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:2.4.2.7 (adenine phosphoribosyltransferase)
692 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The 5'-deoxy-5'-iodo-substituted analogs of adenosine and inosine are cytotoxic to tumor cells that have high activities of 5'-methylthioadenosine phosphorylase and purine nucleoside phosphorylase, respectively (Savarese, T.M., Chu, S-H., Chu, M.Y., and Parks, R. E., Jr. (1984) Biochem. Pharmacol. 34, 361-367). 5-Iodoribose 1-phosphate (5-IRib-1-P), the common intracellular metabolite of these 5'-iodonucleosides, has been synthesized enzymatically from 5'-deoxy-5'-iodoadenosine via adenosine deaminase from Aspergillus oryzae and human erythrocytic purine nucleoside phosphorylase. The purification and chemical properties of 5-IRib-1-P are described. The analog sugar phosphate inhibited purine nucleoside phosphorylase from human erythrocytes, phosphoglucomutase from rabbit muscle, and 5'-methylthioadenosine phosphorylase from Sarcoma 180 cells with Ki values of 26, 100, and 9 microM, respectively. Enzymes that react with 5-phosphoribosyl 1-pyrophosphate (P-Rib-PP), P-Rib-PP amidotransferase, hypoxanthine-guanine phosphoribosyltransferase, adenine phosphoribosyltransferase, and orotate phosphoribosyltransferase-orotidylate decarboxylase from extracts of Sarcoma 180 cells, were inhibited with Ki values of 49, 465, 307, and 275 microM, respectively. 5-IRib-1-P had no effect on P-Rib-PP synthetase. Since the Ki values of the analog sugar phosphate for 5'-methylthioadenosine phosphorylase and P-Rib-PP amidotransferase are much lower than the Km values of the natural substrates, Pi or P-Rib-PP which are reported to be present at nonsaturating concentrations under physiological conditions, these enzymes could be significantly inhibited by 5-IRib-1-P in intact cells.
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PMID:5-Iodoribose 1-phosphate, an analog of ribose 1-phosphate. Enzymatic synthesis and kinetic studies with enzymes of purine, pyrimidine, and sugar phosphate metabolism. 293 89

Cell extracts of Acholeplasma laidlawii B-PG9, Acholeplasma morum S2, Mycoplasma capricolum 14, and Mycoplasma gallisepticum S6 were examined for 37 cytoplasmic enzyme activities involved in the salvage and biosynthesis of purines. All of these organisms had adenine phosphoribosyltransferase activity (EC 2.4.2.7) and hypoxanthine phosphoribosyltransferase activity (EC 2.4.2.8). All of these organisms had purine-nucleoside phosphorylase activity (EC 2.4.2.1) in the synthetic direction using ribose-1-phosphate (R-1-P) or deoxyribose-1-phosphate (dR-1-P); this activity generated ribonucleosides or deoxyribonucleosides, respectively. The pyrimidine nucleobase uracil could also be ribosylated by using either R-1-P or dR-1-P as a donor. The synthesis of deoxyribonucleosides from nucleobases and dR-1-P has been reported from only one other procaryote, Escherichia coli (L. A. Mason and J. O. Lampen, J. Biol. Chem. 193:539-547, 1951). The reverse of this phosphorylase reaction is more widely known, and we found such activity in all mollicutes studied. Some Acholeplasma species but not the Mycoplasma species can phosphorylate deoxyribonucleosides to deoxyribomononucleotides by a PPi-dependent deoxyribonucleoside kinase activity, which was first reported in this group for the ribose analogs (V. V. Tryon and J. D. Pollack, Int. J. Syst. Bacteriol. 35:497-501, 1985). This is the first report of PPi-dependent purine deoxyribonucleoside kinase activity. An ATP-dependent purine deoxyribonucleoside kinase activity is known only in salmon milt extracts (H. L. A. Tarr, Can. J. Biochem. 42:1535-1545, 1964). Deoxyribomononucleotidase activity was also found in cytoplasmic extracts of these mollicutes. This is the first report of deoxyribomononucleotidase activity.
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PMID:Synthesis of deoxyribomononucleotides in Mollicutes: dependence on deoxyribose-1-phosphate and PPi. 303 46

