Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.4.2.7 (adenine phosphoribosyltransferase)
692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The growth inhibitory mechanisms of mizoribine, an immunosuppressive imidazole nucleoside used clinically to inhibit rejection reactions after renal transplantation and in the treatment of systemic lupus erythematosus and rheumatoid arthritis, were studied in human and murine cells. We found that (a) human cells were 20- to 60-fold more resistant than murine cells to both mizoribine and its aglycone, (b) adenine phosphoribosyltransferase (APRT)-deficient human cells were resistant to aglycone but not to mizoribine, (c) hypoxanthine phosphoribosyltransferase (HPRT)-deficient human cells were at least 100-fold more sensitive to both mizoribine and aglycone, and (d) the decrease in intracellular GTP broadly paralleled the cytotoxicity in each case. Therefore, data obtained from studies using non-human tissues should be interpreted carefully before clinical application. Results indicate that the growth inhibitory effect of the aglycone but not of mizoribine is mediated by APRT, and depletion of guanine nucleotides is responsible for the effects of both drugs. Our data also suggest that the drugs may reduce mutant HPRT-deficient somatic cells in vivo, and may cause enhanced adverse reactions in HPRT-deficient individuals. The drug may have altered effects in patients receiving other purine or pyrimidine analogs.
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PMID:Differential cytotoxic effects of mizoribine and its aglycone on human and murine cells and on normal and enzyme-deficient human cells. 757 67

We have determined the relative frequency in vitro of UV-induced cyclobutane pyrimidine dimers (py <> py) and (6-4) pyrimidine pyrimidone photoproducts (py(6-4)pyo) at individual sites in selected regions of the Chinese hamster ovary (CHO) adenine phosphoribosyltransferase (aprt) gene, and compared this to the observed specificity of UV-induced mutations (Drobetsky et al., 1987, 1989). Our results indicate that G:C-->A:T transition "hotspots" (multiple occurrences) at the chromosomal CHO aprt locus, the majority of which occur at 5'TCC-3', are clearly targeted at sites associated with a relatively high yield of py <> py and/or py(6-4)pyo. We conclude that photoproduct frequency plays a major role in UV-induced transition mutagenesis at 5'-TCC-3' sites at an endogenous locus in a rodent cell line, and that both py(6-4)pyo and py <> py have premutagenic potential.
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PMID:UV-induced G:C-->A:T transitions at the APRT locus of Chinese hamster ovary cells cluster at frequently damaged 5'-TCC-3' sequences. 769 Aug 80

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.
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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

Chromosomal aberrations in human gliomas are principally numerical. In tumours of low malignancy, karyotypes are frequently normal, but occasionally an excess of chromosome 7 and a loss of sex chromosome are observed. In highly malignant tumours, the most frequent aberrations are gain of chromosome 7, loss of chromosome 10 and less frequently losses or deletions of chromosomes 9, 22, 6, 13 and 14 or gains of chromosomes 19 and 20. To understand the meaning of these chromosome imbalances, the relationships between chromosome abnormalities and metabolic disturbances were studied. The losses or deletions observed affected principally chromosomes carrying genes encoding enzymes involved in purine metabolism. The activities of ten enzymes were measured: adenosine kinase, adenine phosphoribosyltransferase, adenylate kinase, methylthioadenosine phosphorylase, hypoxanthine phosphoribosyltransferase, adenylosuccinate lyase, inosine monophosphate dehydrogenase, adenosine deaminase, nucleoside phosphorylase and adenosine monophosphate deaminase. In parallel, two enzymes involved in pyrimidine metabolism, thymidine kinase and thymidylate synthase (TS), were studied. The activities of all these enzymes were measured on samples from 30 human primary glial tumours with low or high malignancy, six xenografted tumours at different passages, four portions of normal brain tissue and four non-glial brain neoplasms. As suggested by cytogenetic data, the enzymatic results showed a relatively low activity of purine metabolism in glial tumours when compared with normal brain and non-glial brain neoplasms. Considering the two enzymes involved in pyrimidine metabolism, only TS had higher activity in glial tumours of high malignancy than in normal brain. In comparison with normal brain, the balance between salvage and de novo pathways changes in gliomas, and even more in grafted tumours, in favour of de novo synthesis. The relation between chromosomes and metabolic imbalances does not correspond to a simple gene dosage effect in these tumours. These data suggest that the decrease of adenosine metabolism occurs before chromosomal aberrations appear, since it is observed in tumours of low malignancy when most karyotypes are still normal, and that the de novo pathway increases with tumour progression.
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PMID:Purine and pyrimidine metabolism in human gliomas: relation to chromosomal aberrations. 805 68

