Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.3.2.3 (glutathione synthetase)
 678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

High doses of orally administered vitamin E (1000 IU/day) have been given to ten normal volunteers. Ten control subjects received placebo. Red blood cell glutathione was significantly higher in treated subjects than in the controls (controls: 267.5 +/- 15.7 micrograms/mL; treated: 374.8 +/- 17.3 micrograms/mL). These findings could be explained by an increase of glutathione synthesis brought about by the stimulation of glutathione synthetase activity. An alternative possibility is a reduced utilization of glutathione for the detoxification of free radicals. These two mechanisms could be effective in counteracting the glutathione content feedback of the synthetizing enzymes.
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PMID:Vitamin E and red blood cell glutathione. 402 3

We have studied the effects of acetaminophen metabolites generated by a murine hepatic microsomal system on lymphocytes from two subjects heterozygous for glutathione synthetase deficiency. Heterozygous cells exhibited greater dose-related toxicity than controls. Following a 2-h incubation with acetaminophen and the microsomal system, cells were washed and incubated for 16 h in the presence or absence of N-acetylcysteine, the standard antidote for acetaminophen toxicity. In control cells, glutathione content was replenished to nearly base-line values and toxicity was prevented. N-Acetylcysteine thus prevented toxicity even after covalent binding of acetaminophen metabolites had occurred. Heterozygous cells failed to use N-acetylcysteine as efficiently to resynthesize glutathione, and the cells were not protected from acetaminophen toxicity. Heterozygotes may be at increased risk of toxicity from drugs whose metabolites are detoxified by glutathione conjugation.
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PMID:Acetaminophen toxicity in lymphocytes heterozygous for glutathione synthetase deficiency. 404 89

Two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria) were investigated. Assays of erythrocyte enzyme levels in relatives revealed additional clinically healthy carriers. The girls had chronic metabolic acidosis, which was corrected by substitution with bicarbonate. They had an increased rate of hemolysis which was well compensated. Their granulocyte function was normal when tested in vitro. In both girls mental retardation developed progressively without additional clinical neurological symptoms. Their electroretinograms were abnormal indicating disturbed retinal electrophysiological function. Therapeutic trials were performed with oral administration of glutathione (Tathion), mercaptopropionylglycine (Thiola) and vitamin E. None of these compounds had an effect on the urinary excretion of 5-oxoproline, acid-base balance, pathological electroretinograms or the clinical condition. Initially, Thiola therapy increased the low levels of glutathione in patient erythrocytes but after several months of treatment the concentration of glutathione declined to pretreatment levels. There was no indication that orally administered glutathione, mercaptopropionylglycine or vitamin E had a beneficial effect in the doses used. Nevertheless, vitamin E administration has been continued in addition to the correction of acidosis with sodium bicarbonate.
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PMID:Ophthalmological, psychometric and therapeutic investigation in two sisters with hereditary glutathione synthetase deficiency (5-oxoprolinuria). 404 46

Enzyme studies on placenta, cultured skin fibroblasts, and erythrocytes from two sisters with the inborn error 5-oxoprolinuria (pyroglutamic aciduria) indicate that the metabolic lesion in this disease is at the glutathione synthetase (EC 6.3.2.3) step of the gamma-glutamyl cycle. Excessive urinary excretion of 5-oxoproline by these patients appears to be associated with increased synthesis of gamma-glutamyl-cysteine and formation of 5-oxoproline from this dipeptide. Thus, 5-oxoproline is produced in amounts that exceed the normal capacity of 5-oxoprolinase to convert it to glutamate. The data indicate that it may be possible to identify individuals who are heterozygous for this trait by determinations of erythrocyte glutathione synthetase.
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PMID:Glutathione synthetase deficiency, an inborn error of metabolism involving the gamma-glutamyl cycle in patients with 5-oxoprolinuria (pyroglutamic aciduria). 415 48

Spectrophotometric assay methods are described for glutathione synthetase, gamma-glutamylcysteine synthetase and gamma-glutamyl transpeptidase of erythrocytes. The contents of these enzymes in normal human erythrocytes are reported. Erythrocyte glutathione synthetase is inhibited by ADP; this inhibition is competitive with respect to ATP. gamma-Glutamylcysteine synthetase is subject to feedback inhibition by GSH, and is also inhibited by NADH, and to a lesser extent by NAD(+) and NADPH. This enzyme is irreversibly inactivated by cysteamine.
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PMID:Studies in the enzymology of glutathione metabolism in human erythrocytes. 438 10

