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)

HL-60 human acute promyelocytic leukemia cells that lack hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity have been developed by mutagenization and selection. These cells exhibited markedly decreased sensitivity to the cytotoxic action of 6-thioguanine (TG) and, in contrast to parental HL-60 cells, had the capacity to undergo terminal granulocytic differentiation after treatment with this purine antimetabolite. Analysis of extracellular and intracellular metabolites of TG revealed negligible metabolism of TG in these HGPRT- HL-60 cells. These findings are consistent with the concept that inhibition of cellular replication requires generation of analog nucleotide and suggest that TG itself is capable of initiation of differentiation. 6-Thioguanosine (TGuo) had limited activity, while beta-2'-deoxythioguanosine (dTGuo) was inactive, as an inducer of maturation of HGPRT- HL-60 cells. These cells converted relatively large amounts of the nucleosides to the free base TG; the simultaneous exposure of cells to 8-aminoguanosine (AGuo), an inhibitor of purine nucleoside phosphorylase activity, decreased the degradation of TGuo and dTGuo to TG and promoted the intracellular accumulation of TG nucleotides, presumably through the action of nucleoside kinase activities. In a double mutant deficient in both HGPRT and deoxycytidine kinase (DCK) activities, dTGuo was devoid of cytotoxicity and was an effective inducer of maturation. The potency of dTGuo as an inducer in this system was not significantly affected by the presence of AGuo. These results suggested that dTGuo itself was also an active initiator of maturation. Thus, induction of differentiation appeared to be due to the free base, TG, as well as its deoxynucleoside form, dTGuo, whereas the formation of TG nucleotides appeared to antagonize maturation and produce cytotoxicity.
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PMID:Characterization of the metabolic forms of 6-thioguanine responsible for cytotoxicity and induction of differentiation of HL-60 acute promyelocytic leukemia cells. 659 22

The value of the uric acid to creatinine ratio and the uric acid to creatinine clearance ratio in predicting 24-hour urinary uric acid excretion was assessed in 49 patients with normal enzyme activity and 22 patients with purine enzyme deficiencies. A 24-hour urinary uric acid to creatinine ratio greater than 0.75 was found in six of nine patients with a partial deficiency of hypoxanthine-guanine phosphoribosyltransferase and in all patients with Lesch-Nyhan syndrome. A ratio of less than 0.10 suggested xanthinuria or severe purine nucleoside phosphorylase deficiency. Neither ratio calculated from 2-hour timed collections of the 24-hour specimen showed a high correlation with 24-hour urine uric acid excretion in patients with normal enzyme activity, perhaps because of a diurnal variation in urinary uric acid excretion. The spot-urine uric acid to creatinine ratio does not accurately predict the 24-hour urine uric acid excretion in patients with normal enzyme activity.
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PMID:Limited value of uric acid to creatinine ratios in estimating uric acid excretion. 677 79

We have examined the basis for the recently reported, but unexplained deficiency of S-adenosylhomocysteine hydrolase (AdoHcyase) in the erythrocytes of patients with genetic deficiencies of purine nucleoside phosphorylase and hypoxanthine-guanine phosphoribosyltransferase. We found that a hemolysate from a patient with purine nucleoside phosphorylase deficiency had only 7% of control AdoHcyase activity, conforming the original observation. Of the purine nucleosides known to accumulate in nucleoside phosphorylase-deficient patients, inosine alone caused the phosphate-dependent, irreversible inactivation of purified human placental AdoHcyase, and of AdoHcyase in intact erythrocytes and cultured lymphoblastoid cells. Hypoxanthine did not inactivate purified AdoHcyase, but potentiated the effect of inosine in intact hypoxanthine-guanine phosphoribosyltransferase-deficient human lymphoblastoid cells. This presumably resulted from the ability of hypoxanthine to shift the equilibrium of the nucleoside phosphorylase reaction, preventing inosine breakdown. This could account for the partial AdoHcyase deficiency reported in hypoxanthine-guanine phosphoribosyltransferase-deficient patients. We have also demonstrated the AdoHycase-catalyzed synthesis of S-inosylhomocysteine from inosine and L-homocysteine, a reaction which may occur in nucleoside phosphorylase-deficient patients.
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PMID:Proposed explanation for S-adenosylhomocysteine hydrolase deficiency in purine nucleoside phosphorylase and hypoxanthine-guanine phosphoribosyltransferase-deficient patients. 678 20

