Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ47WVR)

• DOT Name: Inosine triphosphate pyrophosphatase (ITPA)
• Synonyms: ITPase; Inosine triphosphatase; EC 3.6.1.9; Non-canonical purine NTP pyrophosphatase; Non-standard purine NTP pyrophosphatase; Nucleoside-triphosphate diphosphatase; Nucleoside-triphosphate pyrophosphatase; NTPase; Putative oncogene protein hlc14-06-p
• Gene Name: ITPA
• Related Disease:
  Infantile spasm
  Tuberculosis
  Acute lymphocytic leukaemia
  Attention deficit hyperactivity disorder
  Childhood acute lymphoblastic leukemia
  Developmental and epileptic encephalopathy, 35
  HIV infectious disease
  Juvenile idiopathic arthritis
  Liver cirrhosis
  Malaria
  Systemic lupus erythematosus
  Ulcerative colitis
  Zika virus infection
  Immune system disorder
  Inborn error of metabolism
  Inflammatory bowel disease
  Inosine triphosphatase deficiency
  Agranulocytosis
  Dilated cardiomyopathy
  Crohn disease
  Cryohydrocytosis
  Ebola virus infection
  Microscopic polyangiitis
• UniProt ID: ITPA_HUMAN
• PDB ID: 2CAR; 2I5D; 2J4E; 4F95
• EC Number: 3.6.1.9
• Pfam ID: PF01725
• Sequence:
  MAASLVGKKIVFVTGNAKKLEEVVQILGDKFPCTLVAQKIDLPEYQGEPDEISIQKCQEA
  VRQVQGPVLVEDTCLCFNALGGLPGPYIKWFLEKLKPEGLHQLLAGFEDKSAYALCTFAL
  STGDPSQPVRLFRGRTSGRIVAPRGCQDFGWDPCFQPDGYEQTYAEMPKAEKNAVSHRFR
  ALLELQEYFGSLAA
• Function: Pyrophosphatase that hydrolyzes the non-canonical purine nucleotides inosine triphosphate (ITP), deoxyinosine triphosphate (dITP) as well as 2'-deoxy-N-6-hydroxylaminopurine triphosphate (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.
• Tissue Specificity: Ubiquitous. Highly expressed in heart, liver, sex glands, thyroid and adrenal gland.
• KEGG Pathway:
  Purine metabolism (hsa00230)
  Drug metabolism - other enzymes (hsa00983)
  Metabolic pathways (hsa01100)
  Nucleotide metabolism (hsa01232)
• Reactome Pathway:
  Ribavirin ADME (R-HSA-9755088)
  Purine catabolism (R-HSA-74259)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Infantile spasm	DISZSKDG	Definitive	Autosomal recessive	[1]
Tuberculosis	DIS2YIMD	Definitive	Genetic Variation	[2]
Acute lymphocytic leukaemia	DISPX75S	Strong	Genetic Variation	[3]
Attention deficit hyperactivity disorder	DISL8MX9	Strong	Biomarker	[4]
Childhood acute lymphoblastic leukemia	DISJ5D6U	Strong	Genetic Variation	[3]
Developmental and epileptic encephalopathy, 35	DISJ0IOD	Strong	Autosomal recessive	[5]
HIV infectious disease	DISO97HC	Strong	Genetic Variation	[6]
Juvenile idiopathic arthritis	DISQZGBV	Strong	Biomarker	[7]
Liver cirrhosis	DIS4G1GX	Strong	Genetic Variation	[8]
Malaria	DISQ9Y50	Strong	Biomarker	[9]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[10]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[11]
Zika virus infection	DISQUCTY	Strong	Biomarker	[12]
Immune system disorder	DISAEGPH	moderate	Biomarker	[13]
Inborn error of metabolism	DISO5FAY	moderate	Biomarker	[14]
Inflammatory bowel disease	DISGN23E	moderate	Altered Expression	[13]
Inosine triphosphatase deficiency	DISM4LMR	Moderate	Autosomal recessive	[15]
Agranulocytosis	DISJS4LS	Disputed	Genetic Variation	[16]
Dilated cardiomyopathy	DISX608J	Disputed	Biomarker	[17]
Crohn disease	DIS2C5Q8	Limited	Genetic Variation	[18]
Cryohydrocytosis	DISMQHL3	Limited	Genetic Variation	[19]
Ebola virus infection	DISJAVM1	Limited	Biomarker	[20]
Microscopic polyangiitis	DIS74KSO	Limited	Genetic Variation	[21]

This DOT Affected the Drug Response of 6 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Inosine triphosphate pyrophosphatase (ITPA) affects the response to substance of Cisplatin.	[33]
Methotrexate	DM2TEOL	Approved	Inosine triphosphate pyrophosphatase (ITPA) affects the response to substance of Methotrexate.	[34]
Azathioprine	DMMZSXQ	Approved	Inosine triphosphate pyrophosphatase (ITPA) affects the response to substance of Azathioprine.	[35]
Aspirin	DM672AH	Approved	Inosine triphosphate pyrophosphatase (ITPA) increases the Anaemia ADR of Aspirin.	[36]
Interferon	DMYTKF5	Phase 2	Inosine triphosphate pyrophosphatase (ITPA) increases the Pancytopenia ADR of Interferon.	[37]
Ribavirin	DMEYLH9	Phase 1 Trial	Inosine triphosphate pyrophosphatase (ITPA) increases the response to substance of Ribavirin.	[36]

10 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate affects the expression of Inosine triphosphate pyrophosphatase (ITPA).	[22]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[23]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[24]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[25]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[26]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[28]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[30]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[31]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Inosine triphosphate pyrophosphatase (ITPA).	[32]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Inosine triphosphate pyrophosphatase (ITPA).	[29]

