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)

We analyzed the nature of spontaneous mutations at the autosomal locus coding for adenine phosphoribosyltransferase in the human colorectal carcinoma cell line SW620 to establish whether distinctive mutational pathways exist that might underlie the more complex genome rearrangements arising in tumor cells. Point mutations occur at a low rate in aprt hemizygotes derived from SW620, largely as a result of base substitutions at G.C base pairs to yield transversions and transitions. However, a novel pathway is evident in the form of multiple dispersed mutations in which two errors, separated by as much as 1,800 bp, fall in the same mutant gene. Such mutations could be the result of error-prone DNA synthesis occurring during normal replication or during long-patch excision-repair of spontaneously arising DNA lesions. This process could also contribute to the chromosomal instability evident in these tumor cells.
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PMID:Multiple dispersed spontaneous mutations: a novel pathway of mutation in a malignant human cell line. 203 24

Ehrlich carcinoma and P388 leukemia cells were rendered resistant to 4-carbamoylimidazolium 5-olate (SM-108), and assessments were made of biochemical and pharmacological determinants for the sensitivity to SM-108 using both sensitive and resistant sublines. We observed that the treatment of cells with SM-108 in vitro caused a remarkable decrease in the intracellular guanosine 5'-triphosphate pool level in sensitive but not in resistant sublines. There was no difference in the ability to take up SM-108 between sensitive and resistant sublines, but the cellular conversion of SM-108 to its nucleotide, which is the putative active anabolite of SM-108, proceeded only in sensitive sublines. Enzymological studies revealed that the activity of adenine phosphoribosyltransferase (EC 2.4.2.7), which is believed to conjugate SM-108 with 5-phospho-alpha-D-ribose 1-diphosphate, was very low in the resistant sublines. These results strongly support our previous hypothesis that SM-108 is activated by adenine phosphoribosyltransferase to SM-108-nucleotide which then inhibits hypoxanthine-5'-monophosphate dehydrogenase (EC 1.2.1.14), a key enzyme for the de novo synthesis of guanosine 5'-monophosphate.
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PMID:Selective reduction of intracellular guanosine 5'-triphosphate pool by 4-carbamoylimidazolium 5-olate in murine tumor cells. 286 32

The mechanism of action of 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250), which has a broad antitumor spectrum, was examined by in vitro cell culture and enzymatic studies. In the serum-containing culture medium, SL-1250 was rapidly deacylated to 4-carbamoylimidazolium 5-olate (SM-108). Thus, SL-1250 might be acting on the cells in the form of SM-108. The growth of L5178Y cells was completely inhibited by 10(-5) M SL-1250. It should be noted that this growth inhibition was significantly reversed in the presence of equimolar concentrations of guanine, guanosine, or guanosine 5'-monophosphate to those of SL-1250. However, hypoxanthine and xanthine were not effective. These effects of purine addition were observed to be quite similar in growth inhibition by SM-108. It was found that inosine 5'-monophosphate dehydrogenase (EC 1.2.1.14; IMP dehydrogenase), a key enzyme of de novo purine synthesis, from Ehrlich carcinoma cells was inhibited by SM-108 only when 5-phospho-alpha-D-ribose 1-diphosphate (PRPP) and MgCl2 coexisted with SM-108. In contrast, a chemically synthetic ribonucleotide of SM-108 inhibited IMP dehydrogenase without PRPP and MgCl2, and the mode of inhibition was competitive with the Ki value of 2 x 10(-8) M. On the other hand, the inhibition of either growth of L5178Y cells or IMP dehydrogenase in the presence of PRPP and MgCl2 by these compounds was reversed by adenine. A nucleotide of SM-108 was chromatographically identified when [14C]SM-108 was incubated in the enzyme solution with PRPP and MgCl2. This conversion by enzyme was also inhibited by adenine. Viewed together, these results strongly suggest that SL-1250 is, after being converted to SM-108, activated to its nucleotide form by adenine phosphoribosyltransferase (EC 2.4.2.7) and that this SM-108 nucleotide blocks de novo synthesis of guanosine 5'-monophosphate by inhibiting IMP dehydrogenase.
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PMID:New antitumor imidazole derivative, 5-carbamoyl-1H-imidazol-4-yl piperonylate, as an inhibitor of purine synthesis and its activation by adenine phosphoribosyltransferase. 612 Jul 58

