ITP pyrophosphohydrolase and idp phosphohydrolase in rat tissue

Vanderheiden, Bernardo S.

doi:10.1002/jcp.1040860118

Cited by 15 publications

(7 citation statements)

References 26 publications

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“…The distribution of ITPA transcripts in human tissues agrees with the distribution of ITPase enzyme activity in different rat tissues (17). These and other studies also suggested that the enzyme was located in the cytoplasm (6,17). We have confirmed this location by transfection of COS-7 cells with a construct in which hITPase was fused to the C terminus of green fluorescent protein.…”

Section: Discussionsupporting

confidence: 85%

“…The presence of hITPase mRNA in all human tissues examined and its high expression in endocrine glands was shown by Northern blot analysis and by cDNA microarray hybridization. The distribution of ITPA transcripts in human tissues agrees with the distribution of ITPase enzyme activity in different rat tissues (17). These and other studies also suggested that the enzyme was located in the cytoplasm (6,17).…”

Section: Discussionsupporting

confidence: 82%

“…Although mammalian ITPase activities have been identified in human erythrocytes (9), rabbit liver (10), and several rat tissues (17), no gene has been cloned and characterized. Recently a novel bacterial nucleoside triphosphate pyrophosphatase Mj0226, from Methanococcus jannaschii, was revealed by structure-based identification and subsequent biochemical analysis (18).…”

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confidence: 99%

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Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene

Lin

McLennan

Kong

et al. 2001

Journal of Biological Chemistry

129

156

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ITP and dITP exist in all cells. dITP is potentially mutagenic, and the levels of these nucleotides are controlled by inosine triphosphate pyrophosphatase (EC 3.6.1.19). Here we report the cloning, expression, and characterization of a 21.5-kDa human inosine triphosphate pyrophosphatase (hITPase), an enzyme whose activity has been reported in many animal tissues and studied in populations but whose protein sequence has not been determined before. At the optimal pH of 10.0, recombinant hITPase hydrolyzed ITP, dITP, and xanthosine 5-triphosphate to their respective monophosphates whereas activity with other nucleoside triphosphates was low. K m values for ITP, dITP, and xanthosine 5-triphosphate were 0.51, 0.31, and 0.57 mM, respectively, and k cat values were 580, 360, and 640 s ؊1 , respectively. A divalent cation was absolutely required for activity. The gene encoding the hITPase cDNA sequence was localized by radiation hybrid mapping to chromosome 20p in the interval D20S113-D20S97, the same interval in which the ITPA inosine triphosphatase gene was previously localized. A BLAST search revealed the existence of many similar sequences in organisms ranging from bacteria to mammals. The function of this ubiquitous protein family is proposed to be the elimination of minor potentially mutagenic or clastogenic purine nucleoside triphosphates from the cell.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionsupporting

confidence: 82%

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confidence: 99%

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Cloning, Expression, and Characterization of a Human Inosine Triphosphate Pyrophosphatase Encoded by the ITPAGene

Lin

McLennan

Kong

et al. 2001

Journal of Biological Chemistry

129

156

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“…Homologs of ITPA have been identified in all three domains of life. This includes the archaea Methanococcus jannaschii [26] and the bacteria E. coli [49], as well as the eukaryotes Saccharomyces cerevisiae [3, 75], mice [76], rats [77], rabbits [78], and humans [1]. These facts lead to the conclusion that the function of ITPA must be important.…”

Section: Problems Arising From Non-canonical Nucleotidesmentioning

confidence: 99%

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

Simone

Pavlov

Borgstahl

2013

Mutation Research/Reviews in Mutation Research

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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.

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“…ITP-ase is a nucleoside triphosphate pyrophosphohydrolase that is specific for ITP (Vanderheiden 1975). Vanderheiden (1969) reported high levels of ITP in the erythrocytes of two siblings and suggested that this resulted from homozygous deficiency of ITP-ase (MIM 147520).…”

mentioning

confidence: 99%