Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

Zamzami, Mazin A.

doi:10.3390/cells11030384

Cited by 6 publications

(3 citation statements)

References 42 publications

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“…ITPA is a catalytic enzyme that hydrolyzes inosine triphosphate, a toxic noncanonical nucleotide, to less toxic metabolites. 10 The allele frequency of 2 well-known polymorphisms, TPMT and NUDT15, varies among ethnicities, with the latter prevalent in Asian populations. 11 As for ITPA, its allele frequency in this study was 0.23, consistent with other studies on Asian populations.…”

Section: Methodsmentioning

confidence: 99%

Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Svasdisant¹,

Glomglao²,

Siraprapapat³

et al. 2023

Mediterr J Hematol Infect Dis

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Background: 6-Mercaptopurine (6-MP), a thiopurine agent, is an indispensable medication for treating pediatric acute lymphoblastic leukemia (ALL). However, its side effects of neutropenia and hepatotoxicity might interrupt treatment, resulting in poor outcomes. Inosine triphosphate pyrophosphatase (ITPA), an enzyme in the thiopurine pathway, may prevent the accumulation of toxic thiopurine metabolites. Studies on ITPA and thiopurine-associated toxicities are scarce. Methods: This study retrospectively investigated 1- to 15-year-old children with ALL who received 6-MP during the maintenance phase of treatment between 2000 and 2020. Toxicity during the first year of maintenance therapy and the mean dose of 6-MP were analyzed. Results: The 209 patients had a median age of 4.8 (0.3-14.8) years. Of these, 124 patients (59.3%) had wildtype ITPA, 73 patients (34.9%) had heterozygous ITPA 94C>A (hetITPA), and 12 patients (5.7%) had homozygous ITPA 94C>A (homITPA), with an allele frequency of 0.23. The incidence of neutropenia among ITPA polymorphisms did not significantly differ (P = 0.813). In patients harboring homITPA, transaminitis was more frequent than other polymorphisms but without a significant difference (P = 0.063). The mean dose of 6-MP for patients with homITPA was significantly lower than that for patients with hetITPA or wildtype ITPA (P = 0.016). Conclusions: HomITPA had a higher incidence of transaminitis and required a significantly larger dose reduction of 6-MP than wildtype ITPA. Further study is warranted to elucidate the effects of ITPA polymorphisms on toxicity in patients with ALL treated with 6-MP.

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Section: Methodsmentioning

confidence: 99%

Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Svasdisant¹,

Glomglao²,

Siraprapapat³

et al. 2023

Mediterr J Hematol Infect Dis

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“…Mutations can arise not only from damage to the existing bases incorporated into DNA but also from contamination of the nucleotide precursor pool with non-canonical nucleotides. Such contaminants in the precursor pool primarily include deoxy-and ribonucleoside triphosphates of inosine (ITP/dITP), xanthine (XTP/dXTP), and 8-oxoguanine [90] (Fig. 4).…”

Section: Repair Of Noncanonical Bases In the Nucleotide Poolmentioning

confidence: 99%

Role of the Nrf2/ARE Pathway in the mtDNA Reparation

Gureev,

Chernyshova,

Krutskikh

et al. 2024

Front. Biosci. (Landmark Ed)

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Mitochondrial DNA (mtDNA) is located in the mitochondrial matrix, in close proximity to major sources of reactive oxygen species (ROS) in the cell. This makes mtDNA one of the most susceptible components to damage in the cell. The nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway is an important cytoprotective mechanism. It is well-studied and described that Nrf2 can regulate the expression of mitochondrial-targeted antioxidant systems in the cell, indirectly protecting mtDNA from damage. However, the Nrf2/ARE pathway can also directly impact on the mtDNA repair processes. In this review, we summarize the existing data on the impact of Nrf2 on mtDNA repair, primarily base excision repair (BER), as it is considered the main repair pathway for the mitochondrial genome. We explore the crosstalk between Nrf2/ARE, BRCA1, and p53 signaling pathways in their involvement in maintaining mtDNA integrity. The role of other repair mechanisms in correcting mismatched bases and double-strand breaks is discussed. Additionally, the review addresses the role of Nrf2 in the repair of noncanonical bases, which contribute to an increased number of mutations in mtDNA and can contaminate the nucleotide pool.

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“…Proper cellular function requires the preservation of nucleotide pool integrity by maintaining a proper supply of purine and pyrimidine nucleotides while restricting noncanonical and damaged nucleotides (Evans & Guy, 2004; Kamiya, 2003; Pavlov et al, 2016; Simone, Pavlov, & Borgstahl, 2013; Singh & Anand, 2023). There are a number of enzymes that function in nucleotide pool maintenance and one such enzyme is inosine triphosphate pyrophosphatase (ITPase; reviewed in Burgis, 2016; Sakumi et al, 2010; Simone, Pavlov, & Borgstahl, 2013; Pavlov et al, 2016; Zamzami, 2022). ITPase hydrolyzes the noncanonical purine nucleotides inosine triphosphate (ITP) and xanthosine triphosphate (XTP) that arise from purine biosynthesis and their respective deoxy forms dITP/dXTP to monophosphates and pyrophosphate (Galperin et al, 2006; Figure 1).…”

Section: Introductionmentioning

confidence: 99%

Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function

2023

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Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA‐associated pathogenesis which provides evidence for RNA dysfunction.This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development

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Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

Cited by 6 publications

References 42 publications

Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Itpa Polymorphisms and the Incidence of Toxicities in Children With Acute Lymphoblastic Leukemia

Role of the Nrf2/ARE Pathway in the mtDNA Reparation

Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function

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