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:6.3.2.3 (glutathione synthetase)
678 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neutrophils and monocytes are the prime defenders of the body against suppurative bacterial and fungal infections. To accomplish their role in inflammation, they must respond appropriately to chemotactic signals elaborated from complement and bacteria. This response predictably results in the adherence and subsequent directed movement of the phagocytes toward the infected area where they recognize opsonized microbes. Attachment of the microbes to the membrane of the cell leads to their ingestion and subsequent demise, principally by the reduced oxygen by-product H2O2, which is generated by the neutrophils and monocytes during phagocytosis. Optimal killing requires the translocation of granule myeloperoxidase into the phagocytic vacuole containing the bacteria and a suitable halide ion. Degranulation is controlled, in part, by assembled microtubules whereas ingestion requires assembly of submembrane microfilaments. Deficiency states resulting from vitamin E results in diminished membrane-related chemotaxis and ingestion, whereas depletion of cellular GSH results in defective microtubule assembly preventing the normal increase in adherence, chemotaxis, degranulation, and microbicidal activity of the phagocytic cells. Deficiency states resulting in dysfunction of the microtubule system include neutrophil glutathione synthetase deficiency, rodent glutathione peroxidase deficiency, and the Chediak-Higashi syndrome.
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PMID:Role of membrane vitamin E and cytoplasmic glutathione in the regulation of phagocytic functions of neutrophils and monocytes. 39 94

The administration of vitamin E (alpha-tocopherol) was found to improve polymorphonuclear leukocyte function in an infant with congenital deficiency of glutathione synthetase activity. Before therapy with vitamin E the abnormal leukocytes exposed to phagocytic challenge showed oxidant damage. They released 60 per cent more hydrogen peroxide than did normal leukocytes, iodinated only 20 to 25 per cent of the normal number of particles, and were unable to kill bacteria as effectively as normal leukocytes although the rates of phagocytosis were normal. These functional abnormalities disappeared when the patient was placed on 400 IU of alpha-tocopherol daily for three months. Associated with the functional improvement was a normalization of microtubule assembly during phagocytic challenge.
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PMID:Protection of granulocytes by vitamin E in glutathione synthetase deficiency. 48 37

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

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

Important insights have recently been derived from studies of inborn human defects of sulfur metabolism. Metabolic lesions responsible for homocystinuria have been elucidated, with possible implications for understanding atherogenesis in the general population. The cause of cystinosis remains enigmatic, but important information has been gained on the origin of some stored cystine from degraded protein. Cysteamine and ascorbic acid deplete the cystine content of cystinotic fibroblasts in vitro, and clinical trials with these agents have been undertaken. Studies of patients with glutathione synthetase deficiency have provided new understanding of the roles of glutathione as in antioxidant and as a modulator of microtubule-related processes. Studies of patients with this disorder and glucose-6-phosphate dehydrogenase deficiency, in which the capacity to maintain glutathione in the reduced state is compromised, indicate that pharmacologic doses of vitamin E can correct certain functional consequences of an inadequate supply of reduced glutathione both in erythrocytes and polymorphonuclear leukocytes. Much remains to be learned about the mechanisms of membrane damage in these states of enhanced oxidative susceptibility.
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PMID:Genetic disorders of glutathione and sulfur amino-acid metabolism. New biochemical insights and therapeutic approaches. 699 53

GSH, GSSG, vitamin E, and ascorbate were measured in 14-day cultures of chick astrocytes and neurons and compared with levels in the forebrains of chick embryos of comparable age. Activities of enzymes involved in GSH metabolism were also measured. These included gamma-glutamylcysteine synthetase, GSH synthetase, gamma-glutamyl cyclotransferase, gamma-glutamyltranspeptidase, glutathione transferase (GST), GSH peroxidase, and GSSG reductase. The concentration of lipid-soluble vitamin E in the cultured neurons was found to be comparable with that in the forebrain. On the other hand, the concentration of vitamin E in the astrocytes was significantly greater in the cultured astrocytes than in the neurons, suggesting that the astrocytes are able to accumulate exogenous vitamin E more extensively than neurons. The concentrations of major fatty acids were higher in the cell membranes of cultured neurons than those in the astrocytes. Ascorbate was not detected in cultured cells although the chick forebrains contained appreciable levels of this antioxidant. GSH, total glutathione (i.e., GSH and GSSG), and GST activity were much higher in cultured astrocytes than in neurons. gamma-Glutamylcysteine synthetase activity was higher in the cultured astrocytes than in the cultured neurons. GSH reductase and GSH peroxidase activities were roughly comparable in cultured astrocytes and neurons. The high levels of GSH and GST in cultured astrocytes appears to reflect the situation in vivo. The data suggest that astrocytes are resistant to reactive oxygen species (and potentially toxic xenobiotics) and may play a protective role in the brain.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Vitamin E, ascorbate, glutathione, glutathione disulfide, and enzymes of glutathione metabolism in cultures of chick astrocytes and neurons: evidence that astrocytes play an important role in antioxidative processes in the brain. 790 54

