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)

In the majority of patients with gout and excessive uric acid production, underlying enzyme abnormalities have not been identified. In the present study, measurement of both the rate of generation and concentration of phosphoribosylpyrophosphate (PP-ribose-P) and the concentration of ribose-5-phosphate in cultured cells were undertaken to establish a classification of purine overproducers to direct study of additional enzyme defects. Fibroblasts were cultured from 24 individuals assigned to 4 groups: group 1, 5 normal controls; group 2, 5 patients with gout and normal dialy urinary uric acid excretion (gouty controls); group 3, 7 patients with well-defined enzyme abnormalities and excessive urinary acid excretion (4 with hypoxanthine-guanine phosphoribosyltransferase deficiency and 3 with excessive PP-ribose-P synthetase activity); and group 4, 7 patients with gout and excessive uric acid excretion but without grossly abnormal activities of the above enzymes in erythrocyte lysates. In all 14 fibroblast strains from patients showing excessive production of uric acid (groups 3 and 4), rates of purine synthesis de novo and PP-ribose-P concentrations exceeded values for cells from control groups. Cells from group 3 patients with hypoxanthine-guanine phosphoribosyltransferase deficiency showed normal PP-ribose-P generation, while those with excessive PP-ribose-P synthetase activity demonstrated increased generation of this regulatory substrate. All strains from group 3 patients had normal ribose-5-phosphate concentrations. Five cell strains from group 4 patients showed one of the two patterns of abnormalities in these measurements seen in strains from group 3 patients: two resembled hypoxanthine-guanine phosphoribosyltransferase-deficient cells, and three resembled cells with excessive PP-ribose-P synthetase activity. Analyses of erythrocyte enzyme preparations from two of these patients in group 4 have led to identification of a kinetic variant of each enzyme as predicted from the foregoing patterns. Two additional group 4 cell lines that showed increased ribose-5-phosphate concentrations in addition to increased PP-ribose-P concentrations and generation were classified in a separate subgroup, since in the individuals excessive purine synthesis appeared to result from increases ribose-5-phosphate concentration, leading to increased availability of PP-ribose-P. No abnormality in either hypoxanthine-guanine phosphoribosyltransferase or PP-ribose-P synthetase has been found in erythrocyte preparations from one patient so classified.
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PMID:Patterns of phosphoribosylpyrophosphate and ribose-5-phosphate concentration and generation in fibroblasts from patients with gout and purine overproduction. 17 78

De novo purine biosynthesis has been studied in lymphocyte cell lines established from Lesch-Nyhan patients deficient in hypoxanthine-guanine phosphoribosyltransferase (HGPRT), in in vitro differentiating erythroleukaemic cell lines cloned from cells charactistic of virus-induced murine leukaemia, and in mutant hamster cells deficient in amidophosphoribosyltransferase. The relationship between cellular phosphoribosylpyrophosphate (PP-ribose-P) metabolism and the activity of the enzymes which catalyse the early steps of de novo purine biosynthesis has been explored. It was found that hamster cells deficient in amidophosphoribosyltransferase did not accumulate PP-ribose-P as do HGPRT-deficient cells. In these model systems, an accelerated rate of de novo purine biosynthesis tended to be associated with an increase in cellular PP-ribose-P cotent, but decreases in this rate results from the reduction in the activity of amidophosphoribosyltransferase. Regulation of ammonia-dependent de novo purine biosynthesis was similar to that of glutamine-dependent purine biosynthesis.
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PMID:Purine biosynthesis in mutant mammalian cells. 20 59

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

Mutagenized stem cells of a cultured mouse teratocarcinoma cell line were selected for resistance to the purine base analog 6-thioguanine. Cells of a resistant clone were completely deficient in activity of the enzyme hypoxanthine phosphoribosyltransferase (HPRT, IMP:pyrophosphate phosphoribosyltransferase, EC 2.4.2.8), the same X-linked lesion as occurs in human Lesch-Nyhan disease. After microinjection into blastocysts of another genetic strain, the previously malignant cells successfully participated in normal embryogenesis and tumor-free, viable mosaic mice were obtained. Cells of tumor lineage were identified by strain markers in virtually all tissues of some individuals. Mature function of those cells was evident from their tissue-specific products (e.g., melanins, liver proteins). These mutagenized teratocarcinoma cells are therefore developmentally totipotent. Retention of the severe HPRT deficiency in the differentiated state was documented in extracts of mosaic tissues by depressed specific activity of the enzyme, and also by presence of unlabeled clones in autoradiographs of explanted cells incubated in [(3)H]hypoxanthine. Some mosaic individuals had mutant-strain cells in only one or a few tissues. Such animals may provide unique opportunities to identify the tissue sources of particular aspects of the complex disease syndrome. The tissue distribution of HPRT-deficient cells suggests that selection against them is particularly strong in blood of the mosaic mice, as is already known to be the case in human heterozygotes. This phenotypic parallelism supports the expectation that afflicted F(1) male mice that might be obtained from mutant germ cells can serve as a model of the human disease.
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PMID:Mosaic mice with teratocarcinoma-derived mutant cells deficient in hypoxanthine phosphoribosyltransferase. 27 82

A possible association between the Gilles de la Tourette and Lesch-Nyhan syndromes has recently been postulated. Fourteen patients with Tourette syndrome demonstrated no similarity to Lesch-Nyhan based upon patterns of inheritance, behavioral changes, or alterations of purine metabolism. Despite a strong male predominance, a sex-linked pattern of inheritance could not be confirmed. Self-mutilating behavior was found in 4 male patients but was readily differentiated from that characteristic of the Lesch-Nyhan syndrome. Quantitation of hypoxanthine-guanine phosphoribosyltransferase and isoelectric focusing of its isoenzymes produced results that were indistinguishable from those in controls. We speculate that, pathophysiologically, Tourette syndrome represents an imbalance between the central neurotransmitters dopamine and serotonin rather than an alteration in purine metabolism.
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PMID:Gilles de la Tourette syndrome: further studies and thoughts. 27 3

