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:3.5.1.1 (asparaginase)
2,695 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kinetic parameters, substrate specificity and exclusivity of ligands at binding sites of L-glutaminase-L-asparaginase purified from Acinetobacter glutaminasificans were studied in order to gain knowledge about the dual activities of this enzyme and its inhibition by structural analogs. Both L-glutamine and L-asparagine, which showed similar Km (4 approximately 7 X 10(-5) M) and Vmax (molecular activity 1.0 min-1) values, were competitive with each other for the substrate binding site. The products, L-glutamic acid and L-aspartic acid, showed competitive inhibition with respect to either L-glutamine or L-asparagine as substrates. Multiple inhibition of the glutaminase activity by L-glutamic acid and L-aspartic acid indicated that these ligands are mutually exclusive at the product-releasing site. The initial rates of both of the enzyme's activities were competitively inhibited by the following inhibitors (in rates of both of the enzyme's activities were competitively inhibited by the following inhibitors (in decreasing order of activity): 6-diazo-5-oxo-L-norleucine (DON), L-methionine sulfoximine, azaserine, and Acivicin. DON and azaserine inhibited both the asparaginase and glutaminase activities in a time-dependent and irreversible manner. The kinetic data suggest an ordered mechanism with glutamine or asparagine as the first substrate and glutamic acid or aspartic acid, respectively, as the last product. These results also suggest that a single mechanism and a single set of binding sites are responsible for catalyzing both of the enzyme's activities. The data also showed that succinylated enzyme, which has a 10-fold increase of plasma half-life in animals and humans and, thus, has benefit as a cancer chemotherapeutic agent, retained its catalytic activity and maintained Km and Vmax values similar to the native enzyme.
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PMID:Kinetic properties and inhibition of Acinetobacter glutaminase-asparaginase. 683 61

The histidine ammonia-lyase from bacterial strain CAMR 5315 was partially purified to assess its effect on the growth of murine tumours. This strain was selected as the source after an extensive screening programme for histidine ammonia-lyases. The enzyme was partially purified by ammonium sulphate fractionation, chromatography on DEAE-cellulose and Sephadex G-150. The enzyme reduced circulating L-histidine levels in Wistar rats and in mice persisted with a half-life of 6-7 h. Neither LDH virus nor chemical modification with ethylacetimidate increased the half-life as observed with L-asparaginase and L-glutaminase. The enzyme was tested in mice against Ehrlich carcinoma, L5178Y lymphoblastic leukaemia, Mc/S sarcoma, B16 melanoma, P8157 mastocytoma, P1798 lymphosarcoma and the Gardner 6C3HED lymphosarcoma. The only tumours to show sensitivity to the enzyme were the Mc/S sarcoma against which a 65% increase in life span was observed at the highest enzyme dose, 1000 U/kg on alternate days over 14 days and the Ehrlich ascites carcinoma where cures were obtained at 250 U/kg on alternate days over 14 days, but only at inocula levels of 10(5) and 10(3) cells/animal respectively.
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PMID:The effect of histidine ammonia-lyase on some murine tumours. 688 63

L-Asparaginase has been widely used for the treatment of acute lymphoblastic leukemia. Therapeutic and toxic effects in the central nervous system have been noted with systemic treatment. In order to better define the relationship between L-asparaginase administration and cerebrospinal fluid (CSF) asparagine levels, L-asparaginase and asparagine were measured in the CSF of rhesus monkeys following intrathecal and i.v. administration. Following intrathecal injection, the enzyme activity of Escherichia coli L-asparaginase in the CSF demonstrated a more rapid terminal half-life than did that of 111In-labeled diethylenetriaminepentaacetic acid, a marker of CSF bulk flow [4 +/- 0.7 (S.D.) hr versus 5.8 +/- 0.2 hr]. Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days. A similar period of CSF asparagine depletion was observed following i.v. administration of L-asparaginase. Similar results were found in seven patients undergoing systemic L-asparaginase therapy. The minimal plasma level of L-asparaginase necessary to deplete CSF asparagine in both species was 0.1 IU/ml. Two other enzymes, Erwinia L-asparaginase and succinylated Acinetobacter glutaminase-asparaginase, were cleared from the CSF at the same rate as bulk flow. These data indicate that systemic L-asparaginase therapy may be a feasible means of treating central nervous system involvement in patients with acute lymphoblastic leukemia and that there is no therapeutic advantage to using intrathecal L-asparaginase.
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PMID:L-asparaginase pharmacokinetics and asparagine levels in cerebrospinal fluid of rhesus monkeys and humans. 689 81