We report a case of 2, 8-dihydroxyadenine (2, 8-DHA) urolithiasis. A 39-year-old female was referred to our hospital with the complaint of right flank pain. An X-ray examination showed right hydronephrosis. On May 1986, right percutaneous nephrolithotripsy was performed. Infrared spectroanalysis revealed 2, 8-DHA and calcium phosphate mixed calculus. The adenine phosphoribosyltransferase activity in erythrocytes was partially deficient. Since the operation, 300 mg/day of allopurinol has been administered, and there have been no signs of recurrence.
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PMID:[A case of 2,8-dihydroxyadenine stones with a partial deficiency of adenine phosphoribosyltransferase]. 304 75

5'-Deoxy-5'-methylthioadenosine phosphorylase (MTAPase) phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA) generated during polyamine biosynthesis to adenine and 5-methylthioribose-1-phosphate. Two doubly-substituted, 2-fluoroadenine-containing analogs of MTA, 5'-deoxy-2-fluoroadenosine (5'-dFAdo) and 5'-deoxy-5'-iodo-2-fluoroadenosine (5'-IFAdo), were synthesized and studied as substrates of MTAPase: their reaction with this enzyme resulted in the liberation of the cytotoxic base, 2-fluoroadenine, as well as potentially cytotoxic analogs of 5-methylribose-1-phosphate. The activities of these MTA analogs were compared to that of the singly-substituted analog, 5'-deoxy-5'-methylthio-2-fluoroadenosine (5'-MTFAdo). The cytotoxic action of these MTA analogs depended primarily on their conversion to 2-fluoroadenine-containing nucleotides, as a cell line that contains both MTAPase and adenine phosphoribosyltransferase (APRT) activity (HL-60 human promyelocytic leukemia) readily converted these MTA analogs to 2-fluoroadenine-containing nucleotides (especially 2-fluoroadenosine triphosphate) and was highly sensitive to the growth-inhibitory effects of all three compounds (IC50 values in the 10(-8) M range), whereas cell lines lacking MTAPase (CCRF-CEM human T-cell leukemia) or APRT (HL-60/aprt1 cells) did not form analog nucleotides and were relatively insensitive to these compounds (IC50 values in the 10(-5) M range). The doubly-substituted analogs were not more growth inhibitory than 5'-MTFAdo in wild type HL-60 cells as the potent effects of 2-fluoroadenine may mask the activity of the 5-methylthioribose-1-phosphate analogs generated in the reaction of these compounds with MTAPase. 5'-dFAdo and 5'-IFAdo also were irreversible inhibitors of S-adenosylhomocysteine hydrolase, which may explain in part the weak but observable growth inhibitory action of these compounds against MTAPase-deficient cell lines.
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PMID:5'-deoxy-5'-methylthioadenosine phosphorylase--IV. Biological activity of 2-fluoroadenine-substituted 5'-deoxy-5'-methylthioadenosine analogs. 310 31

The purpose of this study was to elucidate the purine enzymic programs of human primary colorectal carcinomas. Marked alteration in the enzymology of the human colon neoplasm clearly distinguished it from that of the normal colon mucosa. In the human colon mucosa, the activities of ribonucleotide reductase, inosine phosphate dehydrogenase, formylglycinamidine ribonucleotide synthetase, guanosine phosphate synthetase, and amidophosphoribosyltransferase were 0.042, 5.2, 5.6, 8.2 and 36.0 nmol/h/mg protein, respectively, and in the colon carcinomas the activities increased to 755, 575, 295, 280, and 294% of the normal values. The activities of the salvage enzymes, adenine and hypoxanthine-guanine phosphoribosyltransferases, were 310, 249, and 602 nmol/h/mg protein, respectively, whereas in the tumors, only the activity of adenine phosphoribosyltransferase was increased (2-fold). The markedly higher absolute enzymic capacity for salvage in the tumors accounts, in part at least, for the lack of chemotherapeutic success of inhibitors of enzymes of de novo synthesis that have been used in the clinical treatment of colorectal carcinomas. Combinations of inhibitors of de novo biosynthesis and blockers of the salvage enzymes or of salvage transport (e.g., dipyridamole) should improve the chemotherapy of colon neoplasms. Since in the colon carcinoma the activities of glutamine-utilizing enzymes (guanosine phosphate and formylglycinamidine ribonucleotide synthetase and amidophosphoribosyltransferase) were markedly increased, and the glutamine concentration was decreased (50%), treatment with an antiglutamine agent (e.g., acivicin) should be of relevance. Since the activity of ribonucleotide reductase, the rate-limiting enzyme of nucleic acid biosynthesis, was markedly increased in the colon neoplasms, combination chemotherapy might include drugs against this enzyme.
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PMID:Purine enzymology of human colon carcinomas. 398 94