Several aspects of purine metabolism were studied in peripheral blood mononuclear cells and fibroblasts from a patient with purine nucleoside phosphorylase deficiency and compared to cells from normal controls. Intact cells were incubated with radioactive purine bases and all purine metabolites were extracted and analyzed. Incubation of purine nucleoside phosphorylase-deficient cells with [3H]hypoxanthine and [3H]guanine resulted in the accumulation of large proportions of the incorporated radioactivity into inosine (60-80%) and to lesser extent into guanosine (15-30%), respectively, whereas normal cells accumulated only minor amounts of inosine and guanosine. This observation indicates that purine nucleoside phosphorylase, together with hypoxanthine-guanine phosphoribosyltransferase and nucleoside monophosphate phosphatase, participate in remarkably active inosine and guanosine cycles. These purine nucleoside cycles may play a role in the regulation of intracellular purine nucleotide levels. The absence of these cycles in purine nucleoside phosphorylase-deficient patients may be detrimental to the differentiation of lymphocytes.
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PMID:Evidence for active purine nucleoside cycles in human mononuclear cells and cultured fibroblasts. 681 84

Adenosine deaminase (ADA), purine nucleoside phosphorylase (PNP), and hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activities were measured in normal human B lymphocytes, T lymphocytes, and T gamma and T mu lymphocyte subsets. Total ADA activity in T cells was 5.5U, activity in T gamma and T mu cells was 3.7U and 5.3U, respectively; B cell ADA levels were 3.3U. PNP activity in T cells was 119U, activity in T gamma and T mu cells was 75U and 155U, respectively. B cell PNP activity was 88U. HGPRT activity in T cells was 20.9U; T gamma and T mu HGPRT levels were 13.0U and 52U respectively. B cell HGPRT levels were 46.8U. These data provides further evidence for the biochemical heterogeneity of normal human lymphocytes.
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PMID:Adenosine deaminase, nucleoside phosphorylase and hypoxanthine-guanine phosphoribosyltransferase activity in normal lymphocyte subpopulations. 681 86

Both enzyme-mediated group translocation and facilitated diffusion have been proposed as mechanisms by which mammalian cells take up purine bases and nucleosides. We have investigated the mechanisms for hypoxanthine and inosine transport by using membrane vesicles from Chinese hamster ovary cells (CHO), Balb/c 3T3 and SV3T3 cells prepared by identical procedures. Uptake mechanisms were characterized by analyzing intravesicular contents, determining which substrates could exchange with the transport products, assaying for hypoxanthine phosphoribosyltransferase activity, and measuring the stimulation of uptake of hypoxanthine by phosphoribosyl pyrophosphate (PRib-PP). We found that the uptake of hypoxanthine in Balb 3T3 vesicles was stimulated 3--4-fold by PRib-PP. The intravesicular product was predominantly IMP. The hypoxanthine phosphoribosyltransferase activity copurified with the vesicle preparation. These results suggest the possible involvement of this enzyme in hypoxanthine uptake in 3T3 vesicles. In contrast to the 3T3 vesicles, CHO vesicles prepared under identical procedures did not retain hypoxanthine phosphoribosyltransferase activity and did not demonstrate PRib-PP-stimulated hypoxanthine uptake. The intravesicular product of hypoxanthine uptake in CHO vesicles was hypoxanthine. These results and data from our kinetic and exchange studies indicated that CHO vesicles transport hypoxanthine via facilitated diffusion. An analogous situation was observed for inosine uptake; CHO vesicles accumulated inosine via a facilitated diffusion mechanism, while in the same experiments SV3T3 vesicles exhibited a purine nucleoside phosphorylase-dependent translocation of the ribose moiety of inosine. Vesicles prepared from a CHO cell line temperature-sensitive for hypoxanthine uptake (Azarts) showed a temperature-sensitivity in Km for uptake parallel to that of the intact cells. This suggests that the defect in Azarts may be caused by a missense mutation in the gene coding for the hypoxanthine transport carrier.
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PMID:Distinct mechanisms of hypoxanthine and inosine transport in membrane vesicles isolated from Chinese hamster ovary and Balb 3T3 cells. 722 83

