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 immunosuppressive effects and circulating life of Achromobacter glutaminase-asparaginase (GA) covalently attached to polyethylene glycol (PEG) were examined in human subjects following a single iv dose of 1000 IU/m2. Plasma half-life of PEG-GA was 72 hours. Skin test reactivity to recall antigens (mumps and tuberculin) was lost in all four patients tested. In vitro phytohemagglutinin-induced blastogenesis, "natural killing," and phytohemagglutinin-induced cell cytotoxicity was diminished as long as enzyme levels were detectable. In vivo and in vitro activities returned to normal following total plasma clearance of enzyme.
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PMID:Immunosuppressive properties and circulating life of Achromobacter glutaminase-asparaginase covalently attached to polyethylene glycol in man. 729 53

The dramatic clinical responses to L-asparaginase led to renewed interest in other enzymes that might be effective antitumor agents. Biochemical and nutritional studies on animal and human tumors have shown that enzymatic depletion of glutamine, arginine, cysteine, citrulline, and serine could have selective cytotoxicity for some tumors. Several glutaminase-asparaginase enzymes have antitumor activity in animals and man. These enzymes are currently in phase I trials. Arginine-depleting enzymes with suitable properties of therapy have been developed and are in preclinical study. Enzymes have not yet been found that can adequately deplete circulating levels of cysteine, citrulline, or serine for treatment of cancer.
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PMID:Enzyme therapy of cancer, future studies. 734 58

Succinylated Acinetobacter glutaminase-asparaginase (SAGA) has broader antitumor activity than Escherichia coli L-asparaginase in experimental systems; moreover, drug resistance does not develop in tumor cell lines initially sensitive to this enzyme. We have investigated the pharmacology and toxicology of SAGA after both single-dose and serial daily dose injections in 20 adult patients. Glutaminase activity in plasma after i.v. injection of single doses did not follow simple first-order kinetics (half-life during the initial 24 hr was 21 +/- 9 hr. A linear relation was observed between increasing doses of SAGA and resultant levels of plasma enzyme activity and blood glutamate. Assay of whole blood which had been deproteinized immediately following phlebotomy showed that single doses of SAGA lowered glutamine only transiently to nondetectable levels; serial daily doses were required to achieve and maintain continuous glutamine depletion. Reversible depression of the central nervous system, ranging from encephalopathy to coma, occurred in a dose-related manner and was dose limiting. Other prominent reactions included respiratory alkalosis, hyperglycemia, nausea, and vomiting. Transient antitumor effects were noted in two patients with solid tumors and in two patients with leukemia. SAGA causes considerable neurotoxicity in adults which requires close patient monitoring. Phase II studies in leukemic patients are in progress.
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PMID:Phase I evaluation of succinylated Acinetobacter glutaminase-asparaginase in adults. 743 89

Oral binders remove intestinal bile acid and prevent its reabsorption and recycling thereby lowering systemic cholesterol levels. The results in this paper demonstrate the presence of another extensive enterorecirculation for amino acids. Pancreatic and other glandular secretions into the intestine contain large amounts of proteins, enzymes and polypeptides. Tryptic digestion converts these into amino acids which are then reabsorbed back into the body as they pass down the intestine. This paper shows that this forms a large enterorecirculation of amino acids between the body and intestine. The dietary protein source of amino acids is negligible when compared to the endogenous source, since this paper shows that protein-free diet did not alter the intestinal amino acid concentration. This raises the possibility of using this for the selective depletion of specific body amino acids. In this paper we use a phenylketonuria (PKU) model in rats to test the use of this hypothesis. In PKU rats, artificial cells microencapsulated phenylalanine ammonia lyase (PAL) given orally is more effective than a phenylalanine-free diet. The enzyme artificial cells are more efficient in lowering PHE in the intestine, plasma and cerebrospinal fluid. Compared to PKU on PHE-free diet, this has resulted in better weight gain and general physical condition. Preliminary studies also show that artificial cells microencapsulated asparaginase, glutaminase and tyrosinase given orally can deplete the corresponding amino acid from the intestine.
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PMID:A new theory of enterorecirculation of amino acids and its use for depleting unwanted amino acids using oral enzyme-artificial cells, as in removing phenylalanine in phenylketonuria. 771 40

The review summarizes and analyzes experimental evidence for the properties of glutamine(asparagine)ase from Pseudomonas aurantiaca-548. The enzyme is a tetramer having a molecular weight of 148 kD and consisting of 4 identical subunits having a molecular weight of 37 kD. For glutaminase activity, the optimum pH is in the range of 6.0-8.0, asparaginase activity increases as pH rises. The enzyme is maximally stable at pH 6.8-8.0. The Michaelis constants are 5.3 +/- 0.7 x 10(-6) M for L-glutamine and 5.7 +/- 0.1 x 10(-6) M for asparagine. The reaction products L-aspartate and L-glutamate are competitive inhibitors anazaserine and 6-diase-5-oxo-1-norleucine are classic inhibitors of glutamine(asparagine)ase. The review also presents data on the conditions for culturing Ps. aurantiaca, on the procedures for isolating glutamine(asparagine)ase from biomass of this microbe, on substrate specificity. The results of searching for regulators of catalytic activity, as well as agents enhancing the resistance of enzymes to heat exposures are considered in the paper. Whether the properties of glutamine(asparagine)ase are in conformity with the criteria for primary choice of promising antitumor agents is discussed.
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PMID:[Molecular and catalytic properties of bacterial glutamin-(asparagin-)ase]. 775 33

