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ITPA  -  inosine triphosphatase (nucleoside...

Homo sapiens

Synonyms: C20orf37, HLC14-06-P, ITPase, Inosine triphosphatase, Inosine triphosphate pyrophosphatase, ...
 
 
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Disease relevance of ITPA

 

High impact information on ITPA

  • Loss of Ca2+ dependency was confirmed by the finding that, in contrast to ATPase, the ITPase activity of cardiac myofibrils was not dependent on Ca2+ concentrations [5].
  • Here we describe the crystal structure of human ITPA in complex with its prime substrate ITP, as well as the apoenzyme at 2.8 and 1.1A(,) respectively [6].
  • Enzyme substrate interactions induce an extensive closure of the nucleotide binding grove, resulting in tight interactions with the base that explain the high substrate specificity of ITPA for inosine and xanthine over the canonical nucleotides [6].
  • RESULTS: Patients carrying the AMPD1 34T allele, ATIC 347CC, or ITPA 94CC were more likely to have a good clinical response, as defined by a DAS of </=2.4 (OR [95% confidence interval] 2.1 [1.0-4.5], 2.5 [1.3-4.7], and 2.7 [1.1-8.1], respectively) [7].
  • CONCLUSION: Polymorphisms in the AMPD1, ATIC, and ITPA genes are associated with good clinical response to MTX treatment [7].
 

Chemical compound and disease context of ITPA

 

Biological context of ITPA

 

Anatomical context of ITPA

  • A high-risk group defined by ITPA 94C > A or TPMT <10 nmol/(mL erythrocytes . h) showed significant association with early drop-out (P = 0.001; OR = 11.3; 95% CI, 2.5-50.0) and all drop-outs (P = 0.002; OR = 4.8; 95% CI, 1.8-13.3) [3].
  • In conclusion, our findings suggest that TPMT, ITPA, and MTHFR genotypes do not predict adverse drug reactions, including bone marrow suppression, in liver transplant patients [11].
  • Here, concordant segregation analysis of enzyme loci and chromosomes in mouse spleen X CHO as well as mouse microcell X CHO somatic cell hybrids established the assignments of ADA and ITPA onto mouse chromosome 2 in the region between the first G-band and the terminus (C1----ter) [15].
  • We show that two genes encoding splicing factor (SF) 2 and inosine triphosphate pyrophosphatase (ITPA) have epitopes recognized by HLA-B46-restricted and tumor cell-reactive CTL lines established from tumor-infiltrating lymphocytes of colon cancer [16].
  • Subcellular fractionation of cultured lymphoid-line cells showed ITPase activity to be in the cytosol [17].
 

Associations of ITPA with chemical compounds

  • Inosine triphosphatase (ITPA) mutations are other pharmacogenetic polymorphisms possibly involved in thiopurine metabolism and tolerance [3].
  • We demonstrate here that this proline to threonine substitution at codon 32 in the ITPA gene is found at low frequency in Central/South American populations (1-2%), at a constant frequency across Caucasian and African populations (6-7%), and is highest in Asian populations (14-19%) [18].
  • Genotyping of ITPA 94C>A polymorphisms showed that two patients were homozygous, both tolerated azathioprine well [8].
  • Intracellular concentrations of the nucleotide inosine triphosphate (ITP) are regulated by ITP-ase (EC 3.6.1.19), which is encoded by ITPA on chromosome 20p [19].
  • Alternative immunosuppressive drugs, particularly 6-thioguanine, should be considered for AZA-intolerant patients with ITPase deficiency [1].
 

Other interactions of ITPA

  • Concordant segregation analysis of isozymes and chromosomes among clone panel members enabled the provisional assignment of ADA, ITPA, and AK1 to Chinese hamster chromosome 6 [13].
  • In humans c-src, ADA, and ITPA remain conserved on chromosome 20, whereas AK1 and c-abl are together on chromosome 9 [15].
  • House-cleaning NTP pyrophosphatases targeting non-canonical NTPs belong to at least four structural superfamilies: MutT-related (Nudix) hydrolases, dUTPase, ITPase (Maf/HAM1) and all-alpha NTP pyrophosphatases (MazG) [20].
  • The results confirmed an autosomal recessive mode of inheritance for ITPase deficiency, but suggested that the co-existence with ADA deficiency was coincidental [21].
 

Analytical, diagnostic and therapeutic context of ITPA

  • CONCLUSIONS: The HPLC procedure provides an excellent ITPA phenotype-genotype correlation and led to the discovery of a novel IVS2 + 68T>C mutation [14].
  • 5. We also genotyped samples for ITPA 94C>A and IVS2 + 21A>C by real-time fluorescence PCR [14].
  • However, after treatment with Chelex 100 the erythrocyte lysates become unsuitable for determination of ITPase activity [22].

