Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.7 (adenine phosphoribosyltransferase)
 692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irradiation of cells with short wave ultraviolet light (UV-C) induces both cyclobutane pyrimidine dimers (CPD) as well as pyrimidine 6-4 pyrimidone photoproducts (6-4 PP). We have focused on the removal of both types of DNA photolesions from the transcriptionally active adenine phosphoribosyltransferase (APRT) and hypoxanthine-guanine phosphoribosyltransferase (HPRT) genes and the inactive c-mos gene. Induction levels of both CPD and 6-4 PP were similar for all three genes analyzed, with the induction of 6-4 PP being about 3-fold lower than of CPD. Repair of CPD was analyzed using the CPD-specific enzyme T4 endonuclease V; repair of 6-4 PP was examined employing Escherichia coli UvrABC excinuclease. Unlike the HPRT gene, in which CPD were removed selectively from the transcribed strand, both strands of the 16-kilobase fragment encompassing the 2.6-kilobase APRT gene were repaired efficiently. This suggests the existence of multiple transcription units in the APRT region including transcription units running in the opposite direction of the APRT gene. Only a marginal part of the CPD was removed from the inactive c-mos gene after 24 h. In all three genes investigated, 6-4 PP were repaired more rapidly than CPD and, as demonstrated for the HPRT and APRT genes, without strand specificity. The difference in the repair phenotype of CPD between the HPRT gene and the APRT gene coincides with differences between both genes with regard to the DNA strand distribution of previously published UV-induced mutations.
J Biol Chem 1994 Dec 16
PMID:Analysis of repair of cyclobutane pyrimidine dimers and pyrimidine 6-4 pyrimidone photoproducts in transcriptionally active and inactive genes in Chinese hamster cells. 798 59

The complete genomic sequence of the rat APRT gene is described and compared with published mammalian sequences. The rat APRT gene organization is typical of other rodent APRTs with five exons, one large intron of 993 bp, and three smaller introns averaging 145 bp. Because complete sequences for mouse and Chinese hamster APRT are also known, it is possible to compare the evolutionary rates of change in the exons with those of the introns. The latter provide one possible estimate of underlying rates of change. It is shown that the APRT exons have differential rates of evolution in rodents and have had a recent and rapid burst of substitutions within the mouse lineage. Rates of change in the exons do not appear to be strongly correlated with the rates of change in the introns.
Genome 1993 Dec
PMID:The rat adenine phosphoribosyltransferase sequence shows evolutionary rate variation among exons in rodents. 811 72

The effects of hydrogen peroxide (H2O2) on the purine metabolism of human endothelial cells were investigated. An incubation with 0.01 mM H2O2 over 60 min led to an increase in the intracellular adenosine-5-triphosphate (ATP) and creatine phosphate (CP) levels by 51.3% and 18.2%, respectively. A 60 min incubation with 0.1 mM H2O2 showed no effect. The uptake and salvage of 14C-adenine (14C-AD) and 14C-adenosine (14C-ADO) was significantly (p < 0.005) increased using 0.01 mM H2O2. Only an increase of 14C-ADO incorporation was observed using 0.1 mM H2O2. A concentration of 0.01 mM H2O2 reduced 5-phosphoribosyl-1-pyrophosphate synthetase (PRPP-S) activity by 60% and at the same time increased the activity of purine nucleoside phosphorylase, which converts inosine to hypoxanthine (PNP I), by 24%. Adenosine kinase (AK) activity was reduced by H2O2, whereas adenine phosphoribosyltransferase (APRT) activity was found to be elevated. In conclusion, the observed elevation of cellular ATP and CP levels could be partially caused by an increased purine salvage resulting from changes in purine enzyme activities.
Free Radic Biol Med 1993 Dec
PMID:The H2O2 induced effects on purine metabolism in human endothelial cells. 813 86

