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)

The inactivation of E. coli asparaginase by 2,3-butanedione studied with L-asparagine and diazooxonorvaline as substrates obeys pseudo first order kinetics. Activity losses are linear with respect to arginine and histidine modification, with complete inactivation being correlated with alteration of one arginine and one histidine per subunit. The rate of inactivation of the enzyme was reduced in the presence of competitive inhibitors like L-2-amino-2-carboxyethane-sulfonamide. Under comparable conditions 1,2-cyclo hexanedione does not affect the activity of L-asparaginase.
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PMID:Inhibition of E. coli L-Asparaginase by reaction with 2,3-butanedione. Chemical modification of arginine and histidine residues. 16 Jun 98

Hydroxamic acids have been reported to be potent and specific inhibitors of urease (EC 3.5.1.5) activity of plant and bacterial origin. The present investigation was performed on the inhibitory effect of hydroxamic acid derivatives of naturally occurring amino acids on the urease activity of the Jack Bean and the alimentary tracts of rats. Methionine-hydroxamic acid was the most powerful inhibitor (I50=3.9 X 10(-6) M) among nineteen alpha-aminoacyl hydroxamic acids. Phenylalanine-, serine-, alanine-, glycine-, histidine-, threonine-, leucine-, and arginine-hydroxamic acids followed, in order of decreasing inhibitory power. The inhibition proceeded with time at a comparable rate to fatty acyl hydroxamic acid inhibition. The I50 values of alpha-aminoacyl hydroxamic acids were found to be almost equal to those of the corresponding fatty acyl hydroxamic acids. This fact shows that the alpha-amino group did not affect inhibitory power. However, aspartic-beta-, lysine-, and glutamic-gamma-hydroxamic acids, in descending order, were much less inhibitory, probably due to the presence of a carboxyl or omega-amino group. Furthermore, the pH optimum of the inhibition shifted to lower pH in the presence of a carboxyl group, and to a higher pH in e presence of an amino group. The results suggest that the dissociation of an acidic or a basic group reduces the inhibitory power of hydroxamic acid. Hydroxamic acid inhibits urease activity with strict specificity, excpet for aspartic-beta-hydroxamic acid, which inhibited asparaginase competitively. Hydroxamic acid derivatives of amino acids inhibited not only the urease activity of the Jack Bean, but also that of the caecum and ileum parts of the rat intestine.
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PMID:Inhibition of urease activity by hydroxamic acid derivatives of amino acids. 23 68

The L-asparagine analogue 5-diazo-4-oxo-L-[5-14C]norvaline binds irreversibly to the active site of Escherichia coli L-asparaginase. Conditions for optimal labeling in buffers containing 50% dimethylsulfoxide have been developed and kinetic parameters of the inactivation have been determined. After reduction, alkylation and subsequent degradation of the modified enzyme with alpha-chymotrypsin, the principal radioactive decapeptide of sequence Val-Gly-Ala-Met-Arg-Pro-Ser-Thr-Ser-Met was isolated. A second radioactive hexapeptide Arg-Pro-Ser-Thr-Ser-Met resulting from chymotryptic digestion of the decapeptide was also isolated. Evidence is presented for the attachment of the 5-diazo-4-oxo-L-norvaline residue to serine-9 in the decapeptide via an acid-labile linkage.
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PMID:Structure of peptide from active site region of Escherichia coli L-asparaginase. 32 49

The development of microbial enzymes for cancer therapy presents difficulties not commonly experienced with biological drugs. The development of the enzyme asparaginase from Escherichia coli in the USA and of the serologically different asparaginase from the plant pathogen Erwinia carotovora in this Establishment, has not only added to the choice of antileukaemia drugs but also provided a valuable guide to the selection and development of new therapeutic enzymes. Our own programme has led to the study of enzymes that degrade other amino acids (glutamine, arginine, phenylalanine and tyrosine) that appear to be important to certain leukaemia cells. Microbes with only remote associations with man were considered as a source of these to minimize initial immunological sensitivity. In the case of erwinia asparaginase the benefits of this have probably included a lower incidence of anaphylaxis compared with the escherichia enzyme. The selection of a stable, high-affinity enzyme that operates efficiently under physiological conditions ensures effective depletion of a circulating amino acid but the choice is very limited. It is also difficult to assess from laboratory tests the likely persistence, toxicity and efficacy of the enzyme in clinical use and to arrive at meaningful biological tests for the quality control of the finished product. Some of the difficulties will be described and proposals made for criteria of acceptance for this type of drug in experimental use.
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PMID:Amino acid degrading enzymes for cancer therapy. 41 22

Since asparagine has been found to inhibit growth of some tumors and to inhibit or delay mitotic activity in other cells, we have studied the effect of asparaginase and of deprivation of some essential amino acids (Arg, Asn, Leu, Ile, Trp) on nucleic acid and protein synthesis in an asparagine-requiring strain of BHK/21 cells. We find that: (1) there is no essential difference in the pattern of synthesis following deprivation of any of the amino acids we tested; (2) that the effect of asparaginase is similar to that of amino acid deprivation; (3) that RNA synthesis is inhibited more rapidly than DNA or protein synthesis; (4) that after 10 hr of amino acid starvation, DNA synthesis is almost totally (reversibly) inhibited while RAN synthesis continues at about 30-50% and protein at about 100% of the initial value.
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PMID:The effect on macromolecular synthesis of amino acid deprivation of hamster kidney cells. 61 19

