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)

Two different clinical syndromes are associated with glutathione synthetase deficiency, one presenting with hemolytic anemia and 5-oxoprolinuria, the other with isolated hemolysis. We have differentiated these disorders on an enzymatic basis. In 5-oxoprolinuria, all cell types examined have grossly deficient enzyme activity and glutathione content. In contrast, in the nonoxoprolinuric variant, erythrocytes have decreased enzyme activity and glutathione content, whereas nucleated cells maintain substantial levels of both. The enzyme in this disorder is unstable in vitro and has shortened survival in intact erythrocytes. Nucleated cells appear able to maintain sufficient enzyme activity and concentrations of glutathione to suppress overproduction of 5-oxoproline.
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PMID:Biochemical heterogeneity in glutathione synthetase deficiency. 65 3

We have studied a patient with 5-oxoprolinuria who presented with hemolysis and metabolic acidosis as a neonate; he has had normal growth and development to one year of age. Compensated hemolytic anemia persists, and he requires alkalinizing agents for correction of acidosis. Biochemical studies have confirmed that a deficiency of glutathione synthetase is responsible for the 5-oxoprolinuria. Genetic heterogeneity was apparent on comparative study of glutathione synthetase kinetics in cells from two patients with this disorder. The consequences of the deficiency of glutathione synthetase, decreased intracellular glutathione, and overproduction of 5-oxoproline are discussed with reference to the possible cellular roles of these compounds.
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PMID:5-oxoprolinuria: biochemical observations and case report. 87 80

Pyroglutamic acidemia, a rare metabolic disorder, usually appears in infancy. It is characterized by retardation, ataxia, hemolytic anemia, and chronic acidosis and is caused by a marked deficiency of glutathione synthetase (EC 6.3.2.3) activity. This disease is inherited as an autosomal recessive trait, but the clinical condition is also detected in heterozygotes. We report an unusual case of high-anion-gap metabolic acidosis in a 52-year-old woman who was admitted with neurological complaints and breathing problems but without the characteristic clinical features of congenital glutathione synthetase deficiency. The etiology of the acidosis could not be attributed to ketoacidosis, lactic acidosis, or ingestion of methanol, salicylate, or ethylene glycol. Analysis of the patient's plasma and urine for organic acids revealed the presence of high concentrations of pyroglutamate (5-oxoproline), which remained high throughout her hospitalization.
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PMID:Pyroglutamic acidemia in an adult patient. 229 27

The oxidized form of glutathione transport was studied in human erythrocytes in pyrimidine 5'-nucleotidase (P5N) deficiency, a disorder in which the amounts of CTP and UTP in the erythrocytes are elevated. The inhibition of ATP-requiring oxidized glutathione (GSSG) transport by CTP and UTP is believed to play a role in elevating the levels of the reduced form of glutathione (GSH) in the erythrocytes of patients with P5N deficiency. The current investigation was undertaken to determine if GSSG transport actually decreases in the erythrocytes of such patients. Erythrocytes from a 17-year-old patient and a 13-year-old patient with P5N deficiency hemolytic anemia and from ten normal subjects were used as materials for the experiment. Erythrocytes, which had been previously incubated with [3H]glycine, were incubated at 37 degrees C, and the rate of [3H]GSSG transported by the cells was estimated. The velocity of GSSG transport out of the erythrocytes was quite low in the patients, 3.17-3.65 nmol GSSG/ml erythrocytes/hr at 37 degrees C in one case, and 3.30 nmol GSSG/ml erythrocytes/hr in the other case, vs that in the normal controls (6.00 +/- 0.80 nmol GSSG/ml erythrocytes/hr; mean +/- SD). The activity of gamma-glutamylcysteine synthetase and glutathione synthetase did not decrease in the patients. Decreased transport activity of GSSG in addition to a normal synthesis rate for GSH may explain the increased concentration of erythrocyte GSH in P5N deficiency.
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PMID:Erythrocyte-oxidized glutathione transport in pyrimidine 5'-nucleotidase deficiency. 288 6

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

Three unrelated Japanese patients with chronic nonspherocytic hemolytic anemia wer found to have marked deficiency of red blood cell (RBC) reduced glutathoine (GSH) (4.4%, 13.1%, and 6.9% of normal, respectively). A panel of RBC enzyme assays showed that one patient had decreased glutathione synthetase activity and the other two were moderately deficient in gamma-glutamylcystine synthetase. Some family members of each patient showed mild deficiency of the respective enzymes. RBCs of these patients also showed a decreased level of glutathione-S-transferase as in previously described GSH-deficient cases. Hemolytic anemia was their only manifestation, and neither 5-oxoprolinemia nor 5-oxoprolinuria, which are usually associated with to generalized type of glutathione synthetase deficiency, was noted in our patients.
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PMID:Three cases of hereditary nonspherocytic hemolytic anemia associated with red blood cell glutathione deficiency. 863 59

Two forms of glutathione synthetase deficiency have been described. While one form is mild, causing hemolytic anemia, the other more severe form causes 5-oxo-prolinuria with secondary neurological involvement. Despite the existence of two deficiency phenotypes, Southern blots hybridized with a glutathione synthetase cDNA suggest that there is a single glutathione synthetase gene in the human genome. Analysis of somatic cell hybrids showed the human glutathione synthetase gene (GSS) to be located on chromosome 20, and this assignment has been refined to subband 20q11.2 using in situ hybridization.
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PMID:The gene encoding human glutathione synthetase (GSS) maps to the long arm of chromosome 20 at band 11.2. 882 53

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. GSSD results in low glutathione levels in erythrocytes and may present with hemolytic anemia alone or together with pyroglutamic aciduria, metabolic acidosis, and CNS damage. Five patients with pyroglutamic aciduria were studied. All presented with hemolytic anemia and metabolic acidosis. Two (brothers) also had Fanconi nephropathy, which is not seen in pyroglutamic aciduria. Molecular analyses of the GSS gene was performed in 3 patients. RT-PCR and heteroduplex analysis identified a homozygous deletion in 1 patient and a homozygous mutation in 2 others (brothers with Fanconi nephropathy). Sequencing of glutathione synthetase (GSS) cDNA from the first patient showed a 141-bp deletion corresponding to the entire exon 4, whilst the corresponding genomic DNA showed a G491 --> A homozygous splice site mutation. Sequencing of GSS cDNA from the Fanconi nephropathy patients showed a C847 --> T [ARG283 --> CYS] mutation in exon 9.
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PMID:Clinical, biochemical, and molecular characterization of patients with glutathione synthetase deficiency. 1045 Aug 61


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