The purine phosphoribosyltransferases have emerged as important enzymes in the metabolic economy of the developing human. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT, EC 2.4.2.8) catalyses the conversion of hypoxanthine and guinine into their respective nucleotides. Inherited variation in HGPRT first became evident through clinical observations with the definition of the Lesch-Nyhan syndrome. In this disorder, HGPRT activity in erythrocytes is almost zero, although the fact that sensitive electrophoretic analysis reveals a tiny amount of activity suggests that a protein of altered structure is present. Furthermore, this variant enzyme has been activated by manipulation in the presence of small amounts of normal enzyme. Nevertheless, no cross-reacting material could be detected in lysates of red cells or fibroblasts of patients with the syndrome when tested with antiserum prepared in rabbits to normal erythrocyte HGPRT. We have tested for the presence of cross-reacting material in 18 patients, and all were negative. More HGPRT variants are coming to light. Most of the patients have renal stone disease or gout but no other feature of the Lesch-Nyhan syndrome. In one family four affected males displayed about 5% of normal activity, and the enzyme migrated electrophoretically more rapidly than normal. Cross-reacting material could not be demonstrated in erythrocyte lysates, although it was clear that a variant protein was present. A boy with renal stone disease has been found to have about 1% of normal erythrocyte activity of HGPRT. Cross-reacting material was found in his erythrocytes. The data indicate that mutations which produce diminished enzyme activity in this protein with a distinct subunit structure may or may not so alter the tertiary state of the protein that immunoreactive sites are no longer available to antibody prepared against the normal enzyme. So far whenever a variant normal HGPRT has been found there has been an identifiable clinical illness. The different forms of illness provide for correlation of molecular structure and function in man.
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PMID:Genetic heterogeneity at the locus for hypoxanthine-guanine phosphoribosyltransferase. 30 34

Genetic defects in purine metabolism are associated with severe immunodeficiency. Adenosine deaminase deficiency impairs the function of both B- and T-lymphocytes whereas in purine nucleoside (inosine) phosphorylase deficiency there is more severe impairment of T-lymphocyte functions than of B-lymphocyte functions. The relative unimportance of the salvage pathway catalysed by hypoxanthine-guanine phosphoribosyltransferase is shown by the normal responses of T-lymphocytes from patients with the Lesch-Nyhan syndrome to antigenic and mitogenic stimulation. A mild deficiency of B-lymphocyte function is found in these patients. Agents inhibiting the de novo pathway of purine synthesis, including azaserine, 6-mercaptopurine and azathioprine in low doses, block the responses of normal human lymphocytes to mitogenic stimulation. These observations emphasize the importance of the de novo pathway of purine synthesis in lymphocyte responses to antigenic and mitogenic stimulation. There is considerable heterogeneity in the amount of labelled uridine incorporated into human and rat lymphocytes. This does not appear to reflect only a difference between T- and B-lymphocytes
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PMID:The role of de novo purine synthesis in lymphocyte transformation. 41 50

The contribution of reduced purine salvage to the hyperuricemia associated with hypoxanthine-guanine phosphoribosyltransferase deficiency was measured by the intravenous administration of tracer doses of [8-(14)C]adenine to nine patients with normal enzyme activity, three patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase, and six patients with the Lesch-Nyhan syndrome. The mean cumulative excretion of radioactivity 7 d after the adenine administration is 5.6+/-2.4, 12.9+/-0.9, and 22.3+/-4.7% of infused radioactivity for control subjects, partial hypoxanthine-guanine phosphoribosyltransferase-deficient subjects, and Lesch-Nyhan patients, respectively. To assess relative rates of nucleotide degradation in control and hypoxanthine-guanine phosphoribosyltransferase-deficient patients two separate studies were employed. With [8-(14)C]inosine administration, three control subjects excreted 3.7-8.5% and two enzyme-deficient patients excreted 26.5-48.0% of the injected radioactivity in 18 h. The capacity of the nucleotide catabolic pathway to accelerate in response to d-fructose was evaluated in control and enzyme-deficient patients. The normal metabolic response to intravenous fructose is a 7.5+/-4.2-mmol/g creatinine increase in total urinary purines during the 3-h after the infusion. The partial hypoxanthine-guanine phosphoribosyltransferase-deficient subjects and Lesch-Nyhan patients show increases of 18.6+/-10.8 and 17.3+/-11.8 mmol/g creatinine, respectively. Of the observed rise in purine exretion in control subjects, 40% occurs from inosine excretion and 32% occurs from oxypurine excretion. The rise in total purine excretion with Lesch-Nyhan syndrome is almost entirely accounted for by an elevated uric acid excretion. Increases in urine radioactivity after fructose infusion are distributed in those purines that are excreted in elevated quantities.The observations suggest that purine salvage is a major contributor to increased purine excretion and that the purine catabolic pathway responds differently to an increased substrate load in hypoxanthine-guanine phosphoribosyltransferase deficiency. The purine salvage pathway is normally an important mechanism for the reutilization of hypoxanthine in man.
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PMID:Overproduction of uric acid in hypoxanthine-guanine phosphoribosyltransferase deficiency. Contribution by impaired purine salvage. 44 34


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