Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cell response to irradiation depends on many micro-environmental and intracellular factors. It is known that proteinases control many physiological functions and are also involved in progression of the cell cycle. They also could be involved in cell response to irradiation. In this work the influence of cathepsin B, which is one of the important lysosomal proteinases, and one of its inhibitors, leupeptin, on the potentially lethal damage repair (PLDR) was studied. Chinese hamster V79 cells were irradiated with gamma rays in the plateau-phase of growth. Immediately after irradiation cathepsin B or leupeptin were added to the growth medium. Four hours later, a determined sufficient period of time for maximal PLDR, the cells were replated to assess survival and mutation induction. Mutation frequency was determined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus using resistance to 6-thioguanine (6-TG). Simultaneously, the activity of cysteine, aspartic and serine proteinases were determined at different postirradiation intervals. The results show that when plateau-phase cells were incubated with cathepsin B during the postirradiation interval strong inhibition of PLDR was observed, accompanied with a reduced number of 6-TG resistant mutants. If leupeptin was added, more modest inhibition of PLDR was observed, accompanied with only slight reduction in the mutation frequency. The addition of cathepsin B or leupeptin to irradiated cells modified the activities of intracellular proteinases. As the highest alterations in proteinase activities were observed at the time when maximum repair of DNA lesions occurred, the biological consequences could involve a series of sequential steps in intracellular proteinase activities.
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PMID:The influence of cathepsin B and leupeptin on potentially lethal damage repair in mammalian cells. 264 61

Hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) (HGPRT) of human red blood cells has been separated into three major isoenzymes, the relative quantities of which change as the cell ages. The predominant isoenzyme in the youngest circulating red blood cells, reticulocytes, has the same isoelectric point as the single enzyme of lymphoblasts. This lymphoblast-like enzyme is diminished in older red cells, and the major fraction of HGPRT activity is recovered in the two more acidic isoenzymes. The HGPRT enzymes of human lymphoblasts and red cells have been purified to apparent homogeneity, as evidenced by the criterion of subunit molecular weight in NaDodSO4 gels. The lymphoblast enzyme dissociates to a single subunit (alpha) upon isoelectric focusing in 8 M urea and is presumed to be a homo dimer (alpha alpha). The red cell isoenzymes dissociate to two subunits, one with the same isoelectric point as that in lymphoblasts (alpha) and one more negatively charged (alpha'). We infer that the three major red cell isoenzymes, I-III, correspond to enzyme species with none (alpha alpha), one (alpha alpha'), or both (alpha' alpha') subunits modified. Tryptic peptide maps of these iodo[2-14C]acetamide-labeled enzyme subunits indicate that the one red cell subunit (alpha) is identical with that in lymphoblasts and that the second subunit (alpha') differs from these in only one of the five cysteine-containing tryptic peptides. These results indicate that the HGPRT subunit is subject to at least one covalent and site-specific modification in human erythroid cells.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase in human erythroid cells: posttranslational modification. 707 65

The ability of the potential chemopreventive agent S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) to protect against radiation-induced mutagenesis at the hprt locus and cell killing was studied using CHO-AA8 cells incubated for 30 min at 37 degrees C in growth medium containing its active thiol 2-[(aminopropyl)amino]ethane-thiol (WR-1065). In parallel experiments, the thiol and disulfide forms of the drug present in cells and incubation medium were determined in order to identify which, if either, of the components were associated with the observed protective effects. Treatment with 4 mM WR-1065 produced significant intracellular levels of the thiol (WRSH) and disulfide (WRSS) forms of the drug, but also caused dramatic elevation of cellular glutathione (GSH) and cysteine levels, accompanied by marked protection against 60Co gamma-photon- and neutron-induced cell killing and mutagenesis. When drug-treated cells were transferred to drug-free medium and incubated for 4 h at 37 degrees C, levels of WRSH and WRSS and protection against cell killing decreased markedly, whereas levels of GSH and cysteine and protection against mutagenesis showed little change. GSH and cysteine levels were not associated with protection against radiation-induced mutagenesis, as established by experiments performed with buthionine sulfoximine to block GSH synthesis. These data do not support the hypothesis that modulation of GSH or cysteine levels by WR-1065 is a major mechanism accounting for protection. Protection against mutagenesis was seen for cells incubated in medium with concentrations of added WR-1065 as low as 10 microM, where cellular levels of WRSH and WRSS became difficult to measure (< or = 5 microM) and no protection against cell killing was found. An unexpected observation was that cells incubated in 40 microM WR-1065 incorporated the drug much more rapidly than expected for uptake by passive diffusion and concentrated the drug to a marked degree; this indicates that a cell-mediated transport system is involved in the uptake of WR-1065 at low drug concentrations.
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PMID:Thiol and disulfide metabolites of the radiation protector and potential chemopreventive agent WR-2721 are linked to both its anti-cytotoxic and anti-mutagenic mechanisms of action. 772 53

