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Siegel GJ, Agranoff BW, Albers RW, et al., editors. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Philadelphia: Lippincott-Raven; 1999.

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Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition.

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Glutathione Metabolism

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Correspondence to Marc Yudkoff, Children's Hospital of Philadelphia, 1 Children's Center, Philadelphia, Pennsylvania 19104.

The tripeptide glutathione (γ-glutamyl-cysteinyl-glycine), which serves as a coreactant in the glutathione peroxidase and glutathione transferase reactions, is the major intracellular antioxidant (Fig. 44-7).

The cycle is renewed after the cysteine formed in reaction 6 (Fig. 44-7) and the glutamate derived from reaction 5 are converted to γ-glutamylcysteine via γ-glutamylcysteine synthetase (Fig. 44-7, reaction 1). The most important congenital defects in glutathione metabolism are glutathione synthetase deficiency (Fig. 44-7, reaction 2), γ-glutamylcysteine deficiency (Fig. 44-7, reaction 1), γ-glutamyltranspeptidase deficiency (Fig. 44-7, reaction 3) and 5-oxoprolinase deficiency (Fig. 44-7, reaction 5).

Glutathione synthetase deficiency leads to excessive formation of 5-oxoproline and may result in severe metabolic acidosis

Patients typically have a severe metabolic acidosis caused by excessive formation of 5-oxoproline, also termed pyroglutamic acid. This occurs because the diminution of intracellular glutathione relieves the feedback inhibition on the γ-glutamylcysteine synthetase pathway (Fig. 44-7, reaction 1), thereby augmenting the concentration of γ-glutamylcysteine and the subsequent conversion of this dipeptide to cysteine and 5-oxoproline in the cyclotransferase pathway (Fig. 44-7, reaction 4).

This lesion has been diagnosed in a young adult with mental retardation, severe metabolic acidosis and evidence of a spastic quadriparesis and cerebellar disease. It also has been observed in patients who were first diagnosed in infancy, and who enjoyed a period of normal psychomotor development until late childhood, when a progressive loss of intellectual function became appreciated. Patients also may manifest a mild hemolysis. Pathological changes in the brain have included atrophy of the cerebellum and lesions in the cortex and thalamus. There is no specific therapy.

Patients with 5-oxoprolinase deficiency excrete increased amounts of oxoproline and have a somewhat elevated concentration. They do not have significant neurological problems.

γ-Glutamylcysteine synthetase deficiency is rare

Patients with this very rare disorder have displayed spinocerebellar degeneration, peripheral neuropathy, myopathy and an aminoaciduria secondary to renal tubular dysfunction. Psychosis and a hemolytic anemia have been features in some patients.

γ-Glutamyltranspeptidase deficiency blocks the major pathway for glutathione utilization and causes glutathionuria

These patients also have shown varying degrees of mental retardation. The precise relationship of the neurological signs to the biochemical lesion is problematic. The enzyme is present in the brain, primarily in the capillaries, where it may facilitate amino acid transport. No specific treatment is available.

Image ch44f7

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 1999, American Society for Neurochemistry.
Bookshelf ID: NBK28123

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