New methods for the determination of L-asparagine and arginine are described. Solutions containing L-asparagine were pumped through an asparaginase tube, which catalyzed the hydrolysis of L-asparagine to L-aspartis acid and ammonium ion. For L-arginine determination, solutions containing L-arginine were pumped through an arginase-urease tube. This dual enzyme tube catalyzed the conversion of L-arginine to L-ornithine, carbon dioxide, and ammonium ion. The ammonium ion concentrations in the effluent of the enzyme tubes were determined quantitatively by an ammounin-ion-selective electrode. The potentiometric response of the electrode was directly proportional to the logarithm of the concentration of L-asparagine and L-arginine in the range of 0.1-50 mM. An equation relating the electrode response and the substrate concentration is derived.
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PMID:Reagentless determination of L-asparagine and L-arginine via the combined use of immobilized enzymes and an ion-selective electrode. 125 83

Exogenous corticoids are known to be potent inhibitors of linear growth in children. We investigated the mechanisms underlying growth failure by evaluating growth hormone (GH) release during short-term high-dose prednisone treatment (40 mg/m2/day given orally in 3 divided doses) and 7 days after steroid withdrawal in 7 prepubertal children (4 males, 3 females, age range 3-12 years), affected by acute lymphoblastic leukemia. Patients also received weekly administrations of vincristine (1.5 mg/m2 i.v.), daunomycin (20 mg/m2 i.v.) and L-asparaginase (6,000 IU/m2 i.m.). Corticoid therapy suppressed GH secretion during deep sleep as well as in response to arginine, insulin and GH-releasing hormone (GHRH) administration. A significant recovery of GH responsiveness after drug discontinuation was observed during deep sleep (14.03 +/- 3.47 vs. 1.49 +/- 0.43 ng/ml, p less than 0.025) as well as in response to arginine (13.63 +/- 2.73 vs. 4.95 +/- 1.54 ng/ml, p less than 0.025) and GHRH (32.62 +/- 4.59 vs. 7.27 +/- 3.52 ng/ml, p less than 0.005) but not to insulin (7.12 +/- 0.88 vs. 4.47 +/- 0.96 ng/ml, p = NS). Insulin-like growth factor 1 levels during deep sleep (0.61 +/- 0.13 IU/ml/min) were found to be low in the course of steroid therapy and did not increase after drug withdrawal (0.41 +/- 0.07 IU/ml/min). Our preliminary data suggest that recovery of adrenergic response to insulin does not immediately follow corticosteroid discontinuation.
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PMID:Effect of corticoid therapy on growth hormone secretion. 182 76

In a previous study we demonstrated thirteen amino acids to be essential and two to be partially essential for lymphocyte proliferation. Arginine is one of the essential amino acids, and the highly purified arginase strongly inhibited lymphocyte proliferation. The modulation of lymphocyte growth by various amino acid-degrading enzymes was studied. Peripheral lymphocytes were cultured in RPMI 1640 with or without amino acid-degrading enzyme for 72 h. A total of 17 commercial L-amino acid-degrading enzymes were studied. At 10 micrograms/ml, both lysine decarboxylase and asparaginase completely inhibited lymphocyte proliferation, arginase resulted in 78% inhibition and tyrosinase 57% inhibition. Other enzymes inhibited less than 20% lymphocyte proliferation; they included alanine dehydrogenase, arginine decarboxylase, aspartase, glutamic decarboxylase, glutamic dehydrogenase, glutaminase, histidase, histidine decarboxylase, leucine dehydrogenase, phenylalanine decarboxylase, phenylalanine hydroxylase, tryptophanase, and tyrosine decarboxylase. All four enzymes that strongly inhibited lymphocyte proliferation degraded amino acids that are essential for lymphocyte growth.
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PMID:Modulation of lymphocyte proliferation by enzymes that degrade amino acids. 212 55

Glucose induced insulin release, from collagenase isolated islets of Langerhans obtained from non diabetic male New Zealand White rabbits, was inhibited in vitro by E. coli L-asparatinase. This inhibition was time and dose dependent with maximal inhibition being attained after 1 1/2 hr incubation using a dose of 1000 I.U. L-asparaginase/ml. Tolbutamide potentiated glucose-induced insulin release in the presence of inhibitory doses of the L-asparaginase. This potentiation was decreased at higher dose levels of L-asparaginase. L-leucine, L-arginine and theophylline also potentiated glucose-induced insulin release in the presence of L-asparaginase. This potentiation was intact in the presence of all doses of L-asparaginase tested. Glucose induced insulin release, from collagense isolated islets obtained from male New Zealand White rabbits rendered hypoinsulinemic and diabetic by daily intravenous injections of L-asparaginase in vivo, was similar to that of islets of non diabetic control rabbits when the islets were incubated in vitro in te absence of L-asparaginase. These data suggest that the hypoinsulinemic diabetic syndrome produced by the anti-tumor enzyme, L-asparaginase, is produced at least in part by the suppression of insulin release and that this suppression requires the enzyme to be present.
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PMID:E. coli L-asparaginase and insulin release in vitro. 675 34

The effect of arginine infusion on blood glucose and plasma levels of insulin, C-peptide and glucagon has been studied in leukemic children before and after treatment with L-asparaginase (10,000 U/m2/day for 10 days). Therapy induced a significant reduction in basal and peak blood glucose, insulin and C-peptide levels, while glucagon was unmodified. The conserved C-peptide-insulin molar ratio suggests the interference of L-asparaginase with proinsulin synthesis. In conclusion our results prove a decreased insulin reserve with a preserved, although reduced, beta-cell function.
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PMID:Pancreatic endocrine function in leukemic children treated with L-asparaginase. 676 89


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