM1 NTPase family.
Genetic Association Studies of Complex Diseases and Disorders
Anemia Hidenori Ochi et al. Gastroenterology 2010, ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy--a genome-wide study of Japanese HCV virus patients., Gastroenterology.
A missense substitution in inosine triphosphate pyrophosphatase gene affects ribavirin-induced anemia in hepatitis C virus-infected Japanese patients.
azathioprine tolerance Marinaki, A. M. et al. 2004, Mutation in the ITPA gene predicts intolerance to azathioprine., Nucleosides, nucleotides & nucleic acids. 2004 Oct;23(9-Aug):1393-7.
Polymorphism in the ITPA gene thus predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
drug hypersensitivity Marinaki, A. M. et al. 2004, Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase), Pharmacogenetics. 2004 Mar;14(3):181-7.
Polymorphism in the ITPA gene predicts AZA intolerance. Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency.
The RNAfold program from the Vienna RNA Package is used to perform the secondary structure predictions and folding calculations. The estimated folding energy is in kcal/mol. The more negative the energy, the more secondary structure the RNA is likely to have.
ModBase Predicted Comparative 3D Structure on Q9BY32
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Orthologous Genes in Other Species
Orthologies between human, mouse, and rat are computed by taking the best BLASTP hit, and filtering out non-syntenic hits. For more distant species reciprocal-best BLASTP hits are used. Note that the absence of an ortholog in the table below may reflect incomplete annotations in the other species rather than a true absence of the orthologous gene.