Physiological and pathological aspects of GSH metabolism.
The antioxidant glutathione is found in low levels in diseases in which increasing evidence implicate oxidative stress in the development of the disease, for example retinopathy of prematurity, necrotizing enterocolitis, bronchopulmonary dysplasia, patent ductus arteriosus and asthma. Glutathione is metabolized in the gamma-glutamyl cycle, which involves six different enzymes. The synthesis of glutathione is a two-step process in which the first step is catalysed by gamma-glutamylcysteine synthetase and the second step by glutathione synthetase. Glutathione synthetase deficiency is an autosomal recessive disease and the most common inborn error of the gamma-glutamyl cycle. Approximately 25% of patients with hereditary glutathione synthetase deficiency die during childhood. Patients present with a clinical picture ranging from compensated haemolytic anaemia to a complex disorder with additional symptoms like 5-oxoprolinuria, metabolic acidosis and central nervous system impairment. Even though the correlation between phenotype and genotype in these patients is complex, an indication of the phenotype can be based on the type of mutation involved. Also, there is a correlation between the glutathione synthetase activity and the level of glutathione in cultured fibroblasts. Inborn errors have also been described in three additional steps of the y-glutamyl cycle, namely gamma-glutamyl-transpeptidase, 5-oxoprolinase and gamma-glutamylcysteine synthetase.


CONCLUSIONS
The range of disorders in patients with inborn errors in the metabolism of glutathione illustrates the intricate metabolism of glutathione and its involvement in numerous essential processes in the cell. By studying these patients, further insight into the functions and metabolism of glutathione can be achieved.
Department of Clinical Science, Division of Paediatrics, Karolinska University Hospital Huddinge, Stockholm, Sweden. runa.njalsson@mednut.ki.se
Runa
R
Njålsson
Svante
S
Norgren
D000138:Acidosis / Q000209:etiology; D000743:Anemia, Hemolytic / Q000209:etiology; D005978:Glutathione / Q000235:genetics / Q000378:metabolism*; D005981:Glutathione Synthase / Q000172:deficiency*; D006801:Humans; D007231:Infant, Newborn; D007235:Infant, Premature, Diseases / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D008661:Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics / Q000628:therapy; D011752:Pyroglutamate Hydrolase / Q000097:blood
D011752:Pyroglutamate Hydrolase; D005981:Glutathione Synthase; D005978:Glutathione