ITPA explained

Inosine triphosphate pyrophosphatase is an enzyme that in humans is encoded by the ITPA gene,^{[1] [2]} by the rdgB gene in bacteria E.coli^[3] and the HAM1 gene in yeast S. cerevisiae;^[4] the protein is also encoded by some RNA viruses of the Potyviridae family.^[5] 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.

Function

The protein encoded by this gene hydrolyzes inosine triphosphate and deoxyinosine triphosphate to the monophosphate nucleotide and diphosphate. The enzyme possesses a multiple substrate-specificity and acts on other nucleotides including xanthosine triphosphate and deoxyxanthosine triphosphate.^[4] 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. The enzyme ITPase dephosphorylates ribavirin triphosphate in vitro to ribavirin monophosphate, and ITPase reduced enzymatic activity present in 30 % of humans potentiates mutagenesis in hepatitis C virus.^[6] 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. ^[7]

Reading

• Holmes SL, Turner BM, Hirschhorn K . Human inosine triphosphatase: catalytic properties and population studies . Clin. Chim. Acta . 97 . 2–3 . 143–53 . 1979 . 487601 . 10.1016/0009-8981(79)90410-8.
• Fraser JH . Individual variation in inosine triphosphate accumulation in human erythrocytes . Clin. Biochem. . 8 . 6 . 353–64 . 1976 . 1204209 . 10.1016/S0009-9120(75)93685-1 . Meyers H . Henderson JF . Brox . Larry W. . McCoy . Ernest E..
• Clawson GA . Interaction of human immunodeficiency virus type I Rev protein with nuclear scaffold nucleoside triphosphatase activity . Cell Growth Differ. . 2 . 11 . 575–82 . 1992 . 1667585 . Song YL . Schwartz AM . Shukla . RR . Patel . SG . Connor . L . Blankenship . L . Hatem . C . Kumar . A.
• Deloukas P . The DNA sequence and comparative analysis of human chromosome 20 . Nature . 414 . 6866 . 865–71 . 2002 . 11780052 . 10.1038/414865a . Matthews LH . Ashurst J . Burton . J. . Gilbert . J. G. R. . Jones . M. . Stavrides . G. . Almeida . J. P. . Babbage . A. K. . 2001Natur.414..865D . free.
• Sumi S . Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency . Hum. Genet. . 111 . 4–5 . 360–7 . 2002 . 12384777 . 10.1007/s00439-002-0798-z . Marinaki AM . Arenas M . Fairbanks . Lynette . Shobowale-Bakre . Monsor . Rees . David . Thein . Swee . Ansari . Azhar . Sanderson . Jeremy . 24240940.
• Cao H, Hegele RA . DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency . J. Hum. Genet. . 47 . 11 . 620–2 . 2003 . 12436200 . 10.1007/s100380200095 . free.
• Strausberg RL . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . Feingold EA . Grouse LH . Derge . JG . Klausner . RD . Collins . FS . Wagner . L . Shenmen . CM . Schuler . GD . 2002PNAS...9916899M . free.
• Gerhard DS . The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC) . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . Wagner L . Feingold EA . Shenmen . CM . Grouse . LH . Schuler . G . Klein . SL . Old . S . Rasooly . R.
• Marinaki AM . Mutation in the ITPA gene predicts intolerance to azathioprine . Nucleosides Nucleotides Nucleic Acids . 23 . 8–9 . 1393–7 . 2005 . 15571265 . 10.1081/NCN-200027639 . Duley JA . Arenas M . Ansari . A. . Sumi . S. . Lewis . C. M. . Shobowale-Bakre . M. . Fairbanks . L. D. . Sanderson . J. . 86308163.
• Marinaki AM . Allele frequency of inosine triphosphate pyrophosphatase gene polymorphisms in a Japanese population . Nucleosides Nucleotides Nucleic Acids . 23 . 8–9 . 1399–401 . 2005 . 15571266 . 10.1081/NCN-200027641 . Sumi S . Arenas M . Fairbanks . L. . Harihara . S. . Shimizu . K. . Ueta . A. . Duley . J. A. . 36126159.
• Maeda T . Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population . Mol. Genet. Metab. . 85 . 4 . 271–9 . 2005 . 15946879 . 10.1016/j.ymgme.2005.03.011 . Sumi S . Ueta A . Ohkubo . Yumiko . Ito . Tetsuya . Marinaki . Anthony M. . Kurono . Yukihisa . Hasegawa . Shinsaku . Togari . Hajime.
• Breen DP, Marinaki AM, Arenas M, Hayes PC . Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation . Liver Transpl. . 11 . 7 . 826–33 . 2005 . 15973722 . 10.1002/lt.20377 . 9301778 . free.
• Porta J . Structure of the orthorhombic form of human inosine triphosphate pyrophosphatase . Acta Crystallographica Section F . 62 . Pt 11 . 1076–81 . 2006 . 17077483 . 10.1107/S1744309106041790 . 2225220 . Kolar C . Kozmin SG . Pavlov . Youri I. . Borgstahl . Gloria E. O..
• Arenas M . The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene . Biochim. Biophys. Acta . 1772 . 1 . 96–102 . 2007 . 17113761 . 10.1016/j.bbadis.2006.10.006 . Duley J . Sumi S . Sanderson . Jeremy . Marinaki . Anthony . free.
• Stenmark P . Crystal structure of human inosine triphosphatase. Substrate binding and implication of the inosine triphosphatase deficiency mutation P32T . J. Biol. Chem. . 282 . 5 . 3182–7 . 2007 . 17138556 . 10.1074/jbc.M609838200 . Kursula P . Flodin S . Graslund . S. . Landry . R. . Nordlund . P. . Schuler . H. . free.
• Atanasova S . 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 . 2007 . 17304144 . 10.1097/FTD.0b013e3180308554 . Shipkova M . Svinarov D . Mladenova . Antoaneta . Genova . Mariana . Wieland . Eberhard . Oellerich . Michael . Ahsen . Nicolas von . 7286658.

