Biologic and pharmacologic regulation of mammalian glutathione synthesis.
Glutathione (L-gamma-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of gamma-glutamylcysteine synthetase (gamma-GCS) and GSH synthetase. The intracellular GSH concentration, typically 1-8 mM, reflects a dynamic balance between the rate of GSH synthesis and the combined rate of GSH consumption within the cell and loss through efflux. The gamma-GCS reaction is rate limiting for GSH synthesis, and regulation of gamma-GCS expression and activity is critical for GSH homeostasis. Transcription of the gamma-GCS subunit genes is controlled by a variety of factors through mechanisms that are not yet fully elucidated. Glutathione synthesis is also modulated by the availability of gamma-GCS substrates, primarily L-cysteine, by feedback inhibition of gamma-GCS by GSH, and by covalent inhibition of gamma-GCS by phosphorylation or nitrosation. Because GSH plays a critical role in cellular defenses against electrophiles, oxidative stress and nitrosating species, pharmacologic manipulation of GSH synthesis has received much attention. Administration of L-cysteine precursors and other strategies allow GSH levels to be maintained under conditions that would otherwise result in GSH depletion and cytotoxicity. Conversely, inhibitors of gamma-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites to certain therapeutic interventions.
Griffith
O W
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Department of Biochemistry, Medical College of Wisconsin, Milwaukee 53226, USA. griffith@mcw.edu
D000818:Animals; D003545:Cysteine / Q000378:metabolism; D005246:Feedback; D015971:Gene Expression Regulation, Enzymologic; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis* / Q000378:metabolism; D005981:Glutathione Synthase / Q000378:metabolism; D006801:Humans; D011499:Protein Processing, Post-Translational; D013379:Substrate Specificity
D005721:Glutamate-Cysteine Ligase; D005981:Glutathione Synthase; D005978:Glutathione; D003545:Cysteine