Cysteine conjugate beta-lyase, an enzyme that converts cysteine S-conjugates to free thiols, pyruvate and ammonia, is normally expressed primarily in the liver and kidney. In theory, this selective distribution affords the opportunity to target thiol-containing drugs to these organs and, perhaps, to tumors derived from them. To assess the potential for delivery of such drugs to kidney-derived tissue, we have used a typical beta-lyase substrate, S-(2-benzothiazolyl)-L-cysteine, to measure the beta-lyase activity in normal and tumor tissue of kidneys removed from patients with renal carcinoma. Although considerable heterogeneity in enzyme activity levels was observed in normal and tumor-derived samples, a high proportion of tumor samples had enzyme activity that was at least 50% of that observed in adjacent normal tissue. Frequently, hypoxanthine-guanine phosphoribosyltransferase activity was observed to be greater in the tumor than in normal tissue. These results may aid in the development of therapy for renal carcinomas.
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PMID:Cysteine conjugate beta-lyase activity in human renal carcinomas. 776 99

Representatives of two classes of thiazolidine prodrug forms of the well-known radioprotective agents L-cysteine, cysteamine, and 2-[(aminopropyl)amino]ethanethiol (WR-1065) were synthesized by condensing the parent thiolamine with an appropriate carbonyl donor. Inherent toxicity of the prodrugs was assessed in V79 cells using a clonogenic survival assay. Protection against radiation-induced cell death was measured similarly after exposure to 0--8 Gy gamma ((137)Cs) radiation. Antimutagenic activity was determined at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus. All thiazolidine prodrugs exhibited less toxicity than their parent thiolamines, sometimes dramatically so. Protection against radiation-induced cell death was observed for the 2-alkylthiazolidine, 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine (RibCyst), which produced a protection factor at 8 Gy of 1.8; the cysteine analogue, 2(R,S)-D-ribo-(1',2',3',4'-tetrahydroxybutyl)thiazolidine-4(R)-carboxylic acid (RibCys), was less active. RibCyst also exhibited excellent antimutational activity, rivaling that of WR-1065. The 2-oxothiazolidine analogues showed little activity in either determination under the conditions tested, perhaps due to their enhanced chemical and biochemical stability.
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PMID:Thiazolidine prodrugs as protective agents against gamma-radiation-induced toxicity and mutagenesis in V79 cells. 1147 18

Epidemiological data have suggested an increased cancer rates in diabetic patients, for which the underlying mechanism is poorly understood. We studied whether high level of glucose (HG) treatment that mimic the hyperglycemic condition in diabetes mellitus is mutagenic. Mutagenesis studies were carried out at both hypoxanthine phosphoribosyltransferase (hprt) and thymidine kinase (tk) loci. Role of p53 in HG-induced mutagenesis was also investigated by using human lymphoblastoid cell lines derived from same donor but differs in p53 statuses; TK6 has wild-type p53, NH32 has null p53, and WTK1 has mutant p53 (ile237). In addition, we studied the influence of antioxidant treatment on HG-induced mutagenesis. Mutation fractions at both loci increased significantly in all three lines at 21 and 28 days after HG treatments. At tk locus, the increase of a class of mutants with normal growth rate is mainly responsible for the overall increased mutant fraction. Compared to TK6 cells, both NH32 and WTK1 cells showed an early onset of mutagenesis. Treatment of cells with antioxidant N-acetyl-L-cysteine partially reduced HG induced mutagenesis. This study is the first to indicate that HG is able to induce gene mutation which may be one of the important mechanisms of diabetes-associated carcinogenesis.
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PMID:High level glucose increases mutagenesis in human lymphoblastoid cells. 1784 82

