Inosine triphosphatase (ITPase) is an enzyme encoded by the ITPA gene. It plays a crucial role in maintaining the integrity of nucleotide pools within cells by hydrolyzing noncanonical nucleoside triphosphates, such as inosine triphosphate (ITP) and deoxyinosine triphosphate (dITP), into their corresponding nucleoside monophosphates (IMP and dIMP) with the release of pyrophosphate (PPi) .
ITPase was first discovered in human erythrocytes in 1964 by Liakopoulou and Alivisatos . The enzyme’s primary function is to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA, which can otherwise lead to harmful mutations and cellular dysfunction . ITPase achieves this by catalyzing the hydrolysis of (deoxy)nucleoside triphosphates (dNTPs) containing noncanonical purines .
In the purine biosynthesis pathway, inosine 5′-monophosphate (IMP), a precursor to adenosine 5′-monophosphate (AMP) and guanosine 5′-monophosphate (GMP), can be phosphorylated to produce ITP and dITP . Additionally, oxidative deamination of adenine or guanine nucleotides results in the formation of inosine-containing nucleotides . ITPase converts these noncanonical purine (d)NTPs into their corresponding nucleoside monophosphates, thereby sanitizing the nucleotide pools .
ITPase activity is essential for human health. Deficiency in ITPase activity due to genetic mutations can lead to severe health conditions. For instance, ITPase deficiency in mice has been shown to be lethal, causing cardiomyopathy and early death . In humans, rare severe mutations in the ITPA gene can result in early infantile encephalopathy and death . Additionally, nearly one-third of the human population has an ITPA status associated with decreased ITPase activity, which can affect the outcomes of certain medical treatments .
ITPase polymorphisms have been linked to altered responses to thiopurine and ribavirin therapies . Thiopurine therapy can be toxic for patients with ITPA polymorphism, while ITPA polymorphism is associated with improved outcomes for patients undergoing ribavirin treatment . Furthermore, ITPA polymorphism has been linked to early-onset tuberculosis susceptibility . These findings suggest that modulation of ITPase activity could be a potential therapeutic strategy for reducing negative outcomes associated with ITPA-related diseases .