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)

Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.
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PMID:Asparagine synthetase activity of mouse leukemias. 568 13

Asparaginase and asparagine synthetase specific activity (enzyme units/mg protein) was determined in chicks and rats fed various protein diets. The specific activity of asparaginase was twofold higher in the kidney compared to the liver of chicks fed a 25% protein control diet, whereas the specific activity of asparaginase was eightfold greater in the liver compared to kidney tissue of rats fed the 25% protein control diet. The asparaginase specific activity in the chick liver, chick kidney, and rat liver were all significantly increased when animals were fed the 75% protein diet. Asparaginase specific activity increased significantly in rat and chick kidneys when the animals were fasted. Dietary supplementation of asparagine did not significantly increase asparaginase specific activity in either animal. The combined kidney and liver asparagine synthetase specific activity for chicks fed the control diets is over seven hundred times less than the corresponding combined asparaginase specific activity. Rats fed the control diet had a combined kidney and liver asparagine synthetase specific activity about 75 times less than the corresponding asparaginase specific activity. The asparagine synthetase specific activity was significantly increased in the rat and chick kidney when a 2% protein diet was fed.
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PMID:Asparagine metabolism in chicks and rats. 610 9

The cell-killing activity of asparaginase on three classes of Chinese hamster ovary cell mutants was examined: a mutant which overproduces asparagine synthetase (AH5); mutants defective in asparagine synthetase (N3 and N4); and mutants conditionally defective in asparagyl-transfer RNA synthetase (Asn 3, Asn 7, and Asn 9). The overproducer was more resistant to the cell-killing activity of asparaginase than wild-type Chinese hamster ovary cells, while mutants defective in asparagine synthetase were more sensitive. Surprisingly, the asparagyl-transfer RNA synthetase mutants were even more sensitive to asparaginase than the asparagine synthetase mutants. In a preliminary survey of four human lymphoid cell lines (RPMI 8402, RPMI 8392, B46M, and Molt-4F) which showed dramatically different asparaginase sensitivity, however, sensitivity to the cell-killing activity of asparaginase was correlated with reduced levels of asparagine synthetase and not with reduced levels of asparagyl-transfer RNA synthetase.
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PMID:Role of asparaginase synthetase and asparagyl-transfer RNA synthetase in the cell-killing activity of asparaginase in Chinese hamster ovary cell mutants. 611 89

The effect of dietary asparagine and protein-equivalents from crystalline amino acid mixtures upon asparagine metabolism in chicks were studied. Liver and kidney asparaginase activities were significantly increased in chicks fed 44.6% protein-equivalents compared to chicks fed the Illinois chick standard amino acid mixture containing 14.8% protein-equivalents. The asparagine synthetase activity in chick liver and kidney was not significantly changed by protein-equivalents or dietary asparagine. Liver and kidney asparaginase activities in chicks fed 14.8% protein-equivalent standard diets were decreased with increasing levels of dietary asparagine (0,2 and 6%). Kidney asparaginase activities in chicks fed 44.6% protein-equivalents also were decreased with increasing levels of asparagine but liver asparaginase in these chicks was not changed with dietary asparagine. The plasma asparagine concentration was dependent on the amount of dietary asparagine and protein-equivalents. Dietary asparagine increased plasma asparagine in chicks fed 14.8 and 44.6% protein-equivalent diets but plasma asparagine in chicks fed the 14.8% protein-equivalent diet plus 6% asparagine was 3.5 times higher than plasma asparagine in chicks fed the diet containing 44.6% protein-equivalent plus 6% dietary asparagine. Plasma asparagine in chicks fed the 44.6% protein-equivalent diet with 6% asparagine was reduced due to increased asparaginase activity.
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PMID:Effect of dietary asparagine and protein-equivalents in crystalline amino acid diets on asparagine metabolism in chicks. 611 49

Methotrexate was found to stimulate asparagine synthetase activity in vivo by approximately six-fold in rat liver. The maximum effect of methotrexate on hepatic asparagine synthetase activity was observed sixteen hours after intraperitoneal injection of the drug. Cycloheximide, like methotrexate, is a protein synthesis inhibitor and was used to determine that asparagine synthetase activity was not preferentially stimulated under stress. As expected, hepatic asparagine synthetase activity falls markedly with the decreased protein synthesis caused by injection of cycloheximide. It is proposed that methotrexate inhibits serine-dependent glycine biosyn-thesis by decreasing the concentration of tetrahydrofolate for serine hydroxymethyltransferase. This leads to a stimulation of asparagine synthetase to provide nitrogen for asparagine-dependent glycine synthesis. This may provide an explanation of the observed chemotherapeutic synergism between asparaginase and methotrexate treatment.
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PMID:Methotrexate stimulation of asparagine synthetase activity in rat liver. 612 50

