L-Asparaginase and L-Asparagine Metabolism

Cooney, David A.; Handschumacher, Robert E.

doi:10.1146/annurev.pa.10.040170.002225

Cited by 152 publications

(69 citation statements)

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“…The correlation between this amide, the surface glycoproteins, and cellular activity (20), the suggestion that the amide groups of aspartic and glutamic acids may be involved in the process of aging of proteins (21), and the essential role that asparagine appears to play in the metabolism of cancer cells (22) …”

Section: Methodsmentioning

confidence: 99%

Enzyme regulation in neuroblastoma cells in a salts/glucose medium: Induction of ornithine decarboxylase by asparagine and glutamine

Chen

Canellakis

1977

Proc. Natl. Acad. Sci. U.S.A.

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L-Asparagine is necessary and sufficient for the maximal induction of ornithine decarboxylase (ODC) (Lornithine carboxy-lyase, EC 4.1.1.17) activity in confluent N18 mouse neuroblastoma cells in a salts/glucose medium; L-asparagine also induces maximal ODC activity when added to a tissue culture medium. L-Glutamine is about one-half as effective as asparagine. Cholera toxin and agents that are known to raise intracellular cyclic AMP concentrations have no effect on the induction of ODC activity unless suboptimal concentrations of asparagine are present in the salts/glucose medium. Whereas actinomycin D does not inhibit induction of ODC activity by asparagine, it inhibits the induction of ODC activity in association with cyclic AMP. In the salts/glucose medium, the rate of loss of ODC activity following the inhibition of protein synthesis by cycloheximide or puromycin depends upon the presence or absence of asparagine; loss is rapid only in the absence of asparagine and does not appear to be related to the inhibition of protein synthesis. These results are discussed in the context that the overlay of the growth medium tends to mask the minimal requirements for enzyme induction, because the composition of the medium defines: (a) the requirements for the induction of ODC activity; (b) the effect, orlack of effect, of cyclic AMP (and of inducers of intracellular cyclic AMP) on the induction of ODC activity; (c) the effect, or lack of effect, of actinomycin D on the induction of ODC activity; and (d) the action of puromycin and of cycloheximide on the rate of loss of ODC activity. It will be interesting to determine whether these results are uniquely applicable to ODC, whether many of the reactions attributed to cyclic AMP in the literature may be mediated by asparagine and glutamine, and whether actinomycin D, cycloheximide, and puromycin can be relied upon to differentiate between transcriptional and post-transcriptional control.Most studies on enzyme induction, including our own, especially in relation to ornithine decarboxylase (ODC) (L-ornithine carboxy-lyase, EC 4.1.1.17), have relied heavily on the use of cell cultures in incubation media of varying complexity or on the use of whole animals (1-3). Such studies tend to provide answers that are modified either by the overall physiology of the cell as affected by the complexity of the medium or by the inherent complexity of the animal as modified by any additional conditions of imposed environmental and experimental stress. For example, when enzyme induction by hormones is being determined in a cell culture, if the hormones have differential positive and negative effects on the transport of various substances, the effectiveness or noneffectiveness of a hormone in inducing an enzyme activity will be completely dependent upon the composition of the medium.In order to minimize such extraneous influences, we induce ODC activity in confluent N18 mouse neuroblastoma cells in a minimal salts/glucose medium. Under these conditions, the addition of L-asparagine is...

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Section: Methodsmentioning

confidence: 99%

Enzyme regulation in neuroblastoma cells in a salts/glucose medium: Induction of ornithine decarboxylase by asparagine and glutamine

Chen

Canellakis

1977

Proc. Natl. Acad. Sci. U.S.A.

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“…The enzyme is of interest for a number of reasons: the rate of synthesis of asparagine synthetase is regulated by dietary asparagine in whole animals (2,3) and by the concentration of asparagine in the medium in cultured cells (4)(5)(6); certain animal and human tumors are responsive to chemotherapy with asparaginase because of a deficiency in asparagine synthetase activity (7)(8)(9); and enzyme activity is differentially expressed in various cell types (1) and during development (10,11 ). Waye and Stanners have isolated a mutant of Chinese hamster ovary cells which lacks asparagine synthetase activity and requires asparagine in the medium for growth (12).…”

Section: Introductionmentioning

confidence: 99%

Assignment of structural gene for asparagine synthetase to human chromosome 7

Arfin

Cirullo

Arredondo-Vega

et al. 1983

Somat Cell Mol Genet

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“…By the action of this enzyme, asparagines hydrolyzed to aspartate. Then there are various pathways possible for Aspartate (5). For example, transamination of aspartate into oxaloacetate (one of critical compound of Tricarboxylic acid cycle (TCA) or conversion into fumarate during the urea cycle (6).…”

Section: Introductionmentioning

confidence: 99%

Applying Bioinformatic Tools for Modeling and Modifying Type II E. coli l-Asparginase to Present a Better Therapeutic Agent/Drug for Acute Lymphoblastic Leukemia

et al. 2017

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Background: Asparginase is known to be one of the most important bedrocks of acute lymphoblastic leukemia (ALL) treatment in almost all pediatric regimens in treatment protocols. Escherichia coli L-Asparginase (EC 3.5.1.1) is one of the most common resources to produce this enzyme. One of the affordable methods to overcome the side effects of drug is utilizing bioinformatic tools in the form of In silico study. In this study we designed a new structure of L-Asparginase to decrease its toxicity, reduce some side effects and increase the stability. Methods: We used some bioinformatics software and servers like Toxin red, Popmusic, kobami and I-TASSER server to reduce toxicity level of enzyme, and to increase stability and enzyme half-life. Results: We obtained 6 protein sequences in which the best was Mut 6 with four changes in structure: L23G, K129L, S263C and R291F. In contrast to the wild type, the new predicted protein is not toxic and has 25 hours more half-life and 600 kcal/mol more stable with no significant change in protein secondary, tertiary structure, antigenicity and allergenicity. Conclusions: Finally, sequence number 6 was the only sequence with all distinct characteristics: non-toxic, more stability and more half life.

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L-Asparaginase and L-Asparagine Metabolism

Cited by 152 publications

References 0 publications

Enzyme regulation in neuroblastoma cells in a salts/glucose medium: Induction of ornithine decarboxylase by asparagine and glutamine

Enzyme regulation in neuroblastoma cells in a salts/glucose medium: Induction of ornithine decarboxylase by asparagine and glutamine

Assignment of structural gene for asparagine synthetase to human chromosome 7

Applying Bioinformatic Tools for Modeling and Modifying Type II E. coli l-Asparginase to Present a Better Therapeutic Agent/Drug for Acute Lymphoblastic Leukemia

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