4-Carbamoylimidazolium 5-olate (CIO), the aglycone of the nucleoside antibiotic, bredinin (4-carbamoyl-1-beta-D-ribofuranosylimidazolium 5-olate), exhibited potent cytotoxic effects of subclonal line F28-7 of C3H mouse mammary carcinoma FM3A cells in culture. We isolated 11 cell lines resistant to CIO from wild-type F28-7 cells mutagenized with N-methyl-N'-nitro-N-nitrosoguanidine. These resistant (cio') lines were 160- to 400-fold less sensitive to CIO than were the wild-type cells and inherited the resistant phenotypes during subculture for more than 3 months in the drug-free medium. They were cross-resistant to an adenine analog, 2,6-diaminopurine, while 2,6-diaminopurine-resistant (dap') lines, isolated independently, were cross-resistant to CIO. Neither of the cio' lines tested were able to form colonies in agar medium containing azaserine and adenine, nor were they able to incorporate tritiated adenine into the macromolecular fraction, indicating that they could not utilize exogenous adenine for growth. Enzyme assays using cell-free extracts revealed that all the cio' lines had undetectable levels of adenine phosphoribosyltransferase (EC 2.4.2.7) activity, but they, except one, had normal levels of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) and adenosine kinase (EC 2.7.1.20) activities. These results demonstrate that the CIO resistance in these lines is attributed to deficient adenine phosphoribosyltransferase activity and therefore that CIO is activated by adenine phosphoribosyltransferase to form a cytotoxic nucleotide within the drug-sensitive cells.
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PMID:Adenine phosphoribosyltransferase deficiency in cultured mouse mammary tumor FM3A cells resistant to 4-carbamoylimidazolium 5-olate. 710 14

To investigate the nature of DNA sequence rearrangements occurring in a highly malignant human colorectal carcinoma cell line (SW620) exhibiting a high level of chromosome instability, we characterized the molecular basis of deletions eliminating APRT. Deletions in SW620 resembled those in a variety of cell lines. They were joined at regions of little similarity through mono-, di-, or trinucleotide repeats. Breakpoint regions were rich in di- and trinucleotide repeats that might constitute pause sites for the replication complex. Deletions ranged in size from 1.8 to approximately 70 kb and were "directional" in that they eliminated sequences upstream of APRT but not downstream. Analysis of downstream sequences suggested that this pattern of deletion was due to the presence of another gene. Transcripts from these two genes converged but did not overlap. Given that this gene was not deleted in any hamster or human mutants, it appears essential for cell viability. This organization has important consequences for the pattern of mutation and repair of this region.
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PMID:Deletion mapping of highly conserved transcribed sequence downstream from APRT locus. 748 30

Stable, oxygen-resistant cell lines (O2R) were isolated from P19 and P19H22 (APRT hemizygote) mouse embryonic carcinoma cells by serial exposures of increasing durations to 95% O2. Neurally differentiated progeny were also oxygen-resistant. P19O2R exhibited reduced oxygen-mediated micronucleation and a 10- to 20-fold reduction of the forward mutation rate at the HPRT locus in 20% O2. P19H22O2R cells showed reduced frequencies of colonies resistant to 2,6-diaminopurine. The modal karyotype of P19O2R was identical to that of a nonmodal karyotype present in the parental line [39,X,-Y, add(14)]. There was no evidence of enhanced resistance to ionizing radiation. We conclude that this general approach, when applied to pluripotent embryonic stem cells, has the potential to lead to the synthesis of antimutator strains of mice.
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PMID:Oxygen-resistant multipotent embryonic carcinoma cell lines exhibit antimutator phenotypes. 782 58