Gout, a common form of inflammatory arthritis, is strongly associated with elevated uric acid concentrations in the blood (hyperuricemia). A recent study in Icelanders identified a rare missense single nucleotide polymorphism (SNP) in the ALDH16A1 gene, ALDH16A1*2, to be associated with gout and serum uric acid levels. ALDH16A1 is a novel and rather unique member of the ALDH superfamily in relation to its gene and protein structures. ALDH16 genes are present in fish, amphibians, protista, bacteria but absent from archaea, fungi and plants. In most mammalian species, two ALDH16A1 spliced variants (ALDH16A1, long form and ALDH16A1_v2, short form) have been identified and both are expressed in HepG-2, HK-2 and HK-293 human cell lines. The ALDH16 proteins contain two ALDH domains (as opposed to one in the other members of the superfamily), four transmembrane and one coiled-coil domains. The active site of ALDH16 proteins from bacterial, frog and lower animals contain the catalytically important cysteine residue (Cys-302); this residue is absent from the mammalian and fish orthologs. Molecular modeling predicts that both the short and long forms of human ALDH16A1 protein would lack catalytic activity but may interact with the hypoxanthine-guanine phosphoribosyltransferase (HPRT1) protein, a key enzyme involved in uric acid metabolism and gout. Interestingly, such protein-protein interactions with HPRT1 are predicted to be impaired for the long or short forms of ALDH16A1*2. These results lead to the intriguing possibility that association between ALDH16A1 and HPRT1 may be required for optimal HPRT activity with disruption of this interaction possibly contributing to the hyperuricemia seen in ALDH16A1*2 carriers.
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PMID:ALDH16A1 is a novel non-catalytic enzyme that may be involved in the etiology of gout via protein-protein interactions with HPRT1. 2334 97

Although cytotoxic alkylating agents possessing two electrophilic reactive groups are thought to act by cross-linking cellular biomolecules, their exact mechanisms of action have not been established. In cells, these compounds form a mixture of DNA lesions, including nucleobase monoadducts, interstrand and intrastrand cross-links, and DNA-protein cross-links (DPCs). Interstrand DNA-DNA cross-links block replication and transcription by preventing DNA strand separation, contributing to toxicity and mutagenesis. In contrast, potential contributions of drug-induced DPCs are poorly understood. To gain insight into the biological consequences of DPC formation, we generated DNA-reactive protein reagents and examined their toxicity and mutagenesis in mammalian cells. Recombinant human O(6)-alkylguanine DNA alkyltransferase (AGT) protein or its variants (C145A and K125L) were treated with 1,2,3,4-diepoxybutane to yield proteins containing 2-hydroxy-3,4-epoxybutyl groups on cysteine residues. Gel shift and mass spectrometry experiments confirmed that epoxide-functionalized AGT proteins formed covalent DPC but no other types of nucleobase damage when incubated with duplex DNA. Introduction of purified AGT monoepoxides into mammalian cells via electroporation generated AGT-DNA cross-links and induced cell death and mutations at the hypoxanthine-guanine phosphoribosyltransferase gene. Smaller numbers of DPC lesions and reduced levels of cell death were observed when using protein monoepoxides generated from an AGT variant that fails to accumulate in the cell nucleus (K125L), suggesting that nuclear DNA damage is required for toxicity. Taken together, these results indicate that AGT protein monoepoxides produce cytotoxic and mutagenic DPC lesions within chromosomal DNA. More generally, these data suggest that covalent DPC lesions contribute to the cytotoxic and mutagenic effects of bis-electrophiles.
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PMID:DNA-reactive protein monoepoxides induce cell death and mutagenesis in mammalian cells. 2356 19

Phenylketonuria is a defect in phenylalanine metabolism resulting in the excretion of phenylketones and severe intellectual disability. The principle of eliminating the offending amino acid from the diet as a successful treatment strategy was demonstrated. The development of a low methionine diet to treat homocystinuria was established after identifying the transsulfuration pathway resulting in cysteine synthesis. Both conditions are examples of disorders of amino acid metabolism. Lesch-Nyhan syndrome, a rare disorder of purine metabolism resulting in intellectual disability and self-injurious behavior, is a classical inborn error of metabolism. Disorders of creatine biosynthesis are relatively newly described and less known diseases.
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PMID:Inborn Errors of Metabolism with Cognitive Impairment: Metabolism Defects of Phenylalanine, Homocysteine and Methionine, Purine and Pyrimidine, and Creatine. 2950 13