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

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Abstract

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
Volume753
Issue number2
DOIs
StatePublished - Oct 1 2013

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Pyrophosphatases
Inosine Triphosphate
Pharmacogenetics
Nucleotides
Alleles
Medical Genetics
Genetic Polymorphisms
Mutant Proteins
Threonine
Amino Acid Substitution
Proline
RNA
Mutation
DNA
Enzymes
Pharmaceutical Preparations
Proteins

Keywords

  • Base analogs
  • DSB
  • Dominant negative
  • HAM1
  • HAP
  • HGPRT
  • 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

Cite this

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title = "ITPA (inosine triphosphate pyrophosphatase): From surveillance of nucleotide pools to human disease and pharmacogenetics",
abstract = "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.",
keywords = "Base analogs, DSB, Dominant negative, HAM1, HAP, HGPRT, ITP, ITPA, ITPA gene polymorphism, MEF, Mercaptopurines, NUDT16, Nucleotide pool, Pharmacogenetics, Protein stability, SSB, TPMT, XTP",
author = "Simone, {Peter D.} and Pavlov, {Youri I} and Borgstahl, {Gloria E}",
year = "2013",
month = "10",
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doi = "10.1016/j.mrrev.2013.08.001",
language = "English (US)",
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pages = "131--146",
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TY - JOUR

T1 - ITPA (inosine triphosphate pyrophosphatase)

T2 - From surveillance of nucleotide pools to human disease and pharmacogenetics

AU - Simone, Peter D.

AU - Pavlov, Youri I

AU - Borgstahl, Gloria E

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

KW - Base analogs

KW - DSB

KW - Dominant negative

KW - HAM1

KW - HAP

KW - HGPRT

KW - ITP

KW - ITPA

KW - ITPA gene polymorphism

KW - MEF

KW - Mercaptopurines

KW - NUDT16

KW - Nucleotide pool

KW - Pharmacogenetics

KW - Protein stability

KW - SSB

KW - TPMT

KW - XTP

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DO - 10.1016/j.mrrev.2013.08.001

M3 - Review article

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JO - Mutation Research - Reviews in Mutation Research

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