Inosine triphosphate pyrophosphatase is an enzyme that in humans is encoded by the ITPAgene,[5][6] by the rdgBgene in bacteria E.coli[7] and the HAM1gene in yeast S. cerevisiae;[8] the protein is also encoded by some RNA viruses of the Potyviridae family.[9] Two transcript variants encoding two different isoforms have been found for this gene. Also, at least two other transcript variants have been identified which are probably regulatory rather than protein-coding.[citation needed]
Function
The protein encoded by this gene hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate.[6] The enzyme possesses specificity to multiple substrates, and acts on other nucleotides including xanthosine triphosphate and deoxyxanthosine triphosphate.[8] The encoded protein, which is a member of the HAM1 NTPase protein family, is found in the cytoplasm and acts as a homodimer.
Clinical significance
Defects in the encoded protein can result in inosine triphosphate pyrophosphorylase deficiency.[6] The enzyme ITPase dephosphorylates ribavirin triphosphate in vitro to ribavirin monophosphate, and reduced ITPase activity in 30% of humans potentiates mutagenesis in hepatitis C virus.[10] Gene variants predicting reduced predicted ITPase activity have been associated with decreased risk of ribavirin-induced anemia, increased risk of thrombocytopenia, lower ribavirin concentrations, as well as a ribavirin-like reduced relapse risk following interferon-based therapy for hepatitis C virus (HCV) genotype 2 or 3 infection.[11]
Further reading
Holmes SL, Turner BM, Hirschhorn K (1979). "Human inosine triphosphatase: catalytic properties and population studies". Clinica Chimica Acta; International Journal of Clinical Chemistry. 97 (2–3): 143–153. doi:10.1016/0009-8981(79)90410-8. PMID487601.
Fraser JH, Meyers H, Henderson JF, Brox LW, McCoy EE (December 1975). "Individual variation in inosine triphosphate accumulation in human erythrocytes". Clinical Biochemistry. 8 (6): 353–364. doi:10.1016/S0009-9120(75)93685-1. PMID1204209.
Clawson GA, Song YL, Schwartz AM, Shukla RR, Patel SG, Connor L, et al. (November 1991). "Interaction of human immunodeficiency virus type I Rev protein with nuclear scaffold nucleoside triphosphatase activity". Cell Growth & Differentiation. 2 (11): 575–582. PMID1667585.
Sumi S, Marinaki AM, Arenas M, Fairbanks L, Shobowale-Bakre M, Rees DC, et al. (October 2002). "Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency". Human Genetics. 111 (4–5): 360–367. doi:10.1007/s00439-002-0798-z. PMID12384777. S2CID24240940.
Marinaki AM, Duley JA, Arenas M, Ansari A, Sumi S, Lewis CM, et al. (October 2004). "Mutation in the ITPA gene predicts intolerance to azathioprine". Nucleosides, Nucleotides & Nucleic Acids. 23 (8–9): 1393–1397. doi:10.1081/NCN-200027639. PMID15571265. S2CID86308163.
Marinaki AM, Sumi S, Arenas M, Fairbanks L, Harihara S, Shimizu K, et al. (October 2004). "Allele frequency of inosine triphosphate pyrophosphatase gene polymorphisms in a Japanese population". Nucleosides, Nucleotides & Nucleic Acids. 23 (8–9): 1399–1401. doi:10.1081/NCN-200027641. PMID15571266. S2CID36126159.
Maeda T, Sumi S, Ueta A, Ohkubo Y, Ito T, Marinaki AM, et al. (August 2005). "Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population". Molecular Genetics and Metabolism. 85 (4): 271–279. doi:10.1016/j.ymgme.2005.03.011. PMID15946879.
Atanasova S, Shipkova M, Svinarov D, Mladenova A, Genova M, Wieland E, et al. (February 2007). "Analysis of ITPA phenotype-genotype correlation in the Bulgarian population revealed a novel gene variant in exon 6". Therapeutic Drug Monitoring. 29 (1): 6–10. doi:10.1097/FTD.0b013e3180308554. PMID17304144. S2CID7286658.
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