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)

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

Activities of orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase were found to be significantly higher in erythrocytes from newborn infants than in erythrocytes from adults, and approximated those observed in patients with deficiency of hypoxanthine-guanine phosphoribosyltransferase. Enzyme activities were increased to a varying extent in patients with reticulocytosis. The results are discussed in relation to red cell age and stabilization of the enzymes by phosphoribosylpyrophosphate. Pyrimidine-5'-nucleotidase was assayed by a new radiochemical method involving thin-layer chromatography for separation of product from substrate. Enzyme activity was higher with orotidine monophosphate than with uridine monophosphate. The activity of this enzyme was similar in erythrocyte of newborns and adults.
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PMID:Pyrimidine metabolism in erythrocytes of the newborn. 43 86

The incorporation of [14C]thymidine and [14C]uridine into the nucleoprotein, and [14C]phenylalanine into the protein by phytohaemagglutinin (PHA) stimulated lymphocytes from a patient with the Lesch-Nyhan syndrome [hypoxanthine-guanine phosphoribosyl transferase (EC 2.4.2.8 HGPRT) deficiency] and controls, was studied over 72 hours of incubation, with and without azaserine to block de novo purine biosynthesis. No difference was observed between the values obtained for Lesch-Nyhan and control lymphocytes, when PHA-stimulated without added azaserine. The percentage reduction in the incorporation of precursors into nucleoprotein and protein after PHA stimulation in the presence of azaserine was more obvious in the lymphocytes of the patient with the Lesch-Nyhan syndrome than in the controls after the shorter incubation periods at the lower rates of synthesis. Blocking the de novo purine biosynthetic pathway, in control PHA stimulated lymphocytes, inhibited transformation, whereas loss of the purine salvage enzyme HGPRT did not have this effect. These results are compatible with the view that the brain and bone-marrow damage that occur in the Lesch-Nyhan syndrome are the result of lack of HGPRT in tissues with little de novo purine biosynthetic capability. Other tissues with both pruine biosynthetic and salvage pathways are less vulnerable to the enzyme defect. Some possible mechanisms by which HGPRT deficiency could act are discussed. We suggest that inability to increase the supply of guanylic acid (GMP) in response to a mitotic stimulus may mediate the effect of HGPRT deficiency.
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PMID:Use of phytohaemagglutinin stimulated lymphocytes to study effects of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency on polynucleotide and protein synthesis in the Lesch-Nyhan syndrome. 93 18

We investigated the effect of high dose methotrexate (HDMTX) therapy on plasma hypoxanthine (Hx) and uridine (UR) concentrations in 12 children with acute lymphoblastic leukemia (ALL) or non-Hodgkin lymphoma (NHL). The initial plasma Hx level before the first administration of HDMTX (1 g/m2) was significantly higher in patients (25.5 +/- 17.5 microM) than that in healthy adult controls (4.0 +/- 1.4 microM). By 48 or 72 hours after the beginning of MTX infusion, the Hx concentration had decreased to 7.9 +/- 7.7 microM and 4.7 +/- 4.1 microM, respectively. This decrease of plasma Hx concentration after MTX infusion was also observed with the second course of HDMTX (3 g/m2) therapy. On the other hand, the plasma UR level did not change significantly. The in vitro treatment with 2 microM MTX of hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-deficient mutant cells selected from HL-60 lowered the excretion of Hx into the culture medium. These data suggest a possible new explanation of the synergism of HDMTX and 6-thiopurines, for example 6-mercaptopurine and 6-thioguanine, since plasma Hx is considered to counteract 6-thiopurine toxicity through competition at the level of HGPRT.
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PMID:Effect of high-dose methotrexate on plasma hypoxanthine and uridine levels in patients with acute leukemia or non-Hodgkin lymphoma in childhood. 143 5

Deficiency of uridine-5'-monophosphate (UMP) synthase in dairy cattle, a condition analogous to human hereditary orotic aciduria, is reviewed with consideration of similarities and differences between the enzyme deficiency in humans and cattle. New findings regarding the bovine condition are reported including presence of the enzyme deficiency in numerous tissues and absence of substantial effects on other aspects of nucleotide metabolism. Specifically, erythrocyte concentration of phosphoribosylpyrophosphate (PRPP) and activities of PRPP synthetase, adenine phosphoribosyltransferase, and hypoxanthine-guanine phosphoribosyltransferase appear to be normal in cattle heterozygous for UMP synthase deficiency.
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PMID:Deficiency of UMP synthase in dairy cattle: a model for hereditary orotic aciduria. 244 44