The molecular and biochemical aspects of purine nucleotide biosynthesis through de novo and salvage pathways, the production of uric acid, and their regulation mechanisms are reviewed for further understanding of hyperuricemia and gout. The metabolic rate of purine nucleotide biosynthesis is chiefly determined by the regulation of the de novo pathway, especially amidophosphoribosyltransferase and PRPP synthetase, and the accumulation of uric acid results from the acceleration of de novo biosynthesis and catabolism of purine nucleotide or the decrease in urinary excretion of uric acid. Moreover, several enzyme mutations of purine nucleotide metabolism are also clinically important including gout with hyperactive HPRT and the deficiency of HPRT (Lesch-Nyhan syndrome), adenylosuccinate lyase, xanthine oxidase, APRT, PNP, or ADA (SCID) with gene therapy.
Nihon Rinsho 1996 Dec
PMID:[Metabolism of purine nucleotides and the production of uric acid]. 897 90

Kidney androgen-regulated protein (Kap) is the most abundant protein in the mouse kidney, but its function is unknown. We previously observed a significant decrease in Kap mRNA expression in whole kidney tissue from male mice with adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadenine (DHA) nephrolithiasis. The disease phenotype is more severe in male mice and is age-dependent. To identify the cellular basis for differential Kap expression, we used in situ hybridization (ISH) and reverse transcription-polymerase chain reaction ISH (RT-PCR ISH) to identify the cell types expressing this mRNA in paraffin-embedded kidney sections. In 1-month-old wild-type male mice, Kap was detected primarily in S3 proximal tubule segments, but expression was very low in female mice. In 1-month-old APRT-deficient male mice, Kap expression was decreased significantly and was undetectable in female mice. Kap mRNA was not detected in 3- or 6-month-old mice using our standard ISH protocol, but we observed intense cytoplasmic staining in S3 proximal tubules in wild-type male mice of these age groups using an improved RT-PCR ISH procedure. Our studies demonstrate age-, gender-, and APRT genotype-dependent changes in Kap mRNA expression in mouse kidney. Kap expression is under multihormonal control, and hormonal changes in DHA-induced nephrolithiasis may account for the decreased Kap expression in APRT-deficient mice.
J Histochem Cytochem 2002 Dec
PMID:Gender- and age-dependent changes in kidney androgen protein mRNA expression in a knockout mouse model for nephrolithiasis. 1248 89

A tritium-adenine suicide procedure was used to select for mutants with reduced uptake of adenine from a population of Chinese hamster V79 cells mutagenized with ethyl methane sulfonate. In one of the mutant lines isolated, designated KC62, the uptake of adenine, hypoxanthine, and guanine was reduced by approximately 70%. The specific activities, Km values, and Vmax values of adenine phosphoribosyltransferase and of hypoxanthine phosphoribosyltransferase were the same in extracts from KC62 and from the parental cell line. Metabolic fate studies of incorporated [3H]adenine and 3[H]hypoxanthine revealed a metabolic block at the level of phosphoribosylation. Determination of phosphoribosylpyrophosphate pool size showed that the mutant contained only 25% of the phosphoribosylpyrophosphate found in the parent. Its reduced availability in KC62 appears to result in a decreased ability to salvage adenine, hypoxanthine, and guaninine via phosphoribosylation. Phosphoribosylpyrophosphate synthetase from KC62 was shown to have an increased sensitivity to inhibition by a variety of nucleotides.
Mol Cell Biol 1982 Dec
PMID:Isolation of a Chinese hamster cell mutant with low intracellular phosphoribosylpyrophosphate concentration. 1458 2

