Disease relevance of Z1051m

• The crystal structure of Escherichia coli asparaginase II (EC 3.5.1.1), a drug (Elspar) used for the treatment of acute lymphoblastic leukemia, has been determined at 2.3 A resolution by using data from a single heavy atom derivative in combination with molecular replacement [1].
• For this study, 118 children with standard-risk acute lymphoblastic leukemia (ALL) were given randomized assignments to receive native or pegylated Escherichia coli asparaginase as part of induction and 2 delayed intensification phases [2].
• We conclude that (1) dexrazoxane does not interfere with the antileukemic effect of doxorubicin, (2) intensive intrathecal chemotherapy is as effective as cranial radiation in preventing CNS relapse in standard-risk patients, and (3) once-weekly Erwinia is less toxic than E coli asparaginase, but also less efficacious [3].
• Compared with E coli asparaginase, Erwinia asparaginase was associated with a lower incidence of toxicity (10% versus 24%), but also an inferior 5-year EFS (78% +/- 4% versus 89% +/- 3%, P = .01) [3].
• Asparaginase is an enzyme used in the treatment of acute lymphoblastic leukemia and lymphoblastic lymphoma in children [4].

High impact information on Z1051m

• There was correlation between asparaginase enzymatic activity and depletion of asparagine or glutamine in serum [2].
• Patients treated with pegaspargase had more rapid clearance of lymphoblasts from day 7 and day 14 bone marrow aspirates and more prolonged asparaginase activity than those treated with native asparaginase [2].
• RESULTS: Antibodies were detectable in 54 patients (35.5%), of whom 30 (55.6%) exhibited hypersensitivity to asparaginase [5].
• Prevention of methotrexate cytotoxicity by asparaginase inhibition of methotrexate polyglutamate formation [6].
• These data demonstrate that the nutrient stress response to asparaginase is tissue-specific and exacerbated by glutamine depletion [7].

Chemical compound and disease context of Z1051m

• The relapse rate in childhood acute lymphoblastic leukemia (ALL) is approximately 30% but few reinduction regimens have investigated the intensive use of polyethylene glycol Escherichia coli asparaginase (PEG-Asp) [8].
• Intrathecal injection of E. coli asparaginase resulted in complete depletion of CSF asparagine for at least 5 days [9].
• 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 [6].
• The crystal structure of Escherichia coli isoaspartyl aminopeptidase/asparaginase (EcAIII), an enzyme belonging to the N-terminal nucleophile (Ntn)-hydrolases family, has been determined at 1.9-A resolution for a complex obtained by cocrystallization with l-aspartate, which is a product of both enzymatic reactions catalyzed by EcAIII [10].
• Escherichia coli asparaginase hydrolyzes both asparagine and glutamine: administration of this enzyme to mice is rapidly immunosuppressive [11].

Biological context of Z1051m

• E. coli asparaginase reduced protein synthesis in liver and spleen but not pancreas via increased phosphorylation of the translation factor eIF2 [7].
• Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia [12].
• Thus, glutamine deamination enhances asparaginase efficacy in ALL patients [13].
• There is immunological cross-reaction between the antibodies against various formulations of native Escherichia coli-asparaginase and polyethylene glycol (PEG)-asparaginases, but not to Erwinia asparaginase, as suggested by laboratory preclinical findings [13].
• The optimal catalysis of ASN and glutamine deamination in serum by asparaginase induces apoptosis of leukaemic lymphoblasts [13].

Anatomical context of Z1051m

• Cerebrospinal fluid asparagine concentrations after Escherichia coli asparaginase in children with acute lymphoblastic leukemia [14].
• Vibrio succinogenes asparaginase hydrolyzes only asparagine and has no apparent effect on immune system function [11].
• Studies have shown that ASN depletion is insufficient to induce apoptosis in T lymphoblasts in vitro and that the inhibitory concentration of CEM T-cell line is correlated with the asparaginase concentration responsible for 50% glutamine deamination [13].
• Mapping of B-cell epitopes in E. coli asparaginase II, an enzyme used in leukemia treatment [15].
• Asparaginase display of polypeptides in the periplasm of Escherichia coli: potential rapid pepscan technique for antigen epitope mapping [16].

Associations of Z1051m with chemical compounds

• Asparaginase modified with N-acetylneuraminyl lactose, in contrast, with approximately 13.6 mol of N-acetylneuraminyl lactose/mol of enzyme, is cleared more slowly, with a t 1/2 that is approximately twice that of the native enzyme [17].
• Two subclones were isolated, designated pDK1 and pDK2; the former complemented the partial defect in the utilization of aspartate, although its exact function was not established. pDK2 encoded the asparaginase I gene (ansA), the coding region of which was further defined within a 1.7-kilobase fragment [18].
• Modification of cystine or tryptophan residues in the asparaginase molecule and their role in conformation and antigenicity [19].
• Asparaginase activity was increased by the addition of L-glutamic acid, L-glutamine, or commercial-grade monosodium glutamate [20].
• Spectroscopic characterization of the modified enzymes allowed the unequivocal assignment of the histidine resonances in 1H-NMR spectra of asparaginase II [21].

Analytical, diagnostic and therapeutic context of Z1051m

• Hypersensitivity or development of antibodies to asparaginase does not impact treatment outcome of childhood acute lymphoblastic leukemia [5].
• PURPOSE: As part of pharmacologic studies of asparaginase (ASNase), we determined the half-life of ASNase activity and protein, and the effect of dose, repeated doses, different drug preparations, and hypersensitivity reactions on the half-life (t1/2) of serum ASNase activity [22].
• Biosensor for asparagine using a thermostable recombinant asparaginase from Archaeoglobus fulgidus [23].
• An enzyme-linked immunosorbent assay (ELISA) was used to measure anti-asparaginase antibodies in plasma samples, diluted 1:3200, using E. coli asparaginase as the antigen [24].
• A catalytic role for threonine-12 of E. coli asparaginase II as established by site-directed mutagenesis [25].

References