Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Biological evidence indicates that the enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) is vital for cell proliferation in malarial parasites but nonessential for mammalian cells. 7-Substituted guanines and hypoxanthines in which the 7 substituent bears functional or hydrophobic groups were prepared with the aim of finding a suitably constituted compound whose resemblance to the normal substrate allows it to compete for the reversible purine binding site of HGRPTase while allowing a substituent group of the inhibitor molecule to form a covalent bond or strong hydrophobic bond with appropriate sites on the enzyme. Multistep syntheses that began with hydroxyalkylations and alkylations of guanosine led to four key guanines substituted at the 7 position by the following chains: 2-aminoethyl, 3-amino-2-hydroxypropyl, 3-aminobenzyl, and 4-aminobenzyl. Similarly, 7-(4-aminobenzyl)hypoxanthine was prepared. Reactions at the side-chain amino groups with bromoacetic anhydride (or, alternatively, 4-nitrophenyl bromoacetate) and 3- and 4-(fluorosulfonyl)benzoyl chlorides afforded derivatives bearing functional groups capable of forming covalent bonds with enzymes through displacement reactions. 4-Chlorobenzyl derivatives were similarly prepared as potential inhibitors that might act through hydrophobic bonding. Three 7-substituted guanines whose side chains bear other functions (7-guanine-3-propranesulfonic acid, guanine-7-acetaldehyde, and the ethyl ester of 7-guanine-4-crotonic acid) were prepared as potential inhibitors and for possible use as intermediates. None of these compounds extended the life span of P. berghei infected mice or showed significant in vitro inhibition of HGPRTase from H.Ep.-2 cells.
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PMID:Synthesis of potential inhibitors of hypoxanthine-guanine phosphoribosyltransferase for testing as antiprotozoal agents. 1. 7-Substituted 6-oxopurines. 699 91

As the primary metabolite of alcohol, acetaldehyde (AA) may be responsible for many pathological effects related to consumption of alcohol, such as esophageal cancer. The spectrum of p53 mutations in esophageal tumors is indicative of the involvement of exogenous agents, such as tobacco smoke. There is, however, no experimental proof for the involvement of alcohol as data on mutational spectrum induced by AA in human genes is completely lacking. The aim of this study is to investigate whether AA leaves mutational fingerprint in the HPRT reporter gene in human peripheral T cells. Pre-existing in vivo HPRT mutants were removed from PHA-stimulated T lymphocytes before in vitro treatment with 2.4 mM AA for 24 h. Following cell growth to allow mutation expression, independent 6-thioguanine-resistant mutants were selected from large numbers of subcultures showing a 3-fold induction of mutant frequency on average. A total of 73 induced and 36 spontaneous mutants were found to carry a missense, nonsense, frameshift or splice mutation. Base substitutions were identified in the coding or splicing sequences of 55 induced and 26 control mutants. The induced base changes were mainly G > A transition (40%, G on non-transcribed strand) followed by A > T transversions (14.5%, A on non-transcribed strand). The control mutants had significantly (P = 0.04) less G > A transition (15.4%) and completely lacked A > T transversions. We also identified 5'-AGG-3' or 5'-AAG-3' as potential target sequences for AA-induced G > A transitions. This specific mutational spectrum induced by AA is consistent with the known formation and persistency of N(2)-ethyl-2'-guanosine adduct and with the predominance of G > A transitions and mutations at A:T base pairs in the p53 gene of esophageal tumors. We conclude that AA may be involved in the pathogenesis of esophageal cancer.
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PMID:Mutational spectrum induced by acetaldehyde in the HPRT gene of human T lymphocytes resembles that in the p53 gene of esophageal cancers. 1169 45

Acetaldehyde (AA) is the major metabolite of ethanol and may be responsible for an increased gastrointestinal cancer risk associated with alcohol beverage consumption. Furthermore, AA is one of the most abundant carcinogens in tobacco smoke and induces tumors of the respiratory tract in laboratory animals. AA binding to DNA induces Schiff base adducts at the exocyclic amino group of dG, N2-ethylidene-dG, which are reversible on the nucleoside level but can be stabilized by reduction to N2-ethyl-dG. Mutagenesis studies in the HPRT reporter gene and in the p53 tumor suppressor gene have revealed the ability of AA to induce G-->A transitions and A-->T transversions, as well as frameshift and splice mutations. AA-induced point mutations are most prominent at 5'-AGG-3' trinucleotides, possibly a result of sequence specific adduct formation, mispairing, and/or repair. However, DNA sequence preferences for the formation of acetaldehyde adducts have not been previously examined. In the present work, we employed a stable isotope labeling-HPLC-ESI+-MS/MS approach developed in our laboratory to analyze the distribution of acetaldehyde-derived N2-ethyl-dG adducts along double-stranded oligodeoxynucleotides representing two prominent lung cancer mutational "hotspots" and their surrounding DNA sequences. 1,7,NH 2-(15)N-2-(13)C-dG was placed at defined positions within DNA duplexes derived from the K-ras protooncogene and the p53 tumor suppressor gene, followed by AA treatment and NaBH 3CN reduction to convert N2-ethylidene-dG to N2-ethyl-dG. Capillary HPLC-ESI+-MS/MS was used to quantify N2-ethyl-dG adducts originating from the isotopically labeled and unlabeled guanine nucleobases and to map adduct formation along DNA duplexes. We found that the formation of N2-ethyl-dG adducts was only weakly affected by the local sequence context and was slightly increased in the presence of 5-methylcytosine within CG dinucleotides. These results are in contrast with sequence-selective formation of other tobacco carcinogen-DNA adducts along K-ras- and p53-derived duplexes and the preferential modification of endogenously methylated CG dinucleotides by benzo[a]pyrene diol epoxide and acrolein.
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PMID:Sequence distribution of acetaldehyde-derived N2-ethyl-dG adducts along duplex DNA. 1786 47