1. An improved radioassay for glutathione synthetase and gamma-glutamylcysteine synthetase was developed. 2. Xenopus laevis liver gamma-glutamylcysteine synthetase was purified 324-fold by saline-bicarbonate extraction, protamine sulphate precipitation, CM-cellulose and DEAE-cellulose column chromatography, and gel filtration. 3. Rat liver gamma-glutamylcysteine synthetase was purified 11400-fold by a procedure similar to that employed for the Xenopus laevis enzyme. 4. Rat liver gamma-glutamylcysteine synthetase activity was inhibited by GSH and activated by glycine. These effects, which were not found in the enzyme from Xenopus laevis, may have a regulatory significance. 5. Isotope-exchange experiments revealed fundamental differences in the partial reactions catalysed by the rat and Xenopus laevis synthetases. The enzyme from Xenopus laevis appears to follow a Bi Bi Uni Uni Ping Pong mechanism, with glutamyl-enzyme as intermediate before the addition of cysteine and the release of gamma-glutamylcysteine. The results for the rat liver enzyme are consistent with a Tri Tri sequential mechanism.
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PMID:Assay, purification, properties and mechanism of action of gamma-glutamylcysteine synthetase from the liver of the rat and Xenopus laevis. 474 28

The two enzymes required to synthesize glutathione de novo have been purified from human erythrocytes. Glutamylcysteine synthetase was purified 4300-fold and was approximately 80% pure based on polyacrylamide gel electrophoresis. The purified enzyme catalyzes the formation of 30.5 mumoles of gamma-glutamyl-cysteine per mg of protein per hr and is inhibited by sulfhydryl inhibitors. Glutathione synthetase was purified 6000-fold from erythrocytes to homogeneity as determined by polyacrylamide gel electrophoresis. The erythrocyte enzyme has a molecular weight of 150,000 and catalyzes the formation of 35.9 mumoles of glutathione per mg of protein per hr. Comparison of the amino acid composition and some kinetic parameters of yeast glutathione synthetase and the erythrocyte enzyme demonstrate similarities between these enzymes.
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PMID:Glutathione synthesis in human erythrocytes. II. Purification and properties of the enzymes of glutathione biosynthesis. 509 71

Evidence is presented that rat kidney contains enzymes that catalyze the synthesis and utilization of glutathione; these reactions, which involve the uptake and release of amino acids from gamma-glutamyl linkage, constitute a cyclical process which is termed "the gamma-glutamyl cycle." The gamma-glutamyl cycle has properties that fulfill the requirements of an amino acid transport system. Thus, gamma-glutamyl transpeptidase may function in translocation and gamma-glutamylcysteine synthetase and glutathione synthetase may catalyze energy-requiring "recovery" steps in transport. These and other considerations suggest that glutathione serves a carrier function in amino acid transport.
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PMID:The gamma-glutamyl cycle: a possible transport system for amino acids. 527 54

The two enzymes required for de novo glutathione synthesis, glutamyl cysteine synthetase and glutathione synthetase, have been demonstrated in hemolysates of human erythrocytes. Glutamyl cysteine synthetase requires glutamic acid, cysteine, adenosine triphosphate (ATP), and magnesium ions to form gamma-glutamyl cysteine. The activity of this enzyme in hemolysates from 25 normal subjects was 0.43+/-0.04 mumole glutamyl cysteine formed per g hemoglobin per min. Glutathione synthetase requires gamma-glutamyl cysteine, glycine, ATP, and magnesium ions to form glutathione. The activity of this enzyme in hemolysates from 25 normal subjects was 0.19+/-0.03 mumole glutathione formed per g hemoglobin per min. Glutathione synthetase also catalyzes an exchange reaction between glycine and glutathione, but this reaction is not significant under the conditions used for assay of hemolysates. The capacity for erythrocytes to synthesize glutathione exceeds the rate of glutathione turnover by 150-fold, indicating that there is considerable reserve capacity for glutathione synthesis. A patient with erythrocyte glutathione synthetase deficiency has been described. The inability of patients' extracts to synthesize glutathione is corrected by the addition of pure glutathione synthetase, indicating that there is no inhibitor in the patients' erythrocytes.
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PMID:Glutathione biosynthesis in human erythrocytes. I. Identification of the enzymes of glutathione synthesis in hemolysates. 554 17

Glutathione is synthesized from gamma-glutamylcysteine and glycine via the action of glutathione synthetase. It is known that gamma-glutamylcyclotransferase is present in many cells and may convert gamma-glutamylcysteine to 5-oxoproline and cysteine, but until now there has not been a credible explanation for the apparent suppression of the gamma-glutamylcyclotransferase reaction during glutathione synthesis. Our data suggest that the gamma-glutamylcyclotransferase and glutathione synthetase pathways are regulated by a simple kinetic mechanism that favors the synthesis of glutathione.
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PMID:Regulation of gamma-glutamylcysteine utilization in erythrocytes. 610 48


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