The purpose of this study was to assess the impact of short-term exposure to diluted diesel exhaust on inflammatory parameters in human airways. We previously exposed control subjects for 1 hour to a high ambient concentration of diesel exhaust (particle concentration 300 pg/m3--a level comparable with that found in North Sea ferries, highway underpasses, etc). Although these exposures did not have any measurable effect on standard indices of lung function, there was a marked neutrophilic inflammatory response in the airways accompanied by increases in blood neutrophil and platelet counts. Endothelial adhesion molecules were upregulated, and the expression of interleukin 8 messenger RNA (IL-8 mRNA*) was increased in a pattern consistent with neutrophilia. Individuals with asthma have inflamed airways and are clinically more sensitive to air pollutants than are control subjects. The present study was designed to assess whether this clinical sensitivity can be explained by acute neutrophilic inflammation or an increase in allergic airway inflammation resulting from diesel exhaust exposure. For this study, we used a lower concentration of diesel exhaust (100 microg/m3 PM10) for a 2-hour exposure. At this concentration, both the control subjects and those with asthma demonstrated a modest but statistically significant increase in airway resistance following exposure to diesel exhaust. This increase in airway resistance was associated with an increased number of neutrophils in the bronchial wash (BW) fluid obtained from control subjects (median after diesel exhaust 22.0 vs median after air 17.2; P = 0.015), as well as an increase in lymphocytes obtained through bronchoalveolar lavage (BAL) (15.0% after diesel exhaust vs 12.3% after air; P = 0.017). Upregulation of the endothelial adhesion molecule P-selectin was noted in bronchial biopsy tissues from control subjects (65.4% of vessels after diesel exhaust vs 52.5% after air). There was also a significant increase in IL-8 protein concentrations in BAL fluid and IL-8 mRNA gene expression in the bronchial biopsy tissues obtained from control subjects after diesel exhaust exposure (median IL-8 expression 65.7% of adenine phosphoribosyl transferase [APRT] gene expression value after diesel exhaust vs 51.0% after air; P = 0.007). There were no significant changes in total protein, albumin, or other soluble inflammatory markers in the BW or BAL fluids. Red and white blood cell counts in peripheral blood were unaffected by diesel exhaust exposure. Airway mucosal biopsy tissues from subjects with mild asthma (defined as forced expiratory volume in 1 second [FEV1] greater than or equal to 70% of the predicted value) showed eosinophilic airway inflammation after air exposure compared with the airways of the corresponding control subjects. However, among the subjects with mild asthma, diesel exhaust did not induce any significant change in airway neutrophils, eosinophils, or other inflammatory cells; cytokines; or mediators of inflammation. The only clear effect of diesel exhaust on the airways of subjects with asthma was a significant increase in IL-10 staining in the biopsy tissues. This study demonstrated that modest concentrations of diesel exhaust have clear-cut inflammatory effects on the airways of nonasthmatic (or control) subjects. The data suggest a direct effect of diesel exhaust on IL-8 production leading to upregulation of endothelial adhesion molecules and neutrophil recruitment. Despite clinical reports of increased susceptibility of patients with asthma to diesel exhaust and other forms of air pollution, it does not appear that this susceptibility is caused either directly by induction of neutrophilic inflammation or indirectly by worsening of preexisting asthmatic airway inflammation. The increased level of IL-10 after diesel exhaust exposure in airways of subjects with asthma suggests that this pollutant may induce subtle changes in airway immunobiology. This is an important topic for further investigation. Other possible explanations for the apparent lack of response to diesel exhaust among subjects with asthma include (1) the time course of the response to diesel may differ from the response to allergens, which peaks 6 to 8 hours after exposure; (2) a different type of inflammation may occur that was not detectable by the standard methods used in this study; and (3) the increased sensitivity of patients with asthma to particulate air pollution may reflect the underlying bronchial hyperresponsiveness found in asthma rather than any specific increase in inflammatory responses.
Res Rep Health Eff Inst 2003 Dec
PMID:Health effects of acute exposure to air pollution. Part I: Healthy and asthmatic subjects exposed to diesel exhaust. 1473 8

Dedifferentiated cells have served as tools to understand the molecular consequences of the loss of tissue-specific pathways. Here we report the characterization of one of these cell lines, M29, which lacks the liver-enriched HNF4-HNF1alpha pathway, in order to determine if this class of variant cell lines could provide additional information regarding requirements for tissue-type expression. We report that although the liver-specific alpha1-antitrypsin (alpha1AT) gene remains silent despite reactivation of the HNF4/HNF1alpha pathway in the M29 cells, the frequency of activation of an integrated alpha1AT-APRT transgene is increased 1000-fold in response to these transcription factors. The human alpha1AT locus (introduced via chromosome transfer) also remained silent on these cells, despite HNF4 and HNF1alpha expression. Results from cell fusion experiments suggest that the defect in the M29 cells is recessive. Results suggest that the M29 cells contain a defect that represses liver gene expression despite the presence of the HNF4/HNF1alpha pathway.
Biosci Rep 2004 Dec
PMID:Dissociation of the hepatic phenotype from HNF4 and HNF1alpha expression. 1615 97