References

1. Lin S, McLennan AG, 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 . 22 . 18695–701 . May 2001 . 11278832 . 10.1074/jbc.M011084200 . free .
2. Web site: Entrez Gene: ITPA inosine triphosphatase (nucleoside triphosphate pyrophosphatase).
3. Burgis NE, Cunningham RP . Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase . J Biol Chem . 282 . 8 . 3531–8 . 2007 . 17090528 . 10.1074/jbc.M608708200 . free .
4. Davies O, Mendes P, Smallbone K, Malys N . Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism . BMB Reports . 45 . 4 . 259–64 . 2012 . 22531138. 10.5483/BMBRep.2012.45.4.259 . free .
5. Pasin . Fabio . Daròs . José-Antonio . Tzanetakis . Ioannis E . Proteome expansion in the Potyviridae evolutionary radiation . FEMS Microbiology Reviews . 2022 . 46 . 4 . en . fuac011 . 10.1093/femsre/fuac011 . 35195244 . 9249622 . 1574-6976.
6. Nyström K, Wanrooij PH, Waldenström J, Adamek L, Brunet S, Said J, Nilsson S, Wind-Rotolo M, Hellstrand K, Norder H, Tang KW, Lagging M. Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus. . Journal of Virology . 92 . 19 . 01087–18 . October 2018 . 10.1002/hep.27009 . free . 30045981 . 6146798 .
7. Rembeck K, Waldenstrom J, Hellstrand K, Nilsson S, Nyström K, Martner A, Lindh M, Norkrans G, Westin J, Pedersen C, Färkkil M, Langeland N, Rauning Buhl M, Morch K, Brehm Christensen P, and Lagging M . Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3 . Hepatology . 59 . 6 . 2131–2139 . June 2014 . 10.1002/hep.27009 . free . 24519039.