1. We have studied purine metabolism in renal failure using high-pressure liquid chromatography to determine metabolite concentrations in erythrocytes and plasma, and microradiochemical assays of enzyme activity in erythrocytes. 2. The mean activities of some of the enzymes involved in purine metabolism were raised in renal failure. Significant elevations of adenylate kinase (EC 2.7.4.3), purine nucleoside phosphorylase (EC 2.4.2.1), hypoxanthine phosphoribosyltransferase (EC 2.4.2.8) and adenosine deaminase (EC 3.5.4.4) but not of adenine phosphoribosyltransferase (EC 2.4.2.7) and ribosephosphate pyrophosphokinase (phosphoribosylpyrophosphate synthetase; EC 2.7.6.1) activities were demonstrated. However, there was an overlap between results from patients with renal failure and normal (control) subjects. Erythrocyte phosphoribosylpyrophosphate levels were also unchanged. 3. Erythrocyte nucleotide concentrations especially those of inosine were raised in renal failure. 4. The plasma inosine was reduced in renal failure. 5. The significance of these changes is discussed.
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PMID:Effect of renal failure on erythrocyte purine nucleotide, nucleoside and base concentrations and some related enzyme activities. 729 37

Information on a familial syndrome of hyperuricemia and renal disease with or without gout was obtained on 33 of 41 blood relatives: Nine had renal disease; abnormalities of the urinary sediments were minimal; serum uric acid levels were elevated in seven and were not measured in two. Hyperuricemia was noted in three additional family members without evidence of renal disease. Goulty arthritis (three patients) did not precede renal disease. One individual had hyperuricosuria. The following erythrocyte purine enzyme levels were normal: adenine phosphoribosyltransferase, hypoxanthine-guanine phosphoribosyltransferase, phosphoribosylpyrophosphate, synthetase, adenosine deaminiase, and purine nucleoside phosphorylase. Renal biopsy specimens showed focal global and segmental sclerosis of glomeruli, occasional hypercellularity, foci of atrophic tubules, chronic interstitial inflammation, and folding and wrinkling of glomerular basement membrane without electron-dense deposits. There were no immunofluorescent abnormalities.
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PMID:Familial hyperuricemia and renal disease. 739 93

The activity of inosine monophosphate dehydrogenase (IMPDH: EC 1.2.1.14) was measured in erythrocyte lysates using a non-radiolabelled method linked to reversed-phase liquid chromatography (RPLC). The mean activity in erythrocytes from healthy controls using this sensitive method was extremely low (mean 85 pmol/h per mg protein, range 4-183). The elevated erythrocyte IMPDH activity reported previously in hypoxanthine-guanine phosphoribosyltransferase (HPRT) deficiency was confirmed (mean 234 pmol/h per mg protein). Erythrocyte IMPDH activity of patients with other disorders of purine metabolism, or with leukaemias and lymphomas, showed no marked difference from controls, except in one instance--an immunodeficient child with purine nucleoside phosphorylase (PNP) deficiency, treated with Ribavirin, where a 30-fold increase in activity was found (2670 pmol/h per mg protein). Investigation of erythrocyte IMPDH in other immunodeficient children with normal PNP activity demonstrated that this grossly elevated erythrocyte activity was attributable to induction of IMPDH by Ribavirin therapy.
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PMID:Demonstration of induction of erythrocyte inosine monophosphate dehydrogenase activity in Ribavirin-treated patients using a high performance liquid chromatography linked method. 758 76

Purine enzyme activities are usually assayed by radiochemical procedures and often TLC is part of the separation method. In screening patients with rheumatic diseases, these procedures have shown disadvantages like a relatively large coefficient of variation (C.V.) and time-instability. We describe a non-radiochemical reversed-phase HPLC micro-method with UV detection for measurement of activities of purine 5'-nucleotidase (5'NT; EC 3.1.3.5), purine nucleoside phosphorylase (PNP; EC 2.4.2.1) and hypoxanthine guanine phosphoribosyltransferase (HGPRT; EC 2.4.2.8) in human peripheral blood mononuclear cells (PBMC). The HPLC procedure is compared with the radiochemical TLC procedure by testing both with a 5'NT and a PNP assay. Reproducibility is tested with 14 healthy controls in each procedure. Short-term and long-term time-stability is tested by comparing enzyme activities measured immediately after preparation of the PBMC (week 0) with those found after freezing and storage at -20 degrees C for a maximum of 10 weeks. The HPLC procedure is preferable to the radiochemical TLC procedure because it shows significantly better reproducibility and better time-stability and in addition is non-radiochemical and less time-consuming.
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PMID:Purine enzyme activities in peripheral blood mononuclear cells: comparison of a new non-radiochemical high-performance liquid chromatography procedure and a radiochemical thin-layer chromatography procedure. 765 19


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