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)

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

Two brothers, aged 16 and 11 years, had recurrent episodes of vomiting, diarrhoea and abdominal pain, starting in infancy. In spite of extensive investigations no cause of their enterocolitis could be established. After several years symptomatic treatment was discontinued without any recurrence of symptoms. Their father and several paternal relatives have had kidney stones. Both boys developed urolithiasis and an oxalate-containing stone was removed from the elder brother's kidney. He had no hypercalciuria. His glomerular and tubular function tests were normal. Gas chromatography of urine from both brothers revealed massive excretion of L-5-oxoproline (pyroglutamic acid). Glutathione levels in erythrocytes of both patients were normal. The activities of enzymes of the gamma-glutamyl cycle were analysed in erythrocytes, leukocytes and cultured skin fibroblasts. The level of glutathione synthetase was normal, as was the affinity of this enzyme for its substrate gamma-glutamyl-cysteine. Feedback inhibition of gamma-glutamyl-cysteine synthetase by glutathione was also normal. Both patients had a specific deficiency of 5-oxoprolinase, the activity of which was 2-4% of that of control subjects. Their parents had intermediate 5-oxoprolinase activities in fibroblasts, indicating a recessive mode of inheritance. Thus, 5-oxoprolinuria in these two patients was due to a lack of 5-oxoprolinase, i.e., a new inborn error in the gamma-glutamyl cycle.
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PMID:5-oxoprolinuria due to hereditary 5-oxoprolinase deficiency in two brothers--a new inborn error of the gamma-glutamyl cycle. 611 26

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.
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PMID:Neonatal 5-oxoprolinuria: difficult-to-diagnose? 640 9

Cultured skin fibroblasts from patients with 5-oxoprolinuria caused by hereditary deficiency of glutathione synthetase have decreased levels of the corresponding enzyme as well as of glutathione. Fibroblasts from the same patients accumulated gamma-glutamyl cysteine, but the levels were lower than those of glutathione in control fibroblasts. The uptake of [35S]cystine was equally rapid in control and patient fibroblasts. In the acid-soluble fraction gamma-glutamyl-[35S]cysteine accumulated in fibroblasts from patients but not from controls. Appreciable turnover of gamma-glutamyl cysteine and glutathione in the respective cell strains was observed, the half-lives of these pools being approximately 5 hours. The growth rate of mutant fibroblasts in culture was significantly slower than that of control fibroblasts. There was no significant accumulation of 5-oxoproline in the culture medium.
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PMID:Glutathione synthetase deficient human fibroblasts in culture. 665 19

Prenatal diagnosis was performed in a family affected by generalized glutathione synthetase deficiency. The disorder is transmitted by autosomal recessive inheritance. The first child born in this family died of the disorder at 6 weeks of age. Prenatal diagnosis was performed in two subsequent pregnancies. Amniotic fluid samples were collected by amniocentesis in the 16th and 17th weeks of pregnancy, respectively. In the case of the second pregnancy the concentration of 5-oxoproline in the amniotic fluid was measured by stable isotope dilution, while both stable isotope dilution and glutathione synthetase activity measurements were employed in the prenatal analysis of the third pregnancy. The 5-oxoproline concentration in the second pregnancy was even lower than that of the controls and in the case of the third pregnancy the results fell within the control range. The second pregnancy resulted in the birth of a clinically healthy girl, and the outcome of 5-oxoproline concentration in a urine sample taken just after birth confirmed the unaffected state. The third pregnancy resulted in the birth of a healthy boy at term, and the 5-oxoproline concentration in his urine and the glutathione synthetase activity in haemolysates were determined. The results confirmed that this infant was also unaffected and he apparently had two normal alleles for the enzyme.
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PMID:Prenatal analysis in two suspected cases of glutathione synthetase deficiency. 829 98

