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Biomedical subjects

A Meister

Publications and source records attributed to A Meister.

At least 181 records · Page 10Linked to original sources
PubMed1984

Radioprotection by glutathione ester: transport of glutathione ester into human lymphoid cells and fibroblasts.

Glutathione is not effectively transported into human lymphoid cells, normal human skin fibroblasts, and fibroblasts from patients with genetic deficiencies of gamma-glutamylcysteine synthetase or glutathione synthetase. On the other hand, the monoethyl ester of glutathione, in which the carboxyl group of the glycine residue is esterified, is readily transported into these cells and is hydrolyzed intracellularly. This leads to greatly increased cellular levels of glutathione, which often exceed those found normally. Glutathione ester was found to protect human lymphoid cells of the CEM line against the lethal effects of irradiation. Under the conditions employed, complete protection was found when the ester was added prior to irradiation. Addition of the ester after irradiation was partially effective, suggesting that GSH may also function in repair processes.

Biological Transport↗
PubMed1984

Biochemical studies of a patient with hereditary hepatorenal tyrosinemia: evidence of glutathione deficiency.

Metabolic and enzymatic studies in a patient with hereditary tyrosinemia demonstrated for the first time a deficiency of erythrocyte and hepatic glutathione. Markedly decreased hepatic fumarylacetoacetate hydrolase activity was demonstrated in this patient. The activities of hepatic enzymes not involved in tyrosine metabolism were also determined. Assay of mixed function oxidase activity demonstrated low levels of aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase, suggesting decreased hepatic detoxification capacity. 5-Aminolevulinic acid dehydratase activity was undetectable. Succinylacetone (4,6-dioxoheptanoic acid), an abnormal metabolic product secondary to fumarylacetoacetate hydrolase deficiency was found in serum and urine. Succinylacetone was demonstrated to inhibit 5-aminolevulinic acid dehydratase in vitro, as did the urine, plasma, and red cell lysates of the patient.

Erythrocytes↗
PubMed1983

Modulation of gamma-glutamyl transpeptidase activity by bile acids.

The free bile acids (cholate, chenodeoxycholate, and deoxycholate) stimulate the hydrolysis and transpeptidation reactions catalyzed by gamma-glutamyl transpeptidase, while their glycine and taurine conjugates inhibit both reactions. Kinetic studies using D-gamma-glutamyl-p-nitroanilide as gamma-glutamyl donor indicate that the free bile acids decrease the Km for hydrolysis and increase the Vmax; transpeptidation is similarly activated. The conjugated bile acids increase the Km and Vmax of hydrolysis and decrease both of these for transpeptidation. This mixed type of modulation has also been shown to occur with hippurate and maleate (Thompson, G.A., and Meister, A. (1980) J. Biol. Chem. 255, 2109-2113). Glycine conjugates are substantially stronger inhibitors than the taurine conjugates. The results with free cholate indicate the presence of an activator binding domain on the enzyme with minimal overlap on the substrate binding sites. In contrast, the conjugated bile acids, like maleate and hippurate, may overlap on the substrate binding sites. The results suggest a potential feedback role for bile ductule gamma-glutamyl transpeptidase, in which free bile acids activate the enzyme to catabolize biliary glutathione and thus increase the pool of amino acid precursors required for conjugation (glycine directly and taurine through cysteine oxidation). Conjugated bile acids would have the reverse effect by inhibiting ductule gamma-glutamyl transpeptidase.

Animals↗
PubMed1983

Selective modification of glutathione metabolism.

Glutathione, a tripeptide thiol found in virtually all cells, functions in metabolism, transport, and cellular protection. It participates in the reduction of disulfides and other molecules, and conjugates with compounds of exogenous and endogenous origin. It protects cells against the destructive effects of reactive oxygen intermediates and free radicals. Modifications of glutathione metabolism may be achieved by administration of selective enzyme inhibitors, and also by giving compounds that increase glutathione synthesis. Such effects are useful in chemotherapy and radiation therapy and in protecting cells against the toxic effects of drugs, other foreign compounds, and oxygen.

Animals↗
PubMed1983

Neonatal 5-oxoprolinuria: difficult-to-diagnose?

A male newborn infant presented with metabolic acidosis and haemolytic anaemia. Renal tubular acidosis was suspected in the absence of amino aciduria and the patient was treated with sodium bicarbonate. Two years later, the chronic acidosis, clinical observation of developmental delay and ataxia prompted further investigational studies. 5-Oxoprolinuria was identified by gas-liquid chromatography and confirmed by mass spectrometry after an initial mass spectrum analysis reported a glutamic acid artifact. Glutathione and glutathione synthetase in erythrocytes were 25% and 5% of control values, respectively. On the basis of neonatal metabolic acidosis, without amino aciduria and an elevated reticulocyte count, a recommendation is made for blood glutathione and urine 5-oxoproline screening, followed by glutathione synthetase assay for confirmation of neonatal 5-oxoprolinuria.

Acidosis↗
PubMed1983

Radioprotection of human lymphoid cells by exogenously supplied glutathione is mediated by gamma-glutamyl transpeptidase.

Human lymphoid cells depleted of glutathione by treatment with buthionine sulfoximine, a specific inhibitor of gamma-glutamylcysteine synthetase, may be partially repleted by adding glutathione in the medium. The mechanism of repletion involves the action of gamma-glutamyl transpeptidase on exogenous glutathione, transport of products of glutathione metabolism, and intracellular synthesis of glutathione. Lymphoid cells, previously shown to export glutathione at rates proportional to intracellular glutathione levels, do not take up intact glutathione to an appreciable extent, even under conditions of marked glutathione deficiency. The role of glutathione in radioprotection was examined by subjecting cells to gamma-radiation after modification of cellular glutathione levels. Glutathione-depleted cells exhibited increased radiosensitivity under aerobic conditions, as compared to the nondepleted controls. Partial repletion of cellular glutathione prior to irradiation led to radiosensitivity comparable to nondepleted controls. Cells were not protected by suspension in media containing glutathione just prior to irradiation; thus, protection appears to require intracellular glutathione.

