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 effect of dietary asparagine on rat growth was investigated. Diets were formulated with L-amino acids so as to contain asparagine, aspartic acid, glutamine and/or glutamic acid in all possible combinations and then fed to weanling rats for 3 weeks. Of the four, only asparagine was found to be essential for optimal growth, and it was essential regardless of the presence or absence of any dietary combination of these related amino acids. In selected dietary groups, the unbound asparagine levels were measured in various tissues over an 8-day period. Muscle asparagine levels were reduced for asparagine-deprived animals over the entire period studied; brain levels were decreased only after 7 days of dietary depletion, while hepatic levels were unaffected by dietary asparagine deprivation. In a related series, animals were more drastically depleted of asparagine by combining dietary deprivation with asparaginase treatment, causing a rapid decrease in cellular concentration of asparagine, which affected protein and DNA synthesis for those organs undergoing hyperplastic growth. Thus, asparagine may be rate limiting to protein synthesis for this extreme case as well as during dietary asparagine deprivation, which also decreased intracellular levels of unbound asparagine and led to irreversible deficits in development.
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PMID:An asparagine requirement in young rats fed the dietary combinations of aspartic acid, glutamine, and glutamic acid. 111 47

L-Asparaginase has long been used in the treatment of acute lymphoblastic leukemia or malignant lymphoma in childhood. To determine cell type specific sensitivity to this drug, the L-asparaginase-mediated inhibition of blastogenesis of human peripheral T or B lymphocytes was compared. The rate of incorporation of [3H]-thymidine into the DNA of either T lymphocytes due to phytohemagglutinin (PHA) or B lymphocytes due to Staphylococcus aureus Cowan I (SAC) was measured by the addition of Escherichia coli L-asparaginase in the medium. The blastogenic response of either T or B lymphocytes was also determined in medium depleted of exogenous asparagine and/or glutamine, both of which are hydrolyzed by this enzyme. The in vitro blastogenesis of either human T lymphocytes due to PHA or B lymphocytes due to SAC was inhibited by the inclusion of asparaginase in the medium. The deprivation of exogenous asparagine did not have any inhibitory effect on the blastogenic response of both T and B lymphocytes to each mitogen. On the other hand, the glutamine concentration in the culture medium provided a critical influence on the proliferative response of T and B lymphocytes. The rate of incorporation of [3H]-thymidine into DNA was increased markedly as the concentration of glutamine was increased from 2(-7)-2 mmol/l. It is concluded that the mechanism of inhibition of PHA- or SAC-stimulated lymphocyte blastogenesis by L-asparaginase is not asparagine deprivation but glutamine deprivation. Glutamine, which is the most abundant amino acid, is thought to have an important role in the immune response of lymphocytes.
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PMID:The inhibition of lymphocyte blastogenesis by asparaginase: critical role of glutamine in both T and B lymphocyte transformation. 128 1

Human glycoasparaginase (N4-(beta-N-acetyl-D-glucosaminyl)-L-asparaginase, EC 3.5.1.26) hydrolyzes a series of compounds that contain L-asparagine residue with free alpha-amino and alpha-carboxyl groups. Substrates include high mannose and complex type glycoasparagines as well as those that lack the di-N-acetylchitobiose moiety, L-aspartic acid beta-methyl ester and L-aspartic acid beta-hydroxamate. The enzyme is inactive toward L-asparagine and L-glutamine and glycoasparagines containing substituted alpha-amino and/or alpha-carboxyl groups. In the presence of the acyl acceptor hydroxylamine, glycoasparaginase catalyzes the synthesis of L-aspartic acid beta-hydroxamate from aspartyl-glucosamine, L-aspartic acid beta-methyl ester, and L-aspartic acid. 13C NMR studies using 18O-labeled L-aspartic acid demonstrate that glycoasparaginase catalyzes an oxygen exchange between water and the carboxyl group at C-4 of L-aspartic acid. These results indicate that glycoasparaginase reacts as an exo-hydrolase toward the L-asparagine moiety of the substrates and the free alpha-amino and alpha-carboxyl groups are required for the enzyme reaction. The results are consistent with an L-asparaginase-like reaction pathway which involves a beta-aspartyl enzyme intermediate. Since glycoasparaginase is active toward a series of structurally different glycoasparagines, we suggest the revised systematic name of N4-(beta-glycosyl)-L-asparaginase for the enzyme.
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PMID:Substrate specificity and reaction mechanism of human glycoasparaginase. The N-glycosidic linkage of various glycoasparagines is cleaved through a reaction mechanism similar to L-asparaginase. 155 92

