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:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixty-eight independent hybrid clones were isolated after irradiated normal human lymphocytes were fused with Chinese hamster fibroblasts lacking hypoxanthine-guanine phosphoribosyltransferase activity. The cells were grown under selective conditions requiring retention of the X chromosome-linked locus for human hypoxanthine-guanine phosphoribosyltransferase. The frequency and patterns of cotransference of human phosphoribosylpyrophosphate synthetase with the selected marker and with additional X-linked enzymatic markers confirm X linkage of the structural gene for human phosphoribosylpyrophosphate synthetase and support assignment of this gene to a position on the long arm of the X, between the loci for alpha-galactosidase and hypoxanthine-guanine phosphoribosyltransferase.
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PMID:Regional localization of the gene for human phosphoribosylpyrophosphate synthetase on the X chromosome. 21 84

A series of 2'-O-acyl derivatives of 6-thioinosine cyclic 3',5'-phosphate (6-HS-cRMP) were prepared and examined for their cytotoxic effects on S49 mouse lymphoma cells which were deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRTase). Cytotoxicity increased with the lipophilicity of the acyl group to a lowest EC50 of 65 micrometer for the 2'-O-palmityl derivative. Addition of a mutation in the gene for cAMP-dependent protein kinase to the HGPRTase-deficient cell line confers resistance to 2'-O-butyryl-cAMP but not to 2'-O-butyryl-6-HS-cRMP, indicating that the latter does not exert its toxic effect via activation of protein kinase. The time course of cell kill by 2'-O-palmityl-6-HS-cRMP resembled that of 6-mercaptopurine and not that of cyclic AMP in these cells. The data suggest that the intact cyclic nucleotides are penetrating the cells and being converted, by phosphodiesterase action and deacylation, to the first toxic metabolite of 6-mercaptopurine, thioinosinic acid.
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PMID:2'-O-Acyl-6-thioinosine cyclic 3',5'-phosphates as prodrugs of thioinosinic acid. 22 58

The isolation and characterization of a mutant murine T-cell lymphoma (S49) with altered purine metabolism is described. This mutant, AU-100, was isolated from a mutagenized population of S49 cells by virtue of its resistance to 0.1 mM 6-azauridine in semisolid agarose. The AU-100 cells are resistant to adenosine mediated cytotoxicity but are extraordinarily sensitive to killing by guanosine. High performance liquid chromatography of AU-100 cell extracts has demonstrated that intracellular levels of GTP, IMP, and GMP are all elevated about 3-fold over those levels found in wild type cells. The AU-100 cells also contain an elevated intracellular level of pyrophosphoribosylphosphate (PPriboseP), which as in wild type cells is diminished by incubation of AU-100 cells with adenosine. However AU-100 cells synthesize purines de novo at a rate less than 35% of that found in wild type cells. In other growth rate experiments, the AU-100 cell line was shown to be resistant to 6-thioguanine and 6-mercaptopurine. Levels of hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) measured in AU-100 cell extracts, however, are 50-66% greater than those levels of HGPRTase found in wild type cell extracts. Nevertheless this mutant S49 cell line cannot efficiently incorporate labeled hypoxanthine into nucleotides since the salvage enzyme HGPRTase is inhibited in vivo. The AU-100 cell line was found to be 80% deficient in adenylosuccinate synthetase, but these cells are not auxotrophic for adenosine or other purines. The significant alterations in the control of purine de novo and salvage metabolism caused by the defect in adenylosuccinate synthetase are mediated by the resulting increased levels of guanosine nucleotides.
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PMID:Abnormal regulation of de novo purine synthesis and purine salvage in a cultured mouse T-cell lymphoma mutant partially deficient in adenylosuccinate synthetase. 22 75

Hypoxanthine-guanine phosphoribosyltransferase (HGPR transferase) (EC 2.4.2.8) has been purified approximately 4500-fold to apparent homogeneity from mouse liver. The procedure involves the use of affinity chromatography and was designed to be readily adaptable to small scale isolations. The enzyme appears to be composed of 3 subunits of identical molecular weight (27,000 per subunit). The subunit molecular weight has also been determined by the analysis of radioactively labeled HGPR transferase immunoprecipitated from wild type and mutant (HGPR transferase) mouse tissue culture cell lines.
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PMID:Purification and characterization of mouse hypoxanthine-guanine phosphoribosyltransferase. 23 83

To study the role of purine ribonucleotides as possible regulators of the rate of de novo purine biosynthesis in living human cells, we measured intracellular ribonucleotide concentrations by high-pressure liquid chromatography in a series of cloned human lymphoblast mutants selected by resistance to 8-azaguanine, in which the severity of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency could be correlated with increases in the rate of de novo purine biosynthesis and increases in intracellular concentrations of phosphoribosyl pyrophosphate (PP-ribose-P). Compared with appropriate normal controls, intracellular purine ribonucleotide concentrations were not reduced in HGPRT-deficient lymphoblasts but there were striking increases in intracellular concentrations of some pyrimidine nucleotides and nucleotide sugars which appeared to be related to the degree of the deficiency. Similar changes were found in lymphoblasts from a Lesch-Nyhan boy. These data support the hypothesis that the accelerated rate of purine biosynthesis in HGPRT-deficient cells result from increases in intracellular PP-ribose-P concentration and not from changes in intracellular purine ribonucleotide concentrations. The possibility that the abnormality of pyrimidine nucleotide metabolism results from coordinate regulation of purine and pyrimidine biosynthesis by PP-ribose-P was not substantiated by measurement of rates of pyrimidine synthesis and experimental elevation of intracellular concentrations of PP-ribose-P after incubation of cells with inorganic phosphate.
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PMID:Purine and pyrimidine nucleotides in some mutant human lymphoblasts. 24 91

