Abstract
Glutathione synthetase (GSH-S) deficiency (5-oxoprolinuria) results in decreased cellular glutathione (GSH) content (10-20% of normal), and secondary over-production of 5-oxoproline. γ-glutamyl transpeptidase (GGTP) is the primary catabolic enzyme for GSH, and inhibition of this enzyme might thus be an approach to correcting the consequences of GSH-S deficiency. L-serine inhibits fibroblast GGTP. Inhibition is markedly enhanced by sodium borate buffer, 20 mM serine-20 mM borate causing>95% inhibition. Serine-borate added to Eagle's MEM produced a dose and time dependent increase in GSH content of GSH-S deficient cultured fibroblasts. GSH content was doubled at 24 hours with 40 mM serine-40 mM borate. Borate alone was without effect. Conversion of 14C-glutamic acid to 5-oxoproline by GSH-S deficient cells was decreased by 70% to near normal levels by 24-hour pre-treatment with 40 mM serine-borate. The increased cell GSH content may block overproduction of 5-oxoproline from excess γ-glutamylcysteine by feed-back inhibiting γ-glutamylcysteine synthetase. Treatment produced no apparent toxicity; cell amino acid concentrations were unaffected other than an increase in serine and phosphoserine. The study demonstrates the possible therapeutic value of an inhibitor of a major catabolic enzyme for a substrate decreased secondary to a deficiency of its synthetic enzyme.
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Spielberg, S., Deb. Butler, J. & Schulman, J. 564 TREATMENT OF GLUTATHIONE SYNTHETASE DEFICIENT FIBROBLASTS BY INHIBITION OF γ-GLUTAMYL TRANSPEPTIDASE WITH SERINE-BORATE. Pediatr Res 12 (Suppl 4), 457 (1978). https://doi.org/10.1203/00006450-197804001-00569
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DOI: https://doi.org/10.1203/00006450-197804001-00569