ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics

Research output: Contribution to journalReview articlepeer-review

49 Scopus citations


Cellular nucleotide pools are often contaminated by base analog nucleotides which interfere with a plethora of biological reactions, from DNA and RNA synthesis to cellular signaling. An evolutionarily conserved inosine triphosphate pyrophosphatase (ITPA) removes the non-canonical purine (d)NTPs inosine triphosphate and xanthosine triphosphate by hydrolyzing them into their monophosphate form and pyrophosphate. Mutations in the ITPA orthologs in model organisms lead to genetic instability and, in mice, to severe developmental anomalies. In humans there is genetic polymorphism in ITPA. One allele leads to a proline to threonine substitution at amino acid 32 and causes varying degrees of ITPA deficiency in tissues and plays a role in patients' response to drugs. Structural analysis of this mutant protein reveals that the protein is destabilized by the formation of a cavity in its hydrophobic core. The Pro32Thr allele is thought to cause the observed dominant negative effect because the resulting active enzyme monomer targets both homo- and heterodimers to degradation.

Original languageEnglish (US)
Pages (from-to)131-146
Number of pages16
JournalMutation Research - Reviews in Mutation Research
Issue number2
StatePublished - Oct 2013


  • Base analogs
  • DSB
  • Dominant negative
  • HAM1
  • HAP
  • ITP
  • ITPA
  • ITPA gene polymorphism
  • MEF
  • Mercaptopurines
  • NUDT16
  • Nucleotide pool
  • Pharmacogenetics
  • Protein stability
  • SSB
  • TPMT
  • XTP

ASJC Scopus subject areas

  • Genetics
  • Health, Toxicology and Mutagenesis


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