We have analyzed spontaneous mutations in the adenine phosphoribosyltransferase gene of Chinese hamster clone B cells that exhibit a mutator phenotype because of defective mismatch binding. The mutator phenotype conferred increases in a limited number of mutational classes. The rates of transitions and most transversions were not significantly increased. The rates of A to T transversions and -2 frameshifts were strikingly elevated. These mutations were in repeated elements and 5 of 9 of the frameshifts were dinucleotide deletions in DNA sequences resembling microsatellites. The mismatch binding protein that is defective in the mutator line is a G-T mismatch recognition factor. Band-shift analysis indicated that the preferred substrate for the mismatch recognition protein is duplex DNA containing an extrahelical mono- or dinucleotide within repeated sequences. In agreement with a role in preventing minus frameshifts, a defective binding protein conferred an instability in clone B microsatellite DNA. A mismatch binding defect was also detected in Lo Vo, a human colorectal carcinoma cell line. Extracts of clone B or a second mismatch binding-deficient line, Raji-F12, did not complement Lo Vo extracts, indicating that these lines share a common defect. Our data provide a mechanistic explanation for the relation between defective mismatch recognition and the microsatellite instability of human colon cancer.
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PMID:A mismatch recognition defect in colon carcinoma confers DNA microsatellite instability and a mutator phenotype. 809 Jul 42

We determined the nature of mutations occurring at the autosomal APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. The analysis of mutations that result in APRT deficiency in a mismatch-repair-deficient strain of DLD-1 heterozygous for this locus enabled us to measure the rate of loss of the wild-type gene through deletion, recombination, or gene conversion as well as the rate of point mutation. The overall rate of mutation at the APRT locus in DLD-1 was elevated 100-fold compared with the mismatch-repair-proficient colorectal carcinoma cell line SW620. Loss of heterozygosity (LOH) at APRT accounted for only 4 to 9% of mutant strains derived from DLD-1, indicating a rate for these types of events of 4 x 10(-7) to 9 x 10(-7). In SW620 the rate of LOH at APRT was about 10-fold higher. LOH was not found at polymorphic markers within the same chromosome subband as APRT, indicating that only a limited portion of the chromosome was affected by these alterations. Chromosome painting of SWS620 mutants revealed that the loss of APRT occurred together with a substantial portion of the long arm of chromosome 16. Differences in the nature of base substitutions at APRT (e.g., the proportion of mutations resulting from transitions or transversions) in these tumor cell lines were also detected. There was also an important similarity---the presence of a mutant APRT gene with multiple base substitutions that may be the result of some sort of error-prone DNA synthesis.
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PMID:Loss of heterozygosity and base substitution at the APRT locus in mismatch-repair-proficient and -deficient colorectal carcinoma cell lines. 888 80

The invasion of monocytes through the endothelial wall of arteries and their transformation from macrophage into form cells has been implicated as a critical initiating event in atherogenesis. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) treatment, and can be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). To identify proteins potentially involved in atherosclerotic processes, we performed a proteomic analysis of THP-1 macrophages exposed to oxLDL generated by treatment with native LDL with hypochlorous acid/hypochlorite (HOCl/OCl(-)). We detected more than a thousand proteins, of which 104 differentially expressed proteins were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) and the NCBI database. The largest differences in expression were observed for bifunctional purine biosynthesis protein, vacuolar protein sorting 33A, breast carcinoma amplified sequence, adenine phosphoribosyltransferase, and tropomyosin alpha 3 chain. Interestingly, many apoptotic proteins such as lamin B1, poly (ADP-ribose) polymerase, Bcl-2 related protein A1 and vimentin were identified by MALDI-TOF analysis. Identities were confirmed by matching the sequence of several tryptic peptides using MALDI-TOF/TOF MS, Western blot analyses and immunofluorescent microscopy. The data described here will contribute to establishing a functional profile of the human macrophage proteome. Furthermore, the proteins identified in this study are attractive candidates for further biomarkers involved in the pathogenesis of atherosclerosis.
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PMID:Proteomic analysis of human macrophages exposed to hypochlorite-oxidized low-density lipoprotein. 1910 13