Biologic and pharmacologic regulation of mammalian glutathione synthesis [1999](IR90)

Biologic and pharmacologic regulation of mammalian glutathione synthesis [1999](IR90)

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Biologic and pharmacologic regulation of mammalian glutathione synthesis

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Free Radical Biology and Medicine
Volume 27, Issues 9-10, November 1999, Pages 922-935
doi:10.1016/S0891-5849(99)00176-8 | How to Cite or Link Using DOI
Copyright © 1999 Elsevier Science Inc. All rights reserved.    

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Biologic and pharmacologic regulation of mammalian glutathione synthesis

Owen W. Griffitha, 2, ,
a Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA

Available online 4 November 1999.

Abstract
Glutathione (L-γ-glutamyl-L-cysteinylglycine, GSH) is synthesized from its constituent amino acids by the sequential action of γ-glutamylcysteine synthetase (γ-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 γ-GCS reaction is rate limiting for GSH synthesis, and regulation of γ-GCS expression and activity is critical for GSH homeostasis. Transcription of the γ-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 γ-GCS substrates, primarily L-cysteine, by feedback inhibition of γ-GCS by GSH, and by covalent inhibition of γ-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 γ-GCS have been used to deplete GSH as a strategy for increasing the sensitivity of tumors and parasites (寄生生物) to certain therapeutic interventions.

Keywords: γ-Glutamylcysteine synthetase; Free radical; Oxidative stress; Transcriptional regulation; Cysteine availability; Feedback inhibition; Nitric oxide; Buthionine sulfoximine

Abbreviations: GSH, glutathione; GSSG, glutathione disulfide; NO, nitric oxide; γ-GCS, γ-glutamylcysteine synthetase; γ-GCSH, γ-GCS heavy subunit; γ-GCSL, γ-GCS light subunit; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; AP-1, activator protein-1; AP-2, activator protein-2; NF-κB, nuclear factor kappa B; ARE/EpRE, antioxidant and elctrophile response elements; Sp-1, PKA, cAMP-dependent protein kinase; PKC, protein kinase C; CMK, Ca2+/calmodulin-dependent protein kinase II; OTC, 2-oxothiazolidine-4-carboxylate; BSO, buthionine sulfoximine; L-SR-BSO, L-buthionine-S,R-sulfoximine; L-S-BSO, L-buthionine-S-sulfoximine; L-S-BSO-P, L-buthionine-S-sulfoximine phosphate

Article Outline

Introduction
The enzymes of synthesis
Modulation of cellular GSH levels—Overview
Control of GSH synthesis by regulation of γ-GCS expression
Control of glutathione synthesis by substrate availability
Feedback inhibition of γ-glutamylcysteine synthetase
Regulation of γ-GCS by post-translational modification
Pharmacologic control of γ-GCS
Acknowledgements
References



Address correspondence to: Owen W. Griffith, Ph.D., Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA; Tel: (414) 456-8435; Fax: (414) 456-6510

2 Dr. Owen W. Griffith earned his undergraduate degree in biochemistry from the University of California, Berkeley, and completed his graduate work at the Rockefeller University in New York City working on carnitine acetyltransferase with Dr. Leonard Spector. His work on γ-glutamylcysteine synthetase (γ-GCS) began in 1975 when he joined Dr. Alton Meister's group in the Department of Biochemistry at Cornell University Medical College. Dr. Griffith joined the faculty of that Department in 1980 and continued his work on the enzymes of glutathione metabolism and on carnitine-dependent enzymes. Among his contributions are the discovery of L-buthionine-S-sulfoximine as a highly selective, physiologically active γ-GCS inhibitor and numerous studies using that inhibitor to elucidate and pharmacologically control glutathione turnover. Other current interests include nitric oxide biology and microbial defenses against oxidative and nitrosative stress. Dr. Griffith is currently Professor and Chairman of Biochemistry at the Medical College of Wisconsin, a position he accepted in 1992.

Free Radical Biology and Medicine
Volume 27, Issues 9-10, November 1999, Pages 922-935
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