The possible factors in the pathogenesis of the brain damage and megaloblastic anaemia in the Lesch-Nyhan syndrome are discussed. Disordered growth and function appear to be limited to the brain, bone marrow and general body stature, yet the purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8, HGPRT), although present in variable amounts in different tissues, is ubiquitous, a fact which suggests that other factors than HGPRT deficiency alone determine the pattern of tissue damage. Recent evidence suggests that the specific tissue damage in the Lesch-Nyhan syndrome is due to lack of NGPRT in tissues with relatively reduced purine de novo capability and a greater dependence on purine salvage pathways at certain stages in their development for their supply of purine ribonucleotides. This evidence is presented together with possible mitigating factors operating in the bone marrow.
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PMID:Factors in the pathogenesis of the brain damage and anaemia in the Lesch-Nyhan syndrome. 24 94

Heterozygotes for the Lesch-Nyhan syndrome have normal hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity in their erythrocyte lysates. However, HGPRT activity in lysates from heterozygotes for the partial HGPRT deficiency states is often between that seen in the affected hemizygote and the normal. An autoradiographic technique was developed which demonstrated the HGPRT activity in individual erythrocytes in vitro. This technique revealed that heterozygotes for the Lesch-Nyhan syndrome had erythrocytes that contained normal HGPRT activity but heterozygotes for the partial deficiency had two populations of erythrocytes, one with normal HGPRT activity and the other with the reduced HGPRT activity characteristic of the hemizygote. With these latter heterozygotes, the proportion of HGPRT-deficient erythrocytes agreed with that calculated on the basis of enzyme activity in erythrocyte lysates.
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PMID:Hypoxanthine-guanine phosphoribosyltransferase activity in individual erythrocytes: autoradiographic studies in heterozygotes. 24 95

Hypoxanthine phosphoribosyltransferase (HPRT, IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) can be purified 5-to 10,000-fold from extracts of HeLa (human) cells by a three-step procedure consisting of high-speed centrifugation, adsorption to Sepharose-conjugated HPRT antibody, and sodium dodecyl sulfate/polyacrylamide gel electrophoresis. Purified enzyme labeled in vivo with radioactive lysine, arginine, or methionine was digested with trypsin and the tryptic peptides were separated by column chromatography on Bio-Rad cation exchanger Aminex A-5. Less than 50 ng (2 pmol) of HPRT is required to produce a tryptic peptide pattern. A methionine-labeled peptide was identified as the COOH-terminus because it was not labeled with either lysine or arginine. We have compared the tryptic peptide patterns of normal HeLaHPRT and a crossreacting HPRT protein lacking enzyme activity from HeLa mutant H23 [Milman et al. (1976) Proc. Natl. Acad. Sci. USA 73, 4589--4593]. The mutant protein has a new lysine-labeled peptide, but the chromatography patterns of arginine- or methionine-labeled peptides appear identical to those of the normal protein. The appearance in the H23 mutant HPRT protein of a new tryptic peptide provides strong evidence for a mutation in the HPRT structural gene. The tryptic peptide patterns were used to determine the total number of residues of labeled amino acid in the protein, and the values are reasonably consistent with those determined by conventional amino acid analysis pf erythrocyte HPRT.
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PMID:Tryptic peptide analysis of normal and mutant forms of hypoxanthine phosphoribosyltransferase from HeLa cells. 26 86

The human hypoxanthine phosphoribosyl-transferase (IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) gene (hprt) has been serially transferred to mouse cells and then to Chinese hamster fibroblasts by two cycles of metaphase chromosome isolation and incubation with recipient cells. Human metaphase chromosomes were incubated with mouse A9 cells deficient in hypoxanthine phosphoribosyltransferase, and independent colonies expressing the human species form of this gene were isolated in a selective medium. Metaphase chromosomes isolated from two of these clonal lines were incubated with Chinese hamster fibroblasts deficient in hypoxanthine phosphoribosyltransferase; five resulting independent colonies again expressed the human species of this gene. The transfer frequencies in the two cycles of chromosome-mediated gene transfer were similar (about 10(-7)). These results indicate that the transferred human chromosome fragment is closely associated with the chromosomes of the mouse A9 cells and it is probably integrated into the chromosomal DNA of the recipient cell.
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PMID:Serial transfer of a human gene to rodent cells by sequential chromosome-mediated gene transfer. 26 45

Trispecific microcell hybrids were prepared by transferring limited numbers of chromosomes from a human/mouse gene-transfer cell line to a Chinese hamster recipient line. The donor cells employed were murine L-cells that stably expressed the human form of the enzyme hypoxanthine phosphoribosyltransferase. Karyotypic, zymographic, and back-selection tests of the resulting human/mouse/Chinese hamster microcell hybrids provided strong genetic evidence for a stable association of the human transgenome with host murine chromosomes in stable gene-transfer cell lines. This association, which may represent physical integration of the transgenome into the host cell genome, occurred at multiple chromosomal sites.
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PMID:Stable association of the human transgenome and host murine chromosomes demonstrated with trispecific microcell hybrids. 26 44


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