Using Uvr proteins we have quantified benzo(a)pyrene diol epoxide (BPDE)-DNA adduct formation and repair at the dihydrofolate reductase (DHFR) and adenine phosphoribosyltransferase (APRT) genes in two Chinese hamster ovary cell lines: B-11 cells, which are 50-fold amplified for DHFR, and AT3-2 cells, which are diploid for DHFR. We have found that: 1) BPDE-DNA adduct formation in different regions of the DHFR gene is proportional to the concentration of BPDE. 2) There is no significant difference in the repair of BPDE-DNA adducts between the coding and noncoding regions in either amplified or nonamplified DHFR gene domains. 3) Repair in the nonamplified DHFR gene is more efficient (30-40%) than in the amplified DHFR genes. 4) There are no significant differences of repair in the transcribed or nontranscribed strands of the DHFR gene. 5) BPDE-DNA adduct formation and repair in the APRT gene in B-11 and AT3-2 cells are the same. These results contrast those for the repair of cyclobutane pyrimidine dimers, which occurs preferentially in the transcribed strand of the DHFR gene and in which gene amplification appears to play no role.
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PMID:Repair of benzo(a)pyrene diol epoxide- and UV-induced DNA damage in dihydrofolate reductase and adenine phosphoribosyltransferase genes of CHO cells. 817 87

An automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography (HPLC) with column switching is described. The system consists of a reversed-phase column, a cation-exchange column, a column switch, four sets of ultraviolet absorbance detectors, a microcomputer and other conventional equipment. As this system permits the simultaneous determination of urinary orotic acid, uracil, dihydrouracil, pseudouridine, xanthine, 2,8-dihydroxyadenine and succinyladenosine, it offers a useful method for the detection of orotic aciduria, dihydropyrimidine dehydrogenase deficiency, dihydropyrimidinuria, xanthinuria, adenine phosphoribosyltransferase deficiency and adenylosuccinase deficiency.
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PMID:Automated screening system for purine and pyrimidine metabolism disorders using high-performance liquid chromatography. 858 Nov 29

2,8-Dihydroxyadenine urolithiasis is an inherited disorder caused by adenine phosphoribosyltransferase deficiency. A fast, simple, sensitive and selective capillary zone electrophoretic method for diagnosis of 2,8-dihydroxyadenine urolithiasis in adenine phosphoribosyltransferase deficiency is described. The method is based on direct measurement of 2,8-dihydroxyadenine in untreated urine in phosphate buffer at pH 3.0 within 8 min. Under the given separation conditions 2,8-dihydroxyadenine is very well separated from other purine and pyrimidine substances and presents characteristic UV spectra which enable identification in case of doubt. The urine samples containing pathological 2,8-dihydroxyadenine could be successfully analysed in levels approaching those relevant for bioanalytical applications. The reliability of the method presented for screening of patients with adenine phosphoribosyltransferase deficiency is demonstrated on a urine sample of a patient with the defect who was already treated with allopurinol at the time of obtaining the sample. No interfering substances were found in 50 urine samples from healthy infants under the analytical condition described.
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PMID:A fast and simple screening method for detection of 2,8-dihydroxyadenine urolithiasis by capillary zone electrophoresis. 864 18