5-Oxoprolinuria (pyroglutamic aciduria) resulting from glutathione synthetase (GSS) deficiency is an inherited autosomal recessive disorder characterized, in its severe form, by massive urinary excretion of 5-oxoproline, metabolic acidosis, haemolytic anaemia and central nervous system damage. The metabolic defect results in low GSH levels presumably with feedback over-stimulation of gamma-glutamylcysteine synthesis and its subsequent conversion to 5-oxoproline. In this study, we cloned and characterized the human GSS gene and examined three families with four cases of well-documented 5-oxoprolinuria. We identified seven mutations at the GSS locus on six alleles: one splice site mutation, two deletions and four missense mutations. Bacterial expression and yeast complementation assays of the cDNAs encoded by these alleles demonstrated their functional defects. We also characterized a fifth case, an homozygous missense mutation in the gene in an individual affected by a milder-form of the GSS deficiency, which is apparently restricted to erythrocytes and only associated with haemolytic anaemia. Our data provide the first molecular genetic analysis of 5-oxoprolinuria and demonstrate that GSS deficiency with oxoprolinuria and GSS deficiency without 5-oxoprolinuria are caused by mutations in the same gene.
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PMID:Mutations in the glutathione synthetase gene cause 5-oxoprolinuria. 889 73

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

Pyroglutamic aciduria (5-oxoprolinuria) is a rare autosomal recessive disorder caused by either glutathione synthetase deficiency (GSSD) or 5-oxoprolinase deficiency. The severe form of the disease, generalized GSSD, is characterized by acute metabolic acidosis, usually present in the neonatal period with hemolytic anemia and progressive encephalopathy. We report a female infant who had a severe metabolic acidosis with high anion gap, hemolytic anemia, and hyperbilirubinemia. High level of 5-oxoproline was detected in her urine and a diagnosis of generalized GSSD was made. She died of severe metabolic acidosis and sepsis at the age of six weeks.
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PMID:A newborn infant with generalized glutathione synthetase deficiency. 1507 78

5-Oxoprolinuria is primarily associated with inborn errors of the gamma-glutamyl cycle. In addition, transient 5-oxoprolinuria has been reported to occur in a variety of conditions, such as prematurity and malnutrition, and during medication. We report an unusual case of permanent 5-oxoprolinuria. The patient presented 3 days after birth with acidosis, and metabolic screening revealed massive excretion of 5-oxoproline. Following recovery, growth and psychomotor development were normal, but 5-oxoprolinuria persisted. Primary defects in the gamma-glutamyl cycle were ruled out since glutathione synthase and 5-oxoprolinase activities were normal. All known secondary causes of 5-oxoprolinuria were also excluded, leaving the basis of the permanent 5-oxoprolinuria in this patient unresolved.
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PMID:Persistent 5-oxoprolinuria with normal glutathione synthase and 5-oxoprolinase activities. 1683 Feb 60

5-Oxoproline (pyroglutamic acid) accumulates in glutathione synthetase deficiency, an inborn metabolic defect of the gamma-glutamyl cycle. This disorder is clinically characterized by hemolytic anemia, metabolic acidosis and severe neurological disorders. Considering that the mechanisms of brain damage in this disease are poorly known, in the present study we investigated whether oxidative stress is elicited by 5-oxoproline. The in vitro effect of (0.5-3.0 mM) 5-oxoproline was studied on various parameters of oxidative stress, such as total radical-trapping antioxidant potential, total antioxidant reactivity, chemiluminescence, thiobarbituric acid-reactive substances, sulfhydryl content, carbonyl content, and 2',7'-dichlorofluorescein fluorescence, as well as on the activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase in cerebral cortex and cerebellum of 14-day-old rats. Total radical-trapping antioxidant potential and total antioxidant reactivity were significantly reduced in both cerebral structures. Carbonyl content and 2',7'-dichlorofluorescein fluorescence were significantly enhanced, while sulfhydryl content was significantly diminished. In contrast, chemiluminescence and thiobarbituric acid-reactive substances were not affected by 5-oxoproline. The activities of catalase, superoxide dismutase and glutathione peroxidase were also not altered by 5-oxoproline. These results indicate that 5-oxoproline causes protein oxidation and reactive species production and decrease the non-enzymatic antioxidant defenses in rat brain, but does not cause lipid peroxidation. Taken together, it may be presumed that 5-oxoproline elicits oxidative stress that may represent a pathophysiological mechanism in the disorder in which this metabolite accumulates.
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PMID:5-Oxoproline reduces non-enzymatic antioxidant defenses in vitro in rat brain. 1723 6


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