Glutamine depletion strongly inhibits the replication of Rauscher murine leukaemia retrovirus (RLV) in vitro. Pseudomonas 7A glutaminase-asparaginase (PGA), capable of depleting glutamine and asparagine for prolonged periods, was used to determine the therapeutic effectiveness of glutamine depletion in mice infected with RLV or Friend virus. During PGA treatment of viraemic animals, serum reverse transcriptase activity fell to control levels and infected animals did not develop splenomegaly. The therapeutic results obtained with PGA compared favourably with those of azidothymidine given intraperitoneally at 30 mg/kg/day. Western blots performed on splenic tissue from control and treated animals indicated that glutamine depletion prevented readthrough of an amber codon at the gag-pol junction, stopping translation of viral mRNA at that point. Treatment of RLV-infected animals with PGA resulted in nearly a 200% increase in mean survival time even when therapy was initiated late in the course of the disease. To our knowledge, this is the first demonstration that a nutrient required for viral replication can be enzymically depleted in vivo to inhibit viral replication.
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PMID:Inhibition of mouse retroviral disease by bioactive glutaminase-asparaginase. 170 10

Natural amino acids possessing common antiamino acids are divided into groups and families according to the genetic code algorithm a-n-n-a (amino acid-codon-anticodon-antiamino acid). In an attempt to study structural evolution of amino acid families, artificial genetic code models were constructed. It is suggested that after inclusion of asparaginase and glutamine into the coding system, one of the two natural amino acid families is split into two parts ("half-families").
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PMID:[The evolution of the structures of amino acid families]. 179 5

An L-asparaginase producing mesophilic fungus Cylindrocarpon obtusisporum MB-10 was isolated from soil. The constitutive intracellular L-asparaginase from the organism was purified. The enzyme after 65-fold purification with an overall yield of 11% and specific activity of 100 unit.mg-1 seemed to be homogeneous in native, SDS-PAGE and thin layer isoelectric focusing gel. The apparent Mr of the enzyme was 216,000, and it constituted four identical subunits. The pI of the enzyme was 5.5. It was a conjugate protein with 37.3% (w/w) carbohydrate. The enzyme was stable to storage at -20 degrees C and to repeated freezing and thawing. The L-asparaginase from the organism was very much specific for L-asparagine and did not hydrolyze D-asparagine and L-glutamine. The pH and temperature optima for the enzyme activity were 7.4 and 37 degrees C, respectively. The Km of the L-asparaginase was found to be 1 x 10(-3)M. Metal ions, such as Zn2+, Fe2+, Cu2+, Hg2+ and Ni2+ potentially inhibited the enzyme activity, while metal chelators like EDTA, CN-, cysteine, etc., enhanced the activity indicating that the enzyme was not a metalloprotein. Its activity was also enhanced in the presence of reduced glutathione but not with dithiothreitol and 2-mercaptoethanol. Differential inhibition of the enzyme activity was observed with iodoacetamide and p-chloromercuribenzoate, thus indicating possible involvement of free-SH group in the enzyme catalysis.
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PMID:Purification and properties of an L-asparaginase from Cylindrocarpon obtusisporum MB-10. 208 Sep 24

We performed analyses of electrolytes, amino acids, albumin, alpha 2-macroglobulin, gamma-globulin and LDH in the lumbar cerebrospinal fluid of children undergoing treatment for acute lymphoblastic leukemia, non-Hodgkin-lymphoma or acute myeloid leukemia. At the time of diagnosis signs of a disturbance of the blood-brain barrier were found in some patients. During induction treatment with L-asparaginase a rise of glutamic acid and a decrease of glutamine occurred. This finding correlated with slowing of the EEG. Treatment with vincristine was associated with a slight drop of sodium and chloride concentration in serum, but not in the cerebrospinal fluid. Central nervous system prophylaxis with cranial irradiation, and to a lesser degree with intravenous medium-dose methotrexate, gave rise to a further deterioration of the blood-brain barrier function as indicated by an increase in albumin, alpha 2-macroglobulin and LDH levels. During radiotherapy the concentration of several amino acids rose, probably due to a disturbance of active carrier mechanisms. Patients with elevated albumin at the end of radiotherapy more often suffered an early leukemia relapse while still on treatment. No other clinical or electroencephalographic correlations of altered barrier function could be found.
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PMID:Electrolytes, amino acids and proteins in lumbar CSF during the treatment of acute leukemia in childhood. 233 48