References

  1. Adverse drug reactions to azathioprine therapy are associated with polymorphism in the gene encoding inosine triphosphate pyrophosphatase (ITPase). Marinaki, A.M., Ansari, A., Duley, J.A., Arenas, M., Sumi, S., Lewis, C.M., Shobowale-Bakre, e.l.-.M., Escuredo, E., Fairbanks, L.D., Sanderson, J.D. Pharmacogenetics (2004) [Pubmed]
  2. Inosine triphosphate pyrophosphatase and thiopurine s-methyltransferase genotypes relationship to azathioprine-induced myelosuppression. Zelinkova, Z., Derijks, L.J., Stokkers, P.C., Vogels, E.W., van Kampen, A.H., Curvers, W.L., Cohn, D., van Deventer, S.J., Hommes, D.W. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. (2006) [Pubmed]
  3. Association of inosine triphosphatase 94C>A and thiopurine S-methyltransferase deficiency with adverse events and study drop-outs under azathioprine therapy in a prospective Crohn disease study. von Ahsen, N., Armstrong, V.W., Behrens, C., von Tirpitz, C., Stallmach, A., Herfarth, H., Stein, J., Bias, P., Adler, G., Shipkova, M., Oellerich, M., Kruis, W., Reinshagen, M. Clin. Chem. (2005) [Pubmed]
  4. Lack of association between the ITPA 94C>A polymorphism and adverse effects from azathioprine. Gearry, R.B., Roberts, R.L., Barclay, M.L., Kennedy, M.A. Pharmacogenetics (2004) [Pubmed]
  5. Calcium ion-insensitive contraction of glycerinated porcine cardiac muscle fibers by Mg-inosine triphosphate. ITP as a tool to dissociate the contraction mechanism from the regulatory mechanism. Toyo-oka, T. Circ. Res. (1981) [Pubmed]
  6. Crystal Structure of Human Inosine Triphosphatase: SUBSTRATE BINDING AND IMPLICATION OF THE INOSINE TRIPHOSPHATASE DEFICIENCY MUTATION P32T. Stenmark, P., Kursula, P., Flodin, S., Gräslund, S., Landry, R., Nordlund, P., Schüler, H. J. Biol. Chem. (2007) [Pubmed]
  7. Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Wessels, J.A., Kooloos, W.M., Jonge, R.D., De Vries-Bouwstra, J.K., Allaart, C.F., Linssen, A., Collee, G., Sonnaville, P.D., Lindemans, J., Huizinga, T.W., Guchelaar, H.J. Arthritis Rheum. (2006) [Pubmed]
  8. Pharmacogenetics of thiopurine therapy in paediatric IBD patients. De Ridder, L., Van Dieren, J.M., Van Deventer, H.J., Stokkers, P.C., Van der Woude, J.C., Van Vuuren, A.J., Benninga, M.A., Escher, J.C., Hommes, D.W. Aliment. Pharmacol. Ther. (2006) [Pubmed]
  9. ITPA genotyping test does not improve detection of Crohn's disease patients at risk of azathioprine/6-mercaptopurine induced myelosuppression. Allorge, D., Hamdan, R., Broly, F., Libersa, C., Colombel, J.F. Gut (2005) [Pubmed]
  10. Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency. 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. Hum. Genet. (2002) [Pubmed]
  11. Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation. Breen, D.P., Marinaki, A.M., Arenas, M., Hayes, P.C. Liver Transpl. (2005) [Pubmed]
  12. Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene. 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. J. Biol. Chem. (2001) [Pubmed]
  13. Assignment of ADA, ITPA, AK1, and AK2 to Chinese hamster chromosomes. Genetic and structural evidence for the conservation of mammalian autosomal synteny. Stallings, R.L., Siciliano, M.J. J. Hered. (1982) [Pubmed]
  14. Measurement of erythrocyte inosine triphosphate pyrophosphohydrolase (ITPA) activity by HPLC and correlation of ITPA genotype-phenotype in a Caucasian population. Shipkova, M., Lorenz, K., Oellerich, M., Wieland, E., von Ahsen, N. Clin. Chem. (2006) [Pubmed]
  15. Regional assignment of ADA and ITPA to mouse chromosome 2 (C1----ter). A demonstration of the conserved linkage of enzyme and proto-oncogene loci. Siciliano, M.J., Fournier, R.E., Stallings, R.L. J. Hered. (1984) [Pubmed]
  16. Identification of two novel tumor-associated antigens recognized by HLA-B46-restricted cytotoxic T lymphocytes. Shichijo, S., Azuma, K., Komatsu, N., Kawamoto, N., Takedatsu, H., Shomura, H., Sawamizu, H., Maeda, Y., Ito, M., Itoh, K. Int. J. Mol. Med. (2003) [Pubmed]
  17. Human inosine triphosphatase: catalytic properties and population studies. Holmes, S.L., Turner, B.M., Hirschhorn, K. Clin. Chim. Acta (1979) [Pubmed]
  18. Distribution of ITPA P32T alleles in multiple world populations. Marsh, S., King, C.R., Ahluwalia, R., McLeod, H.L. J. Hum. Genet. (2004) [Pubmed]
  19. DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency. Cao, H., Hegele, R.A. J. Hum. Genet. (2002) [Pubmed]
  20. House cleaning, a part of good housekeeping. Galperin, M.Y., Moroz, O.V., Wilson, K.S., Murzin, A.G. Mol. Microbiol. (2006) [Pubmed]
  21. Inosine triphosphate pyrophosphohydrolase deficiency in a kindred with adenosine deaminase deficiency. Duley, J.A., Simmonds, H.A., Hopkinson, D.A., Levinsky, R.J. Clin. Chim. Acta (1990) [Pubmed]
  22. Determination of ITPase Activity in Erythrocyte Lysates Obtained for Determination of Tpmt Activity. Bierau, J., Bakker, J.A., Lindhout, M., van Gennip, A.H. Nucleosides Nucleotides Nucleic Acids (2006) [Pubmed]
 
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