Use of L-asparaginase by the extracorporeal route in the therapy of acute lymphoblastic leukemia (ALL) has been proposed. Results, however, are not so satisfactory as i.v. administration of this enzyme, because the levels of L-asparagine do not fall for a sufficient length of time due to the antagonistic action of the L-asparagine-synthetase. To avoid the L-asparagine rebound we have utilized, by extracorporeal route, L-glutaminase together with L-asparaginase, in order to reduce L-asparagine and L-glutamine levels. We have therefore performed a series of experiments in vitro and in vivo either using L-asparaginase alone or together with L-glutaminase. Results show that, contrary to what happens when L-asparaginase is used alone, L-asparagine levels decrease and remain low even after 24 hours from the treatment, when L-glutaminase is added to the system. Thus a lowering of L-glutamine levels, which seems to play an important role in the therapy of ALL, is obtained.
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PMID:L-glutaminase and L-asparaginase by extracorporeal route in acute lymphoblastic leukemia therapy. 694 66

Amino acid utilization was evaluated in seven children with acute lymphocytic leukemia treated with succinylated Acinetobacter glutaminase-asparaginase. All patients received food p.o. ad libitum and glucose-electrolyte solutions i.v.; four patients received an i.v. amino acid supplement (1.5 g/kg/day). Although all patients were in negative energy balance, there was a significant linear regression between nitrogen balance and nitrogen intake during Days 1 to 7 and Days 8 to 14 of the study. The slope of the regression line, reflecting exogenous nitrogen utilization, was not significantly different from that found in healthy young men ingesting adequate or subadequate energy intakes. The Y-intercept (-210 mg/kg/day) indicated an obligatory nitrogen loss that was much greater than normal. Most of the nitrogen loss was due to urinary excretion. Ammonia and urea accounted for 77 to 91% of the urine nitrogen. Urinary glutamate accounted for 4 to 10% of this loss. Urine protein excretion was abnormally high in each of the patients, ranging from 987 to 3440 mg/day. Urine excretion of N-acetyl-beta-glucosaminidase and beta 2-microglobulin was also abnormally high, despite normal blood urea nitrogen and serum creatinine, suggesting that these children had renal tubular dysfunction. The antileukemic effect of succinylated Acinetobacter glutaminase-asparaginase did not appear to be altered by amino acid supplementation. These data indicate that amino acid supplementation can improve nutritional status in patients treated with succinylated Acinetobacter glutaminase-asparaginase.
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PMID:Amino acid utilization and urine protein excretion in children treated with succinylated Acinetobacter glutaminase-asparaginase. 701 7

We treated 13 adult patients with acute leukemia or chronic myelocytic leukemia (CML) in blast phase using succinylated Acinetobacter glutaminase-asparaginase (SAGA) administered on a daily dose schedule. SAGA reduced the peripheral blast count in two patients with acute lymphoblastic leukemia and two with blastic CML; however, no patient achieved either complete or partial remission. Marked central nervous system toxic effects (encephalopathy and coma) were observed, limiting treatment in patients whose disease appeared responsive; this effect finally prompted early discontinuance of the trial. Other toxic effects observed included nausea, hyperglycemia, and respiratory alkalosis. Hypersensitivity reactions to the enzyme were not seen. Pharmacologic analyses showed that prolonged blood glutamine depletion was achieved only by daily enzyme administration; however, we noted the importance of performing amino acid analysis on blood which was deproteinized immediately following phlebotomy. Our results demonstrate excessive central nervous system toxicity when glutaminase-asparaginase is administered on a daily schedule. Because of this effect, we propose that future trials of similar enzymes be limited to short courses of enzyme therapy, possibly with the addition of antimetabolites or amino acid analogs, which could enhance the antitumor effect without increasing toxicity.
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PMID:Clinical evaluation of succinylated Acinetobacter glutaminase-asparaginase in adult leukemia. 704 29