Deficiency of the enzyme adenine phosphoribosyltransferase (APRT) has been associated with hypersensitivity to the mutagenic effects of ethyl methanesulphonate (EMS) and 254 nm ultraviolet (UV) radiation in clone 707 of Friend mouse erythroleukaemia (FEL) cells. The molecular nature of spontaneous EMS- and UV-induced mutations in the coding region of hypoxanthine-guanine phosphoribosyltransferase (HPRT) was determined for wild-type FEL cells and two APRT-deficient mutant sub-clones which have significantly reduced ATP pool levels, and are mutagen-hypersensitive. Mis-sense base substitutions were the predominant type of spontaneous mutation. However, exon deletions, possibly involving aberrant splicing of HPRT mRNA, and a non-sense mutation were also observed. EMS-induced mutations in wild-type and APRT-deficient mutant sub-clones were GC-->AT transitions, which is consistent with O6-ethylguanine being the primary pre-mutagenic lesion. All UV-induced mutations in both cell types were targeted to dipyrimidine sites where the two most common classes of photoproducts (cyclobutane pyrimidine dimers and [6-4] photoproducts) are formed. The similarity in the mutations observed in both cell types indicates that the mutagen hypersensitivity of APRT-deficient cells may be the result of decreased efficiency in the excision repair processes due to reduced levels of ATP.
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PMID:Molecular mechanisms of mutagen hypersensitivity in adenine phosphoribosyl transferase-deficient Friend mouse erythroleukaemia cells. 949 94

High energy phosphate levels fall rapidly during cardiac ischemia and recover slowly (more than one week) during reperfusion. The slow recovery of ATP may reflect a lack of purine metabolic precursors and/or increased activity of purine catabolic enzymes such as 5'-nucleotidase (5'-NT, EC 3.1.3.5) and adenosine deaminase (ADA, EC 3.5.4.4). The activity of enzymes involved in both the catabolism of ATP precursors (5-NT and ADA) and the restoration of ATP from slow synthetic pathways [adenosine kinase (AK, EC 2.7.1.20), adenine phosphoribosyl transferase (APRT, EC 2.4.2.7) and hypoxanthine phosphoribosyl transferase (HPRT, EC 2.4.2.8)] may directly affect the rate of ATP recovery. Strategies to enhance recovery will depend on the relative activity of these enzymes following ischemia. Their activity in different species and their response to ischemia are not well characterized. Hence, rapid assay methods for these enzymes would facilitate detailed time course studies of their activities in postischemic myocardium. We modified a single ion-exchange column chromatographic method using DEAE-Sephadex to determine the products of incubation of 5'-NT, AK, APRT and HPRT with their respective substrates. The uniformity of the final product measurement procedure for all assays permits the activities of the four enzymes to be rapidly determined in a single tissue sample and facilitates the study of a large number of samples. This technique should also be useful for enzymes of the pyrimidine metabolic pathway.
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PMID:Ion-exchange column chromatographic method for assaying purine metabolic pathway enzymes. 961 62

In this paper, we extend our previous observation on the mobilization of the ribose moiety from a purine nucleoside to a pyrimidine base, with subsequent pyrimidine nucleotides formation (Cappiello et al., Biochim. Biophys. Acta 1425 (1998) 273-281). The data show that, at least in vitro, also the reverse process is possible. In rat brain extracts, the activated ribose, stemming from uridine as ribose 1-phosphate, can be used to salvage adenine and hypoxanthine to their respective nucleotides. Since the salvage of purine bases is a 5-phosphoribosyl 1-pyrophosphate-dependent process, catalyzed by adenine phosphoribosyltransferase and hypoxanthine guanine phosphoribosyltransferase, our results imply that Rib-1P must be transformed into 5-phosphoribosyl 1-pyrophosphate, via the successive action of phosphopentomutase and 5-phosphoribosyl 1-pyrophosphate synthetase; and,in fact, no adenosine could be found as an intermediate when rat brain extracts were incubated with adenine, Rib-1P and ATP, showing that adenine salvage does not imply adenine ribosylation, followed by adenosine phosphorylation. Taken together with our previous results on the Rib-1P-dependent salvage of pyrimidine nucleotides, our results give a clear picture of the in vitro Rib-1P recycling, for both purine and pyrimidine salvage.
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PMID:In vitro recycling of alpha-D-ribose 1-phosphate for the salvage of purine bases. 1069 92


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