Abstract

Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA. Specifically, the ITPase catalyzed the hydrolysis of (deoxy) nucleoside triphosphates ((d) NTPs) into the corresponding nucleoside monophosphate with the concomitant release of pyrophosphate. Recently, thiopurine drug metabolites such as azathioprine have been included in the lists of ITPase substrates. Interestingly, inosine or xanthosine triphosphate (ITP/XTP) and their deoxy analogs, deoxy inosine or xanthosine triphosphate (dITP/dXTP), are products of important biological reactions such as deamination that take place within the cellular compartments. However, the incorporation of ITP/XTP, dITP/dXTP, or the genetic deficiency or polymorphism of the ITPA gene have been implicated in many human diseases, including infantile epileptic encephalopathy, early onset of tuberculosis, and the responsiveness of patients to cancer therapy. This review provides an up-to-date report on the ITPase enzyme, including information regarding its discovery, analysis, and cellular localization, its implication in human diseases including cancer, and its therapeutic potential, amongst others.

Highlights

  • Inosine triphosphate pyrophosphatase (ITPase) was first discovered in human erythrocytes in 1964 by Liakopoulou and Alivisatos

  • By using partially isolated ITPase, it was shown in the year 1970 by Vanderheide that the enzyme delivers PPi from human erythrocytes [1]

  • It was distinguished in terms of enzyme kinetics for ITP, isolated 2-3000-fold from human erythrocytes, and studied to understand its work against ATP (Figure 1), GTP, CTP, and UTP

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Summary

Introduction

Inosine triphosphate pyrophosphatase (ITPase) was first discovered in human erythrocytes in 1964 by Liakopoulou and Alivisatos. It was distinguished in terms of enzyme kinetics for ITP, isolated 2-3000-fold from human erythrocytes, and studied to understand its work against ATP (Figure 1), GTP, CTP, and UTP. Competitive inhibition is shown in human ITPase at inosine 5 -diphosphate. There are several roles of ITPase which are still unknown, such as the role of ITP in cellular substrate inhibition. It effects the regulation of the concentration of ITP, IPM, or inosine inside the cell, and whether the enzyme is allosterically regulated or post-translationally modified [9]. The central idea of this study tells us that the substrate binding of ITPase activity may have a pivotal role in the development of therapeutics

ITPA Mutations and Association with Clinical Disease
ITPA Mutations and Therapeutic Implications
Infantile Encephalopathy
Findings
Conclusions
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