A high L-asparaginase (L-asparagine amidohydrolase: EC 3.5.1.1) activity was found under conditions of lysine overproduction in cultures of Corynebacterium glutamicum. L-Asparaginase was purified 98-fold by protamine sulphate precipitation. DEAE-Sephacel anion exchange, ammonium sulphate precipitation and Sephacryl S-200 gel filtration. The asparaginase protein was subjected to PAGE under non-denaturing conditions, identified by an in situ reaction and eluted from the gel in an active form. The estimated Mr from gel filtration and SDS-PAGE was 80,000. The L-asparaginase activity was inhibited by the L-asparagine analogue 5-diazo-4-oxo-L-norvaline. Neither D-asparagine nor L-glutamine was a substrate for the enzyme. L-Asparaginase was produced constitutively: its role may be that of an overflow enzyme, converting excess asparagine into aspartic acid, the direct precursor of lysine and threonine.
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PMID:Characterization and partial purification of L-asparaginase from Corynebacterium glutamicum. 239 90

A human histiocytic lymphoma cell line, U937, is highly sensitive to L-asparaginase with an ID50 of about 0.0001 U/ml after 72 hr of culture. When U937 cells were made resistant to either L-asparaginase (1 U/ml) or asparagine deprivation, the activity of asparagine synthetase increased to 80- or 7-fold of the wild type, respectively. The phenotype of the resistance to L-asparaginase turned out to be stable under nonselective conditions for over several months. The hybrids between L-asparaginase sensitive (Molt4) and resistant (HL-60) cell lines revealed the latter phenotype in terms of L-asparaginase sensitivity and the activity of asparagine synthetase. Furthermore, U937 cells resistant to L-asparaginase could survive in glutamine-free media with 1.5-fold elevation of glutamine synthetase activity. These results altogether clarify the role of asparagine synthetase in L-asparaginase toxicity and have a good implication for the clinical use of L-asparaginase.
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PMID:Biochemical characterization of U937 cells resistant to L-asparaginase: the role of asparagine synthetase. 256 53

Escherichia coli asparaginase (Asnase) pretreatment of Asnase-sensitive L5178Y cells in vitro is thought to antagonize methotrexate (MTX) cytotoxicity through nonspecific inhibition of protein synthesis and MTX uptake. We have reexamined the mechanism of this interaction in view of recent data demonstrating the importance of MTX metabolism to polyglutamate derivatives (MTXPGs) in the cytotoxic effects of the antifolate. After a 3-hr exposure to 0.5 microM MTX, 67% of intracellular drug was in the form of MTXPGs containing a total of 2 to 5 glutamyl residues (MTX-Glu2-5), and cloning efficiency in drug-free medium was only 7% of untreated control. After a 3-hr pretreatment with E. coli Asnase (0.1 unit/ml), [3H]thymidine incorporation dropped by 29%, MTXPG formation during subsequent MTX exposure decreased by more than one-half (MTX-Glu2 unchanged; MTX-Glu3 and 4 decreased to 51.7 and 18.5% of levels achieved in cells not pretreated with Asnase; no MTX-Glu5 formed), and cloning efficiency increased to 71% of untreated control. This effect was not due to decreased MTX uptake into L5178Y cells or to decreased intracellular free L-glutamate or L-glutamine levels. A 3-hr exposure of L5178Y cells to media lacking L-isoleucine, an essential amino acid for cell growth, prior to MTX exposure inhibited [3H]thymidine incorporation by 37%, decreased subsequent MTXPG formation by 62%, and increased subsequent cloning in drug-free medium to control levels. Decreased MTXPG formation was responsible for the prevention of MTX cytotoxicity seen after both pretreatments. Unmetabolized MTX rapidly left L5178Y cells after removal of extracellular MTX. Consequently, lower levels of unbound intracellular drug, a prerequisite of drug activity, were maintained in pretreated than in control cells after passage in drug-free medium. Asnase pretreatment protects L5178Y cells from the cytotoxic effects of MTX, possibly through inhibition of cell growth which nonspecifically decreases MTXPG formation.
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PMID:Prevention of methotrexate cytotoxicity by asparaginase inhibition of methotrexate polyglutamate formation. 257 94


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