Abstract
Two siblings suffering from metabolic acidosis and hemolytic anemia excreted gram quantities of 5-oxoproline in the urine. In erythrocytes, cultured fibroblasts and placenta the levels of glutathione were markedly decreased. The same tissues contained decreased activity of glutathione synthetase, whereas the activities of other enzymes involved in the metabolism of glutathione were normal. Extracts of erythrocytes from the patients and control subjects catalyzed the synthesis of 5-oxoproline from glutamate, provided ATP, Mg ions and cysteine were added. This occurred in two steps: gamma-glutamyl-cysteine synthetase catalyzed the formation of gamma-glutamyl-cysteine, which was converted to 5-oxoproline and cysteine by gamma-glutamyl cyclotransferase. Reduced glutathione specifically inhibited gamma-glutamyl-cysteine syuthetase. The following molecular mechanism for 5-oxoprolinuria is proposed: The lack of glutathione synthetase leads to a deficiency of glutathione. The absence of this feedback inhibitor results in increased synthesis of gamma-glutamyl-cysteine which is converted to 5-oxoproline /and cysteine/. The overproduction of 5-oxoproline exceeds the capacity of the 5-oxoprolinase. Therefore 5-oxoproline accumulates in body fluids.
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Larsson, A., Zetterström, R. 5-OXOPROLINURIA /PYROGLUTAMIC ACIDURIA/ AN INBORN ERROR OF GLUTATHIONE METABOLISM. Pediatr Res 9, 856 (1975). https://doi.org/10.1203/00006450-197511000-00026
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DOI: https://doi.org/10.1203/00006450-197511000-00026