Human DNA was used to transform adenosine kinase (AK)-deficient BHK cells followed by selection of AK+ cells in medium containing alanosine, adenosine, and uridine (AAU medium). Twenty AAUr isolates were analyzed, and none of them contained AK activity. Several purine salvage enzymes were, however, found to be affected in these cells. The levels of hypoxanthine-guanine phosphoribosyltransferase and adenylosuccinate synthetase activities were elevated, while the adenylosuccinase activity was reduced. AAU-resistance may be explained by elevated activity of adenylosuccinate synthetase to overcome the alanosine block; thus AAUr cells were able to convert exogenous adenosine----inosine----hypoxanthine----IMP----AMPS----AMP. Moreover, these AAUr cells required exogenous purines for growth. HPLC analyses of endogenous nucleotide pools of AAUr cells showed that the levels of adenine nucleotides have diminished to less than 10% of the parental levels. These results suggest that the AAU-resistant mutation, which elicits pleiotropic phenotypes in BHK cells, affects an important component in the regulation of adenine nucleotide synthesis. By including erthyro-9-(2-hydroxy-3-nonyl)adenine in the AAU medium (renamed as AAUE medium) to block deamination of adenosine, AK+ BHK cells were isolated.
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PMID:Imbalance of purine nucleotides in alanosine-resistant baby hamster kidney cells. 253 26

The feasibility of using RNA synthesis in freshly isolated, human peripheral blood lymphocytes to detect 6-thioguanine (TG)- and 8-azaguanine (AG)-resistant variants in an autoradiographic assay similar to that of Strauss and Albertini (1979) has been evaluated. In phytohemagglutinin (PHA)-stimulated cultures RNA synthesis and HPRT activity began well in advance of DNA synthesis and increased in parallel during the first 44 h of culture. Introduction of TG or AG with PHA at the beginning of culture completely inhibited DNA synthesis during the first 44 h and reduced RNA synthesis to low levels within 24 h. When TG or AG was added after cells had been in culture for 38 h, DNA synthesis was reduced quickly while RNA synthesis was inhibited more slowly. An autoradiographic assay is described in which freshly isolated lymphocytes are cultured with PHA for 24 h, with or without TG or AG, then labeled with [3H]uridine for 1 h. TG-resistant and AG-resistant variant frequencies for 2 normal individuals and a Lesch-Nyhan individual were determined with this assay. The variant frequencies for the normal individuals ranged from 0.46 to 10.6 X 10(-5) depending upon the selective conditions used. All the Lesch-Nyhan cells were resistant to 0.2 microM-2 mM AG; some were sensitive to 0.2 mM TG and most were sensitive to 2.0 mM TG.
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PMID:Autoradiographic detection of HPRT variants of human lymphocytes resistant to RNA synthesis inhibition. 257 32

Giardia lamblia, an aerotolerant anaerobe, respires in the presence of oxygen by a flavin, iron-sulfur protein-mediated electron transport system. Glucose appears to be the only sugar catabolized by the Embden-Meyerhof-Parnas and hexose monophosphate pathways, and energy is produced by substrate level phosphorylation. Substrates are incompletely oxidized to CO2, ethanol and acetate by nonsedimentable enzymes. The lack of incorporation of inosine, hypoxanthine, xanthine, formate or glycine into nucleotides indicates an absence of de novo purine synthesis. Only adenine, adenosine, guanine and guanosine are salvaged, and no interconversion of these purines was detected. Salvage of these purines and their nucleosides is accomplished by adenine phosphoribosyltransferase, adenosine hydrolase, guanosine phosphoribosyltransferase and guanine hydrolase. The absence of de novo pyrimidine synthesis was confirmed by the lack of incorporation of bicarbonate, orotate and aspartate into nucleotides, and by the lack of detectable levels of the enzymes of de novo pyrimidine synthesis. Salvage appears to be accomplished by the action of uracil phosphoribosyltransferase, uridine hydrolase, uridine phosphotransferase, cytidine deaminase, cytidine hydrolase, cytosine phosphoribosyltransferase and thymidine phosphotransferase. Nucleotides of uracil may be converted to nucleotides of cytosine by cytidine triphosphate synthetase, but thymidylate synthetase and dihydrofolate reductase activities were not detected. Uptake of pyrmidine nucleosides, and perhaps pyrimidines, appears to be accomplished by carrier-mediated transport, and the common site for uptake of uridine and cytidine is distinct from the site for thymidine. Thymine does not appear to be incorporated into nucleotide pools. Giardia trophozoites appear to rely on preformed lipids rather than synthesizing them de novo.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Biochemistry and metabolism of Giardia. 265 35