In T. thermophila two forms of L-asparaginase (EC 3.5.1.1) were extracted and purified to near homogeneity which are associated with membranes. These two forms of L-asparaginase, I or II, act optimally at pH 8.6 and do not present any glutaminase or kinase activity. Both activities reach maximal values at the stationary phase of growth of T. thermophila. L-Asparaginases are solubilized by treatment of the particulates with 2% w/v Triton X-100 and then by sodium phosphate buffer pH 8.0. Both forms cross reacted with antibodies raised against T. pyriformis L-asparaginase and show isoelectric points 7.4 and 8.2. Among the metals tested, Ca2+ is the most effective in activating L-asparaginase I or II activity. Sorbitol alone up to 30% w/v in the assay mixture activates more than 10 x fold the activity of L-asparaginase II. Incubation of L-asparaginase I or II with increasing concentration of phospholipase C results in gradually loss of their activities. The relative effectiveness of a variety of phospholipids to reconstitute enzyme activity is presented as well.
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PMID:Two forms of L-asparaginase in Tetrahymena thermophila. 801 91

The amino acid sequence and a 2-A-resolution crystallographic structure of Pseudomonas 7A glutaminase-asparaginase (PGA) have been determined. PGA, which belongs to the family of tetrameric bacterial amidohydrolases, deamidates glutamine and asparagine. The amino acid sequence of PGA has a high degree of similarity to the sequences of other members of the family. PGA has the same fold as other bacterial amidohydrolases, with the exception of the position of a 20-residue loop that forms part of the active site. In the PGA structure presented here, the active site loop is observed clearly in only one monomer, in an open position, with a conformation different from that observed for other amidohydrolases. In the other three monomers the loop is disordered and cannot be traced. This phenomenon is probably a direct consequence of a very low occupancy of product(s) of the enzymatic reaction bound in the active sites of PGA in these crystals. The active sites are composed of a rigid part and the flexible loop. The rigid part consists of the residues directly involved in the catalytic reaction as well as residues that assist in orienting the substrate. Two residues that are important for activity residue on the flexible loop. We suggest that the flexible loops actively participate in the transport of substrate and product molecules through the amidohydrolase active sites and participate in orienting the substrate molecules properly in relation to the catalytic residues.
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PMID:Structural characterization of Pseudomonas 7A glutaminase-asparaginase. 806 64

To determine whether the activities of certain hydrolases (arylesterase, beta-glucuronidase, cathepsin L, plasminogen activators, arginase, glutaminase, asparaginase and adenosine deaminase) are changed during pregnancy, three groups of 15 apparently healthy women (aged 18-38 years) in their first, second and third trimester of pregnancy were compared to a control group formed of 15 non-pregnant women of similar ages. Enzyme and specific activities gradually increased from the first to the end of the third trimester of pregnancy for arylesterase and beta-glucuronidase, these increases being statistically significant (P < 0.01) in comparison to controls. However, as regards cathepsin L and plasminogen activators, the greatest increase was found in the second trimester. Arginase, glutaminase and asparaginase activities were very low and not distinguishable from the controls. In conclusion, differences in the activities of several hydrolases have been found in the sera of healthy pregnant women in comparison to controls.
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PMID:Variation in serum arylesterase, beta-glucuronidase, cathepsin L and plasminogen activators during pregnancy. 893 58

Pseudomonas 7A glutaminase-asparaginase (PGA) catalyzes the hydrolysis of D- and L-isomers of glutamine and asparagine. X-ray quality type-1 crystals of PGA have been obtained from 2.0 M ammonium sulfate. The space group is C222(1) with unit-cell dimensions a = 78.62, b = 135.80, and c = 137.88 A. The tetrameric molecule is located on a crystallographic 2-fold axis, and two subunits form the asymmetric portion of the unit cell. The structure was solved by the molecular replacement method and refined at 1.7 A resolution to an R = 19.9% with a good geometry of the model, G = 0.05. The resultant electron density maps enabled us to resolve individual constituent atoms of most residues and introduce minor revisions to the amino acid sequence. The catalytic loop, Thr20-Gly40, is in the closed conformation with excellent electron density in both subunits. A sulfate ion and an ammonium ion are bound in the substrate binding site and interect with the loop. This interaction appears to be responsible for the observed closed conformation. New arguments supporting Thr20 as the catalytic nucleophile in the asparaginase activity are proposed.
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PMID:Ion binding induces closed conformation in Pseudomonas 7A glutaminase-asparaginase (PGA): crystal structure of the PGA-SO4(2-)-NH4+ complex at 1.7 A resolution. 902 Jul 92

Helicobacter pylori can utilise amino acids as the sole carbon energy source. The present study demonstrated that H. pylori grown in continuous culture in a defined medium containing glucose and amino acids utilised alanine, arginine, asparagine, aspartate, glutamine, glutamate, proline and serine. Specific asparaginase and glutaminase enzymes deaminated asparagine and glutamine respectively to aspartate and glutamate, with the production of ammonia. The glutaminase activity was inhibited by 6-diazo-5-oxo-L-norleucine. All the 13 strains of H. pylori tested produced both glutaminase and asparaginase activities. Glutamine is important in the health of the gastric and intestinal mucosa and is a primary energy source for lymphocytes. Depletion of glutamine at the site of H. pylori infection may be of significance in the pathogenesis of H. pylori-associated diseases such as peptic ulcer and gastric cancer.
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PMID:Amino acid utilisation and deamination of glutamine and asparagine by Helicobacter pylori. 929 92


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