In the gamma-glutamyl cycle, hereditary defects have been described in four of the six enzymes namely: gamma-GC synthetase; GSH synthetase; gamma-glutamyl transpeptidase and 5-oxoprolinase. Mutants are still to be found in gamma-glutamyl cyclotransferase and in the dipeptidase. Deficiency of GSH synthatase or gamma-GC synthetases results in low levels of GSH. In gamma-GC synthetase deficiency hemolytic anemia is the most prominent symptom, with or without hepatosplenomegaly. In generalized GSH synthetase deficiency 5-oxoproline is overproduced due to lack of feedback inhibition of gamma-GC synthetase. These patients have metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and about 50% of them also have progressive neurological symptoms. Treatment includes acidosis correction, high doses of vitamin E and C and avoidance of drugs precipitating hemolytic crises in G6PD deficiency. Therapeutic trials with GSH analogues, N-acetylcysteine and GSH esters have been carried out. Glutathione synthetase deficiency restricted to erythrocytes results in hemolytic anemia but no 5-oxoprolinuria. gamma-Glutamyl transpeptidase deficiency is associated with GSH-emia and GSH-uria whereas 5-oxoprolinase deficiency is associated with 5-oxoprolinuria. In diagnostic work it must be emphasized that erythrocytes contain an incomplete gamma-glutamyl cycle; they lack both gamma-glutamyl transpeptidase and 5-oxoprolinase and these enzyme activities must therefore be analyzed in other types of cells such as leukocytes and fibroblasts. It is also important to investigate other patients with inherited defects in the gamma-glutamyl cycle to learn more about the biological role of GSH in man.
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PMID:Patients with genetic defects in the gamma-glutamyl cycle. 967 48

The exposure of Saccharomyces cerevisiae cells to 13-L-hydroperoxylinoleic acid (LOOH) caused their death, the degree of which was dependent on the growth phase of the cells. Pre-application of ethanol, hydrogen peroxide (H2O2) and LOOH to S. cerevisiae cells reduced the effect of LOOH on the cells, showing the transient cross adaptation to LOOH. Antioxidants such as N,N',-diphenyl-p-phenylenediamine (DPPD), melatonin and vitamin E, and inhibitors of permeability transition of mitochondria, cyclosporin A and trifluoperazine, inhibited the LOOH-triggered cell death, while an inhibitor of glutathione synthetase, buthionine sulfoximine (BSO), enhanced the cell death by LOOH. Reactive oxygen species (ROS) were detected by flow cytometry, using the ROS-specific fluorescent indicator. A ferric iron chelator, deferoxamine, inhibited the LOOH-triggered cell death, and peroxyl radicals (LOO.) were detected by a spin trapping method. These reactive radicals possibly induced the death of S. cerevisiae cells. However, the DNA fragmentation characteristic of apoptosis was not observed in S. cerevisiae cells after exposure to LOOH, staurosporine, dexamethasone or etoposide, which have been reported to cause apoptosis in mammalian cells.
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PMID:Generation of free radicals during the death of Saccharomyces cerevisiae caused by lipid hydroperoxide. 1042 87

In certain tissues, glutathione biosynthesis is connected to methionine metabolism via the trans-sulfuration pathway. The latter condenses homocysteine and serine to cystathionine in a reaction catalyzed by cystathionine beta-synthase followed by cleavage of cystathionine to cysteine and alpha-ketoglutarate by gamma-cystathionase. Cysteine is the limiting amino acid in glutathione biosynthesis, and studies in our laboratory have shown that approximately 50% of the cysteine in glutathione is derived from homocysteine in human liver cells. In this study, we have examined the effect of pro- and antioxidants on the flux of homocysteine through the trans-sulfuration pathway in the human hepatoma cell line, HepG2. Our studies reveal that pyrrolidine dithiocarbamate and butylated hydroxyanisole enhance the flux of homocysteine through the trans-sulfuration pathway as has been observed previously with the pro-oxidants, H(2)O(2) and tertiary butyl hydroperoxide. In contrast, antioxidants such as catalase, superoxide dismutase and a water-soluble derivative of vitamin E elicit the opposite effect and result in diminished flux of homocysteine through the trans-sulfuration pathway. These studies provide the first evidence for the reciprocal sensitivity of the trans-sulfuration pathway to pro- and antioxidants, and demonstrate that the upstream half of the glutathione biosynthetic pathway (i.e. leading to cysteine biosynthesis) is redox sensitive as is the regulation of the well-studied enzymes in the downstream half (leading from cysteine to glutathione), namely, gamma-glutamyl-cysteine ligase and glutathione synthetase.
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PMID:Redox regulation of homocysteine-dependent glutathione synthesis. 1263 46

Oxidative stress is a major contributing factor in neurodegeneration and can arise from dietary, environmental, and genetic sources. Here we examine the separate and combined impact of deprivation of folate and vitamin E, coupled with dietary iron as a prooxidant, on normal mice and transgenic mice lacking apolipoprotein E (ApoE-/- mice). Both mouse strains exhibited increased levels of glutathione when deprived of folate and vitamin E, but a substantial further increase was observed in ApoE-/- mice. To determine the mechanism(s) underlying this increase, we quantified transcription and activity of glutathione synthase (GS). Both normal and ApoE-/- mice demonstrated increased GS activity when deprived of folate and vitamin E. However, transcription was increased only in ApoE-/- mice deprived of folate and vitamin E. These findings demonstrate that deficiency in one gene can result in compensatory up-regulation in a second relevant gene and, furthermore, indicate that compensation for oxidative stress can occur in brain tissue at epigenetic and genetic levels depending on the nature and/or extent of oxidative stress.
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PMID:Increased transcription and activity of glutathione synthase in response to deficiencies in folate, vitamin E, and apolipoprotein E. 1474 34


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