To find general metabolic profiles of purine ribo- and deoxyribonucleotides in potato (Solanum tuberosum L.) plants, we looked at the in situ metabolic fate of various (14)C-labelled precursors in disks from growing potato tubers. The activities of key enzymes in potato tuber extracts were also studied. Of the precursors for the intermediates in de novo purine biosynthesis, [(14)C]formate, [2-(14)C]glycine and [2-(14)C]5-aminoimidazole-4-carboxyamide ribonucleoside were metabolised to purine nucleotides and were incorporated into nucleic acids. The rates of uptake of purine ribo- and deoxyribonucleosides by the disks were in the following order: deoxyadenosine > adenosine > adenine > guanine > guanosine > deoxyguanosine > inosine > hypoxanthine > xanthine > xanthosine. The purine ribonucleosides, adenosine and guanosine, were salvaged exclusively to nucleotides, by adenosine kinase (EC 2.7.1.20) and inosine/guanosine kinase (EC 2.7.1.73) and non-specific nucleoside phosphotransferase (EC 2.7.1.77). Inosine was also salvaged by inosine/guanosine kinase, but to a lesser extent. In contrast, no xanthosine was salvaged. Deoxyadenosine and deoxyguanosine, was efficiently salvaged by deoxyadenosine kinase (EC 2.7.1.76) and deoxyguanosine kinase (EC 2.7.1.113) and/or non-specific nucleoside phosphotransferase (EC 2.7.1.77). Of the purine bases, adenine, guanine and hypoxanthine but not xanthine were salvaged for nucleotide synthesis. Since purine nucleoside phosphorylase (EC 2.4.2.1) activity was not detected, adenine phosphoribosyltransferase (EC 2.4.2.7) and hypoxanthine/guanine phosphoribosyltransferase (EC 2.4.2.8) seem to play the major role in salvage of adenine, guanine and hypoxanthine. Xanthine was catabolised by the oxidative purine degradation pathway via allantoin. Activity of the purine-metabolising enzymes observed in other organisms, such as purine nucleoside phosphorylase (EC 2.4.2.1), xanthine phosphoribosyltransferase (EC 2.4.2.22), adenine deaminase (EC 3.5.4.2), adenosine deaminase (EC 3.5.4.4) and guanine deaminase (EC 3.5.4.3), were not detected in potato tuber extracts. These results suggest that the major catabolic pathways of adenine and guanine nucleotides are AMP --> IMP --> inosine --> hypoxanthine --> xanthine and GMP --> guanosine --> xanthosine --> xanthine pathways, respectively. Catabolites before xanthosine and xanthine can be utilised in salvage pathways for nucleotide biosynthesis.
Planta 2006 Dec
PMID:Profiles of purine biosynthesis, salvage and degradation in disks of potato (Solanum tuberosum L.) tubers. 1684 29

Adenine phosphoribosyltransferase plays a role in purine salvage by catalyzing the direct conversion of adenine to adenosine monophosphate. The involvement of the purine salvage pathway in tumor proliferation and angiogenesis makes adenine phosphoribosyltransferase a potential target for oncology drug discovery. We have expressed and characterized recombinant, N-terminally His-tagged human adenine phosphoribosyltransferase. Two assay formats were assessed for use in a high throughput screen: a spectrophotometric-based enzyme-coupled assay system and a radiometric ionic capture scintillation proximity bead assay format. Ultimately, the scintillation proximity assay format was chosen because of automated screening compatibility limitations of the coupled assay. We describe here the biochemical characterization of adenine phosphoribosyltransferase and the development of a robust, homogeneous, 384-well assay suitable for high throughput screening.
Assay Drug Dev Technol 2006 Dec
PMID:Configuration of a scintillation proximity assay for the activity assessment of recombinant human adenine phosphoribosyltransferase. 1719 4


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