1. 5-Phosphoribosyl 1-methylenediphosphonate was isolated after reaction of ribose 5-phosphate and O-adenylyl methylenediphosphonate with 5-phosphoribosyl pyrophosphate synthetase from Ehrlich ascites-tumour cells. 2. The analogue reacted with adenine phosphoribosyltransferase, hypoxanthine phosphoribosyltransferase and nicotinamide phosphoribosyltransferase [K(m) (analogue)/K(m) (5-phosphoribosyl pyrophosphate) 0.17, 0.19 and 6.3 respectively; V(max.) (analogue)/V(max.) (5-phosphoribosyl pyrophosphate) 0.011, 0.26 and 1.1 respectively]. 3. The analogue was not a substrate for 5-phosphoribosyl pyrophosphate amidotransferase or orotate phosphoribosyltransferase. 4. Ribose 5-phosphorothioate was synthesized by allowing ribose to react with thiophosphoryl chloride in triethyl phosphate. The analogue was a substrate for 5-phosphoribosyl pyrophosphate synthetase from Ehrlich ascites-tumour cells. When this reaction was coupled to either adenine phosphoribosyltransferase or hypoxanthine phosphoribosyltransferase, adenosine 5'-phosphorothioate or inosine 5'-phosphorothioate was formed respectively.
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PMID:Analogues of ribose 5-phosphate and 5-phosphoribosyl pyrophosphate. The preparation and properties of ribose 5-phosphorothioate and 5-phosphoribosyl 1-methylenediphosphonate. 430 74

1. It has been reported that the rate of purine nucleotide synthesis de novo in the immature rat uterus is doubled at 6h after administration of oestradiol-17beta. The present work confirms an increased incorporation of glycine and adenine into uterine nucleotides between 2 and 6h after hormone treatment and investigates the mechanism of this response. 2. Activation of regulatory enzymes is unlikely to promote increased nucleotide synthesis: the activities of 5-phosphoribosyl 1-pyrophosphate amidotransferase (EC 2.4.2.14) and adenine phosphoribosyltransferase (EC 2.4.2.7) are the same in uterine extracts from control and oestrogen-treated rats. 3. Therefore it was proposed that oestradiol might promote an increased supply of a rate-limiting substrate. The low oestrogen-sensitive rate of AMP synthesis from adenine and endogenous 5-phosphoribosyl 1-pyrophosphate in the intact uterus compared with the high, oestrogen-insensitive rate in uterine extracts supplemented with 5-phosphoribosyl 1-pyrophosphate is evidence that the supply of 5-phosphoribosyl 1-pyrophosphate limits purine nucleotide formation and may increase after hormone treatment. This proposal is supported by the decrease in AMP synthesis in the whole tissue in the presence of guanine and 7-amino-3-(beta-d-ribofuranosyl)pyrazolo[3,4-d]pyrimidine (formycin). These compounds do not inhibit adenine uptake or adenine phosphoribosyltransferase activity, but they both decrease the availability of 5-phosphoribosyl 1-pyrophosphate, the former by promoting its utilization by hypoxanthine/guanine phosphoribosyltransferase (EC 2.4.2.8) and the latter by inhibiting its synthesis from ribose 5-phosphate and ATP by ribose 5-phosphate pyrophosphokinase (EC 2.7.6.1). 4. It is unlikely that the increased availability of 5-phosphoribosyl 1-pyrophosphate results from hormonal stimulation of ribose 5-phosphate formation. Methylene Blue and phenazine methosulphate both increase ribose 5-phosphate without altering the supply of 5-phosphoribosyl 1-pyrophosphate. 5. The activity of ribose 5-phosphate pyrophosphokinase is low in uterine extracts and increases rapidly in response to oestradiol. Therefore the hormonal activation of the routes of purine nucleotide synthesis both de novo and from preformed precursors may be due, at least in part, to an increased availability of the common rate-limiting substrate 5-phosphoribosyl 1-pyrophosphate, mediated by activation of ribose 5-phosphate pyrophosphokinase.
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PMID:A possible role for 5-phosphoribosyl 1-pyrophosphate in the stimulation of uterine purine nucleotide synthesis in response to oestradiol-17 . 434 97