1. Activities of asparagine synthetase, asparaginase, glutamine synthetase and glutaminase have been determined in red muscle, white muscle, brain, kidney, liver and gills of goldfish. 2. Muscle and brain show a capacity for net amide synthesis, while liver and gills are capable of both amide synthesis and degradation. 3. These results are consistent with the hypothesis that amide synthesis and degradation functions as a mechanism controlling tissue ammonia levels and ammonia excretion rates.
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PMID:Nitrogen metabolism in goldfish, Carassius auratus (L.) activities of amidases and amide synthetases in goldfish tissues. 612 4

Pharmacology is the study of the properties of a drug with respect to its interaction with the host, toxicology, and with the disease, therapeutics. Since both the toxicology and therapeutic activity of L-asparaginase are presented by others at this symposium, I will give only a brief overview of the pharmacology of L-asparaginase with particular reference to how it differs from other chemotherapeutic agents. Primarily, I would like to discuss how it may be possible to modify some of the pharmacological constraints on the therapeutic responses to L-asparaginase by combining the enzyme with inhibitors of asparagine synthetase and by using polymer-modified forms of the enzyme.
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PMID:Pharmacology of L-asparaginase and the effects of host and enzyme modification. 612 60

We isolated pleiotropic mutants of Klebsiella aerogenes with the transposon Tn5 which were unable to utilize a variety of poor sources of nitrogen. The mutation responsible was shown to be in the asnB gene, one of two genes coding for an asparagine synthetase. Mutations in both asnA and asnB were necessary to produce an asparagine requirement. Assays which could distinguish the two asparagine synthetase activities were developed in strains missing a high-affinity asparaginase. The asnA and asnB genes coded for ammonia-dependent and glutamine-dependent asparagine synthetases, respectively. Asparagine repressed both enzymes. When growth was nitrogen limited, the level of the ammonia-dependent enzyme was low and that of the glutamine-dependent enzyme was high. The reverse was true in a nitrogen-rich (ammonia-containing) medium. Furthermore, mutations in the glnG protein, a regulatory component of the nitrogen assimilatory system, increased the level of the ammonia-dependent enzyme. The glutamine-dependent asparagine synthetase was purified to 95%. It was a tetramer with four equal 57,000-dalton subunits and catalyzed the stoichiometric generation of asparagine, AMP, and inorganic pyrophosphate from aspartate, ATP, and glutamine. High levels of ammonium chloride (50 mM) could replace glutamine. The purified enzyme exhibited a substrate-independent glutaminase activity which was probably an artifact of purification. The tetramer could be dissociated; the monomer possessed the high ammonia-dependent activity and the glutaminase activity, but not the glutamine-dependent activity. In contrast, the purified ammonia-dependent asparagine synthetase, about 40% pure, had a molecular weight of 80,000 and is probably a dimer of identical subunits. Asparagine inhibited both enzymes. Kinetic constants and the effect of pH, substrate, and product analogs were determined. The regulation and biochemistry of the asparagine synthetases prove the hypothesis strongly suggested by the genetic and physiological evidence that a glutamine-dependent enzyme is essential for asparagine synthesis when the nitrogen source is growth rate limiting.
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PMID:Asparagine synthetases of Klebsiella aerogenes: properties and regulation of synthesis. 612 99

The early hope that L-asparaginase would be a breakthrough in medical treatment, with selective toxic effects based on the qualitative presence or absence of a specific enzyme (asparagine synthetase), has not been realized. Despite its failure to live up to early hopes, L-asparaginase is now commercially available because of its usefulness in treating selected forms of acute leukemia and T-cell lymphoid neoplasms. By and large, hints of useful activity in other tumors have not been confirmed, and L-asparaginase remains experimental for all other indications. It is variably toxic in man, and severe toxic effects are not unusual. Toxic reactions are generally hypersensitivity reactions or depression of protein synthesis.
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PMID:L-Asparaginase: human toxicology and single agent activity in nonleukemic neoplasms. 704 81

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


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