Nucleoside and nucleobase transport and metabolism were measured in ATP-depleted and normal Aedes albopictus mosquito cells (line C-7-10) by rapid kinetic techniques. The cells possess a facilitated diffusion system for nucleosides, which in its broad substrate specificity and kinetic properties resembles that present in many types of mammalian cells. The Michaelis-Menten constant for uridine transport at 28 degrees C is about 180 microM. However, the nucleoside transporter of the mosquito cells is resistant to inhibition by nmolar concentrations of nitrobenzylthioinosine and the cells lack high affinity nitrobenzylthioinosine binding sites. The cells also possess an adenine transporter, which is distinct from the nucleoside transporter. They lack, however, a hypoxanthine transport system and are deficient in hypoxanthine phosphoribosyltransferase activity, which explains their failure to efficiently salvage hypoxanthine from the medium. The cells possess uridine and thymidine phosphorylase activities and, in contrast to cultured mammalian cells, efficiently convert uracil to nucleotides. An adenosine-resistant variant (CAE-3-6) of the C-7-10 cell line is devoid of significant nucleoside transport activity but transports adenine normally. Residual entry of various nucleosides into these cells and of hypoxanthine and cytosine into wild type and mutant cells is strictly non-mediated. The rate of permeation of various nucleosides and of hypoxanthine into the CAE-3-6 cells is related to their hydrophobicity. Uridine permeation into CAE-3-6 cells exhibits an activation energy of about 20 kcal/mol. At high uridine concentrations permeation is sufficiently rapid to partly overcome the limitation in nucleoside salvage imposed by the nucleoside transport defect in these cells.
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PMID:Nucleoside and nucleobase transport and metabolism in wild type and nucleoside transport-deficient Aedes albopictus cells. 381 94

Of 142 purines, purine nucleosides, and analogues tested for inhibition of growth of Escherichia coli B Hill, 45 were active. Of these, 27 were evaluated for inhibition of other E. coli lines, including those resistant to 6-thioguanine, 2-fluoroadenosine, 2,6-diaminopurine, or 6-mercaptopurine. Most toxic to the parent lines were 2-fluoroadenosine, 2-fluoroadenine, 2-fluoro-5'-deoxyadenosine, adenosine, 6-thioguanosine, 6-thioguanine, 6-mercaptopurine, 6-mercaptopurine ribonucleoside, 2-azaadenine, 2'-deoxyinosine, 6-N-aminoadenine, and inosine. Hypoxanthine was strongly inhibitory only to E. coli B Hill. Evidence regarding the substrate specificity of the three purine phosphoribosyltransferases was obtained by assaying for these enzymes in extracts of the various cell lines and by cross-resistance studies. The line selected for resistance to 6-thioguanine had low guanine phosphoribosyltransferase activity (guanosine monophosphate: pyrophosphate phosphoribosyltransferase, EC 2.4.2.8) and was deficient in activity for xanthine and 6-thioguanine. The lines selected for resistance to 2-fluoroadenosine and 2,6-diaminopurine were deficient in adenine phosphoribosyltransferase activity (adenosine monophosphate: pyrophosphate phosphoribosyltransferase, EC 2.4.2.7), and that selected for resistance to 6-mercaptopurine had low hypoxanthine phosphoribosyltransferase activity and undetectable activity with 6-mercaptopurine as a substrate. Purine, 6-methylpurine, 2-fluoroadenine, 2,6-diaminopurine, and 2-azaadenine were classified as adenine analogues; 6-mercaptopurine and 8-aza-2,6-diaminopurine, as hypoxanthine analogues; and 6-thioguanine and 2-amino-6-chloropurine, as analogues of guanine. The inhibition of bacterial growth by hypoxanthine, inosine, 2'-deoxyinosine, or adenosine was prevented by small amounts of thiamine or by relatively high concentrations of either cytidine or uridine. Cytidine also reversed the inhibition by some purine and purine ribonucleoside analogues. Orotate phosphoribosyltransferase (OMP: pyrophosphate phosphoribosyltransferase, EC 2.4.2.10), a possible site of action for these compounds, was not inhibited directly by the toxic agents.
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PMID:Use of Escherichia coli mutants to evaluate purines, purine nucleosides, and analogues. 459 16


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