Supplementing the salts-glucose medium of Escherichia coli with adenine initiates induction of adenosine deaminase (adenosine aminohydrolase, EC 3.5.4.4), growth inhibition, and an increased potential for the net deamination of adenine. The extent and duration of these events are proportional to the initial adenine concentration and are dependent upon adenylate pyrophosphorylase and repression of histidine biosynthesis for maximal expression. The conversion of adenine to hypoxanthine, though limited in rate, occurs concurrently with induction and accounts for the progressively decreasing rate of deaminase induction, since hypoxanthine is a relatively ineffective inducer. The subsequent decrease in deaminase activity is due to dilution by continued cell division and by enzyme inactivation which occurs during the late-log and early-stationary phases. The partially purified deaminase is labile to a number of environmental conditions, particularly to phosphate buffers of pH 6.8 or less. A disproportionately slow rate of adenine deamination by cells utilizing lactate permits a more prolonged period of induction and, consequently, a greater quantity of enzyme to be synthesized; cell division, but not enzyme inactivation, reduces enzyme concentration. The adenosine deaminases of Aerobacter aerogenes and Salmonella typhimurium are not inducible.
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PMID:Induction of adenosine deaminase in Escherichia coli. 487 15

Sealed and unsealed plasma membrane vesicles were prepared from human erythrocytes and lymphocytes. Phosphoribosylpyrophosphate synthetase (PRibPP synthetase), hypoxanthine phosphoribosyltransferase (HPRTase), and adenine phosphoribosyltransferase (APRTase) activities are detectable on both inside-out and right-side-out sealed vesicles. Ghost preparations were about 0.2%, 1%, and 1.2% of the total erythrocyte and 0.5%, 5.3%, and 9.7% of the lymphocyte APRTase, HPRTase, and PRibPP synthetase activities. The rapid decrease in these enzyme activities, upon further purification of the membranes, seemed to suggest that they might be loosely bound extrinsic proteins. Evidence confirming the localization of these enzymes on the cell surface was obtained by measuring production of [14C]AMP by intact cells in medium containing [14C]adenine, ribose 5-phosphate, and Mg2+ATP. The formation of AMP was linear with time and number of cells present. Magnesium and phosphate exerted different effects on the production of extracellular AMP than on intracellular, which involves transport as well as phosphoribosylation. Cytosoluble and membrane-bound APRTase and PRibPP synthetase exhibited different catalytic properties and sensitivities to effectors. Membranes of erythrocytes of HPRTase-deficient patients contain little or no HPRTase activity when assayed in the absence of Triton. Reisolation of these membranes from admixture with normal hemolysates did not result in any bound activity; thus, the membrane-bound activity is not an artifact of the isolation procedure. Lysis with Triton released activity equal to about half that of control membranes. This is further evidence that the enzyme is firmly bound to the membrane.
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PMID:Membrane-associated purine metabolizing enzyme activities of human peripheral blood cells. 629 41

Superactivity of phosphoribosylpyrophosphate (PRPP) synthetase is one of several hereditary enzyme abnormalities associated with gout and excessive uric acid excretion. Although measurement of PRPP synthetase activities in erythrocyte lysates should provide a practical means to detect abnormalities of the enzyme, reported values for normal individuals have varied considerably. We describe a radioisotopic procedure for measurement of PRPP synthetase activities in dialyzed hemolysates under a variety of conditions permitting evaluation of enzyme catalytic function and responsiveness to inhibitors and activators. Utilizing this procedure, enzyme activities for normal individuals were higher than generally reported, a difference attributable in part to the following measures undertaken to assure accuracy in activity determinations: precise control of pH of reaction mixtures, provision of verified excesses of the auxiliary enzyme adenine phosphoribosyltransferase, and measurement of all of the radiolabeled products of the assay. Under each condition of measurement, enzyme activities in 44 normal individuals, 13 patients with gout and normal uric acid excretion, and 10 patients with gout and uric acid overproduction were indistinguishable. In four additional individuals with uric acid overproduction, however, excessive enzyme activities were identifiable at all inorganic phosphate concentrations, but responses to purine nucleotide inhibitors were normal. In hemolysates from a patient with an inhibitor-resistant PRPP synthetase, an altered pattern of inorganic phosphate activation and diminished nucleotide inhibitor response was demonstrated. Our studies confirm the ability of the assay procedure to detect kinetically distinct variant forms of PRPP synthetase. Application of this procedure should aid in evaluation of the prevalence of derangements of PRPP synthetase among patients with gout and uric acid overproduction.
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PMID:Diagnostic evaluation of phosphoribosylpyrophosphate synthetase activities in hemolysates. 632 65


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