Acyltransferases↗
PubMed1983

Transport of glutathione, as gamma-glutamylcysteinylglycyl ester, into liver and kidney.

Administration of gamma-glutamylcysteinylglycyl monomethyl (or monoethyl) ester to mice leads to substantial increases in the levels of glutathione in the liver and kidney. Mice depleted of glutathione by treatment with buthionine sulfoximine, a potent inhibitor of gamma-glutamylcysteine synthetase, exhibited about a 4-fold increase in liver and kidney glutathione levels after administration of glutathione monomethyl ester. This ester also prevented the marked decline in liver glutathione level found after giving mice acetaminophen, and it protected mice from toxicity due to this compound. The findings indicate that the monomethyl and monoethyl esters of glutathione are transported into cells and hydrolyzed to glutathione. Such esters may be useful in experimental work on glutathione metabolism and function and may provide a relatively safe method for protecting cells against damage by toxic compounds, oxygen, and radiation.

Animals↗
PubMed1983

Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis.

Administration of gamma-glutamylcystine or of gamma-glutamylcysteine disulfide to mice leads to significantly increased levels of glutathione in the kidney as compared to controls given glutamate plus cysteine (or cystinylbisglycine). Studies with gamma-glutamylcystine selectively labeled with 35S in either the internal or external S atom indicate preferential utilization of the gamma-glutamylcysteine moiety of this compound for glutathione synthesis. Mice depleted of glutathione by treatment with buthionine sulfoximine do not significantly use the disulfides gamma-glutamylcystine or gamma-glutamylcysteine disulfide but do use gamma-glutamylcysteine for glutathione synthesis. These findings suggest a pathway in which gamma-glutamylcystine, formed by transpeptidation between glutathione and cystine, is transported and reduced by transhydrogenation with glutathione to cysteine and gamma-glutamylcysteine; the latter is used directly for glutathione synthesis. The findings show transport of gamma-glutamyl amino acids, indicate an alternative pathway of glutathione synthesis, and demonstrate a means of increasing kidney glutathione levels.

Animals↗
PubMed1983

Glutathione.

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Acyltransferases↗
PubMed1982

Regulation of Escherichia coli carbamyl phosphate synthetase. Evidence for overlap of the allosteric nucleotide binding sites.

Regulation of Escherichia coli carbamyl phosphate synthetase by UMP and IMP was examined in studies with various analogs of these nucleotides. Whereas UMP inhibits enzyme activity, the arabinose analog of UMP was found to be an activator. dUMP neither activates nor inhibits, but binds to the enzyme in a manner similar to UMP as evaluated by direct binding studies, sedimentation behavior, and ultraviolet difference spectral measurements. dUMP decreases inhibition by UMP and activation by IMP, but has no effect on activation by L-ornithine. The findings are in accord with the view that IMP and UMP bind to the same region of the enzyme; a possible general model for such overlapping binding sites is considered. Additional evidence is presented that inorganic phosphate can modulate regulation of the activity by nucleotides. Phosphate (and arsenate) markedly increase inhibition by UMP, decrease activation by IMP, but do not affect activation by L-ornithine. The extent of activation by IMP and by L-ornithine and that of inhibition by UMP are decreased when Mg2+ concentrations are increased relative to a fixed concentration of ATP. The findings suggest that the allosteric effectors may affect affinity of the enzyme for divalent metal ions as well as, as previously shown, the affinity of the enzyme for Mg-ATP.

Allosteric Regulation↗
PubMed1982

New substrates of 5-oxo-L-prolinase.

Interaction of 5-oxo-L-prolinase (which catalyzes stoichiometric cleavage of 5-oxo-L-proline to L-glutamate coupled to that of cleavage of ATP to ADP and Pi), with a number of new 5-oxo-L-proline analogs was examined in studies in which (a) analogs were substituted for 5-oxo-L-proline and the formation of products was determined, (b) the effects of the analogs on the normal catalytic reaction were observed, and (c) the effects of the analogs on the ITPase activity exhibited by the enzyme were examined. Some of these reactions are partially coupled, i.e. the molar formation of ADP exceeds that of amino acid; others are uncoupled, i.e. cleavage of ATP, but not that of imino acid occurs. Analogs in which the 4-methylene moiety of 5-oxo-L-proline is replaced by O, S, and NH (L-2-oxooxazolidine-4-carboxylate, L-2-oxothiazolidine-4-carboxylate, and 2-imidazolidone-4-carboxylate) participate in reactions that are, partially coupled, coupled, and uncoupled respectively. Partial coupling occurs with cis- and trans-2-oxo-5-methyloxazolidine-4-carboxylate, and uncoupled reactions occur with L-2-iminothiazolidine-4-carboxylate, 2-thiazolinone-4-carboxylate, and 2-oxo-5,5-dimethylthiazolidine-4-carboxylate. These and earlier findings indicate that significant binding of the imino acid substrate requires a 5-carbonyl (or = NH), an unsubstituted N-1 and a C-2 of the L-configuration; substantial modification of 5-oxo-L-proline in the region of C-3 and C-4 is possible with retention of binding properties. Uncoupling and partial coupling may be associated with significant differences in the orientations of the analogs at the active site that facilitate (to various extents) the access of water to the nucleoside triphosphate.

Adenosine Triphosphate↗