References

• [1] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [2] A disease spectrum for ITPA variation: advances in biochemical and clinical research.J Biomed Sci. 2016 Oct 22;23(1):73. doi: 10.1186/s12929-016-0291-y.
• [3] Classification and regression tree-based prediction of 6-mercaptopurine-induced leucopenia grades in children with acute lymphoblastic leukemia.Cancer Chemother Pharmacol. 2019 May;83(5):875-880. doi: 10.1007/s00280-019-03803-8. Epub 2019 Feb 26.
• [4] Vibrio cholerae FeoB contains a dual nucleotide-specific NTPase domain essential for ferrous iron uptake.Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4599-4604. doi: 10.1073/pnas.1817964116. Epub 2019 Feb 13.
• [5] Analysis of ITPA phenotype-genotype correlation in the Bulgarian population revealed a novel gene variant in exon 6. Ther Drug Monit. 2007 Feb;29(1):6-10. doi: 10.1097/FTD.0b013e3180308554.
• [6] Erythrocyte Inosine triphosphatase activity: A potential biomarker for adverse events during combination antiretroviral therapy for HIV.PLoS One. 2018 Jan 12;13(1):e0191069. doi: 10.1371/journal.pone.0191069. eCollection 2018.
• [7] 5-Aminoimidazole-4-carboxamide ribonucleotide-transformylase and inosine-triphosphate-pyrophosphatase genes variants predict remission rate during methotrexate therapy in patients with juvenile idiopathic arthritis.Rheumatol Int. 2015 Apr;35(4):619-27. doi: 10.1007/s00296-014-3131-y. Epub 2014 Sep 21.
• [8] ITPase activity modulates the severity of anaemia in HCV-related cirrhosis treated with ribavirin-containing interferon-free regimens.Antivir Ther. 2017;22(7):551-558. doi: 10.3851/IMP3134. Epub 2017 Feb 6.
• [9] Functional genetic evaluation of DNA house-cleaning enzymes in the malaria parasite: dUTPase and Ap4AH are essential in Plasmodium berghei but ITPase and NDH are dispensable.Expert Opin Ther Targets. 2019 Mar;23(3):251-261. doi: 10.1080/14728222.2019.1575810. Epub 2019 Feb 13.
• [10] Effect of genetic polymorphisms on effectiveness of low-dose azathioprine in Japanese patients with systemic lupus erythematosus.Am J Health Syst Pharm. 2012 Dec 1;69(23):2072-8. doi: 10.2146/ajhp120179.
• [11] Review article: thiopurines in inflammatory bowel disease.Aliment Pharmacol Ther. 2006 Sep 1;24(5):715-29. doi: 10.1111/j.1365-2036.2006.02980.x.
• [12] Structure and flexibility of non-structural proteins 3 and -5 of Dengue- and Zika viruses in solution.Prog Biophys Mol Biol. 2019 May;143:67-77. doi: 10.1016/j.pbiomolbio.2018.08.008. Epub 2018 Aug 29.
• [13] ITPA Activity in Children Treated by Azathioprine: Relationship to the Occurrence of Adverse Drug Reactions and Inflammatory Response.Basic Clin Pharmacol Toxicol. 2018 Jun;122(6):588-595. doi: 10.1111/bcpt.12958. Epub 2018 Feb 26.
• [14] Identification of a novel homozygous variant confirms ITPA as a developmental and epileptic encephalopathy gene.Am J Med Genet A. 2019 May;179(5):857-861. doi: 10.1002/ajmg.a.61103. Epub 2019 Feb 28.
• [15] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [16] Thiopurine S-methyltransferase and inosine triphosphate pyrophosphohydrolase genes in Japanese patients with inflammatory bowel disease in whom adverse drug reactions were induced by azathioprine/6-mercaptopurine treatment.J Gastroenterol. 2009;44(3):197-203. doi: 10.1007/s00535-008-2307-1. Epub 2009 Feb 13.
• [17] ITPase deficiency causes a Martsolf-like syndrome with a lethal infantile dilated cardiomyopathy.PLoS Genet. 2019 Mar 11;15(3):e1007605. doi: 10.1371/journal.pgen.1007605. eCollection 2019 Mar.
• [18] Allele frequency of inosine triphosphate pyrophosphatase (ITPA) and thiopurine-S-methyl transferase (TPMT) genes in the Tunisian population.Clin Res Hepatol Gastroenterol. 2012 Apr;36(2):178-84. doi: 10.1016/j.clinre.2011.12.001. Epub 2012 Jan 4.
• [19] Tolerability of Erythrocyte Ribavirin Triphosphate Concentrations Depends on the ITPA Genotype.Ther Drug Monit. 2019 Aug;41(4):497-502. doi: 10.1097/FTD.0000000000000626.
• [20] Ebola virus VP35has novel NTPase and helicase-like activities.Nucleic Acids Res. 2019 Jun 20;47(11):5837-5851. doi: 10.1093/nar/gkz340.
• [21] Neutropenia related to an azathioprine metabolic disorder induced by an inosine triphosphate pyrophosphohydrolase (ITPA) gene mutation in a patient with PR3-ANCA-positive microscopic polyangiitis?"Honda K. Niikura T
• [22] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [23] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [24] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [25] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [26] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [27] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [28] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [29] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [30] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [31] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [32] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [33] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.
• [34] Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 2006 Sep;54(9):2830-9. doi: 10.1002/art.22032.
• [35] 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. doi: 10.1097/00008571-200403000-00006.
• [36] ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy--a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010 Oct;139(4):1190-7. doi: 10.1053/j.gastro.2010.06.071. Epub 2010 Jul 14.
• [37] Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients. J Hepatol. 2012 Feb;56(2):313-9. doi: 10.1016/j.jhep.2011.04.021. Epub 2011 May 20.