Perturbations of specific nutrient availability is the basis of a large number of chemotherapeutic modalities used in cancer treatment. The creation of transient nutrient deprivation states by deficient diets (deficiency), nutrient destruction or displacement (depletion), the presence of antimetabolites or analogs (deficiency state), or combinations of the above has shown significant antitumor effect in several animal and human cancers. Pair-fed isocalonic diets deficient in micronutrients such as carbohydrates (with or without gluconeogenesis inhibition) or micronutrients such as zinc or pyridoxine have demonstrated antitumor potential. Amino acid depletion by enzymes such as L-asparaginase or L-glutaminase has become a popular modality for treatment of human leukemias. Purine and pyrimidine analogs or folate antimetabolites have been used successfully for several decades in the treatment of human tumors. Excess pyridoxine in tissue culture has demonstrated antineoplastic potential. Dietetic supplementation with naturally occurring sugars, sugar derivatives, or analogs has also demonstrated tumorotropic effects.
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PMID:Tumoricidal potential of nutritional manipulations. 705 14

The pathways of the utilization of dicarboxylic amino acids and their amides in 55 Klebsiella strains have been studied. These organisms have been found to be capable of carboxylating glutaminic acid with the subsequent utilization of the product of this reaction, gamma-amino butyric acid, by reamidization with alpha-glutaric acid. Aspartate decarboxylase with low activity has been detected only in a small number of strains. Most of the strains have been shown to be capable of deamidizating equally asparaginic and glutaminic acids. The presence of active asparaginase and glutaminase has been detected in a considerable number of these strains. Microorganisms of the genus Klebsiella have low asparagine synthetase and glutamine synthetase activity. Aspartate aminotransferase has been found to occur twice as frequently as alanine aminotransferase, both having the same level of activity.
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PMID:[Metabolism of dicarboxylic amino acids and their amides in bacteria of the genus Klebsiella]. 711 27

Cultured human pancreatic carcinoma cells (MIA PaCa-2) have been shown previously to be very sensitive to E. coli L-asparaginase (EC II). The present studies have demonstrated that another enzyme, Acinetobacter glutaminase-asparaginase (AGA) is much more effective in inhibiting cell growth. At the concentration of 0.0025 U/ml of AGA activity the enzyme totally inhibited cell growth, whereas the EC II with the same concentration did not show any effect. The inhibition of cell growth correlated well with inhibition of protein and glycoprotein synthesis. The addition of L-glutamine at the concentration of 1 mM completely reversed the inhibition of protein synthesis. Similarly, the addition of L-glutamine at the concentration of 3 mM daily on 3 successive days after adding AGA resulted in significant reversal of growth inhibition. The results of this study indicate that the action of AGA on MIA PaCa-2 is, to a great extent, exerted through its L-glutaminase activity.
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PMID:Sensitivity of cultured pancreatic carcinoma cells to Acinetobacter glutaminase-asparaginase. 717 49

Mouse P388 and L1210 leukemia cells grown in vitro were found to be 4 to 10 times more sensitive to 6-diazo-5-oxo-L-norleucine and 3 to 5 times more sensitive to Acivicin than were 3T3 and C57BL x DBA/2 F1 embryonic fibroblasts. The combined actions of succinylated Acinetobacter glutaminase-asparaginase and 6-diazo-5-oxo-L-norleucine or Acivicin produced synergistic inhibition of nucleic acid synthesis in P388 tumor cells. An uptake system for Acivicin is described. Its properties in P388 and 3T3 cells are similar in their strong temperature dependence, utilization of the "L" transport system, presumably competitive inhibition by glutamine, similar Km's (about 200 microM), and potent inhibition by p-chloromercuribenzene sulfonate, NA+. However, Acivicin uptake was inhibited in 3T3 (but not in P388) cells by KCN or 2,4-dinitrophenol. At equilibrium in P388 cells, the intracellular level of Acivicin was approximately 57-fold greater than was the extracellular concentration. The accumulated Acivicin was not metabolized by P388 cells, nor does exchange of 3H label into water occur. Rapid efflux of Acivicin occurred with both cell lines at 37 degrees, but efflux from 3T3 cells was greatly diminished at 0 degrees. The rate of efflux was accelerated by including glutamine or unlabeled Acivicin in the extracellular medium.
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PMID:Enhancement of antitumor activity of glutamine antagonists 6-diazo-5-oxo-L-norleucine and acivicin in cell culture by glutaminase-asparaginase. 721 22


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