Chronic alcohol consumption is a major risk factor for upper aero-digestive tract cancers, including cancer of the esophagus. Whereas alcohol as such is not thought to be directly carcinogenic, acetaldehyde, its first metabolite, has been proven genotoxic and mutagenic in the HPRT gene. As mutations in the tumour suppressor gene TP53 are the most common genetic alterations involved in human cancers, especially esophageal tumours, the aim of this work was to establish the mutational pattern induced by acetaldehyde in vitro on the TP53 gene, and to compare this pattern with that found in human alcohol-related tumours. For this purpose, we used a functional assay in yeast, the FASAY (functional analysis of separated alleles in yeast), after in vitro exposure of human normal fibroblasts AG1521 to acetaldehyde. We noted 35 mutations, of which 32 were single-nucleotide substitutions including 2 nonsense and 30 missense mutations. The pattern showed that the main mutations were G>A transitions (n=23, of which 14 in CpG sites), followed by G>T transversions (n=4), A>G transitions (n=2) and A>T transversions (n=2). Other mutations were one-base insertion and two deletions, leading to frameshifts. Eleven mutations (31%) were located in TP53 hot-spots in codons 245, 248, 249 and 273. Finally, we compared this pattern with that found for esophageal cancers in humans. These results support the notion that acetaldehyde plays a role in TP53 mutations in esophageal cancers. The key feature of this approach is that mutagenesis is directly studied in a key gene in human carcinogenesis, allowing direct comparison of mutational patterns with those in human tumours.
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PMID:Acetaldehyde-induced mutational pattern in the tumour suppressor gene TP53 analysed by use of a functional assay, the FASAY (functional analysis of separated alleles in yeast). 1824 17

Vinyl acetate monomer (VAM) produced rat nasal tumors at concentrations in the hundreds of parts per million. However, VAM is weakly genotoxic in vitro and shows no genotoxicity in vivo. A European Union Risk Assessment concluded that VAM's hydrolysis to acetaldehyde (AA), via carboxylesterase, is a critical key event in VAM's carcinogenic potential. In the following study, we observed increases in micronuclei (MN) and thymidine kinase (Tk) mutants that were dependent on the ability of TK6 cell culture conditions to rapidly hydrolyze VAM to AA. Heat-inactivated horse serum demonstrated a high capacity to hydrolyze VAM to AA; this activity was highly correlated with a concomitant increase in MN. In contrast, heat-inactivated fetal bovine serum (FBS) did not hydrolyze VAM and no increase in MN was observed. AA's ability to induce MN was not impacted by either serum since it directly forms Schiff bases with DNA and proteins. Increased mutant frequency at the Tk locus was similarly mitigated when AA formation was not sufficiently rapid, such as incubating VAM in the presence of FBS for 4 hr. Interestingly, neither VAM nor AA induced mutations at the HPRT locus. Finally, cytotoxicity paralleled genotoxicity demonstrating that a small degree of cytotoxicity occurred prior to increases in MN. These results established 0.25 mM as a consistent concentration where genotoxicity first occurred for both VAM and AA provided VAM is hydrolyzed to AA. This information further informs significant key events related to the mode of action of VAM-induced nasal mucosal tumors in rats.
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PMID:Nonlinear responses for chromosome and gene level effects induced by vinyl acetate monomer and its metabolite, acetaldehyde in TK6 cells. 2403 27

Vinyl laurate is a potential residual monomer in chewing gum base formulated with polyvinyl acetate vinyl laurate copolymer (PVAcVL). The genotoxic potential of vinyl laurate was examined in a battery of in vitro and in vivo genotoxicity tests. Vinyl laurate was not mutagenic in Ames tests. In addition, it was not mutagenic in the HPRT mutation assay in L5178Y cells. An in vitro mammalian chromosome aberration assay performed in CHO cells was equivocal. Vinyl laurate and/or its metabolites were not clastogenic in the mouse bone marrow micronucleus test. Kinetic data indicate that VL is metabolised to acetaldehyde and lauric acid. Both metabolites are well known and have been studied previously. Model calculations show, that any exposure to acetaldehyde from the consumption of PVAcVL containing chewing gum will remain far below levels of acetaldehyde exposure from food in which acetaldehyde occurs naturally. Direct exposure to VL will primarily be at the site of entry. The lack of toxicity in a 90-day repeated dose toxicity test, performed with VL doses up to approximately 3000 times higher than the maximal VL intake from the consumption of a typical piece of chewing gum, demonstrates a high safety margin.
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PMID:Evaluation of vinyl laurate in a battery of in vitro and in vivo tests for genotoxicity. 2544 1