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What is Gamma-Glutamylcysteine (GGC)

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Gamma-glutamylcysteine (GGC) is a dipeptide and is the immediate precursor to the tripeptide glutathione (GSH). The intracellular concentration of gamma-glutamylcysteine (GGC) is generally low because gamma-glutamylcysteine (GGC) reacts rapidly with glycine to form glutathione (GSH). This second and final reaction step in glutathione biosynthesis is catalyzed by the activity of the ATP dependent glutathione synthase (GS) enzyme.

Gamma-glutamylcysteine (GGC) is essential to mammalian life. Mice that have had the glutamate-cysteine ligase (GCL) gene knocked out do not develop beyond the embryo stage and die before birth [5]. This is because gamma-glutamylcysteine (GGC) is vital for the biosynthesis of glutathione (GSH). Since the production of cellular gamma-glutamylcysteine (GGC) in humans slows down with age, as well as during the progression of many chronic diseases, it has been postulated that supplementation with gamma-glutamylcysteine (GGC) could offer health benefits. Other benefits of gamma-glutamylcysteine (GGC) supplementation may extend to situations where glutathione (GSH) has been acutely lowered below optimum such as following strenuous exercise, and during trauma or episodes of poisoning.

Several review articles have been published regarding the therapeutic potential of gamma-glutamylcysteine (GGC) to replenish glutathione in age-related [6] and chronic disease states such as Alzheimer’s disease [7]. Gamma-glutamylcysteine (GGC) is also capable of being a powerful antioxidant in its own right [8-10].

A human clinical study in healthy, non-fasting adults demonstrated that orally administered gamma-glutamylcysteine (GGC) can significantly increase lymphocyte glutathione (GSH) levels indicating systemic bioavailability, validating the therapeutic potential of gamma-glutamylcysteine (GGC) [16].

Animal model studies with gamma-glutamylcysteine (GGC) have supported it’s potential therapeutic role in both the reduction of oxidant stress-induced damage in tissues including the brain [17] and as a treatment for sepsis [18].

Supplementation with glutathione (GSH) is incapable of increasing cellular glutathione (GSH) since the glutathione (GSH) concentration found in the extracellular environment is much lower than that found intracellularly by about a thousand-fold. This large difference means that there is an insurmountable concentration gradient that prohibits extracellular glutathione entering cells. Although currently unproven, gamma-glutamylcysteine (GGC) may be the pathway intermediate of glutathione transportation in multicellular organisms [19, 20].

References

  1. Orlowski, M. and A. Meister, The gamma-glutamyl cycle: a possible transport system for amino acids. Proc Natl Acad Sci U S A, 1970. 67(3): p. 1248-55.
  2. Meister, A. and M.E. Anderson, Glutathione. Annu Rev Biochem, 1983. 52: p. 711-60.
  3. Anderson, M.E. and A. Meister, Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis. Proceedings of the National Academy of Sciences of the United States of America., 1983. 80(3): p. 707-11.
  4. Mårtensson, J., Method for determination of free and total glutathione and γ-glutamylcysteine concentrations in human leukocytes and plasma. Journal of Chromatography B: Biomedical Sciences and Applications, 1987. 420(0): p. 152-157.
  5. Dalton, T.P., et al., Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radical Biology and Medicine, 2004. 37(10): p. 1511-1526.
  6. Ferguson, G. and W. Bridge, Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics, 2016. 593: p. 12-23.
  7. Cao, P., et al., Therapeutic approaches to modulating glutathione levels as a pharmacological strategy in Alzheimer’s disease. Curr Alzheimer Res, 2015. 12(4): p. 298-313.
  8. Quintana-Cabrera, R. and J.P. Bolanos, Glutathione and gamma-glutamylcysteine in the antioxidant and survival functions of mitochondria. Biochemical Society Transactions, 2013. 41: p. 106-110.
  9. Quintana-Cabrera, R., et al., γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nat Commun, 2012. 3: p. 718.
  10. Nakamura, Y.K., M.A. Dubick, and S.T. Omaye, γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells. Life Sciences, 2011(0).
  11. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
  12. Le, T.M., et al., gamma-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. Neurotoxicology, 2011. 32(5): p. 518-25.
  13. Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.
  14. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
  15. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
  16. Chandler, S.D., et al., Safety assessment of gamma-glutamylcysteine sodium salt. Regulatory Toxicology and Pharmacology, 2012. 64(1): p. 17-25.
  17. Braidy, N., et al., The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GGC), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes. Frontiers in Aging Neuroscience, 2019. 11(177).
  18. Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.
  19. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
  20. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
  21. Chandler, S.D., et al.,Safety assessment of Gamma-glutamylcysteine sodium salt. Regulatory Toxicology and Pharmacology, 2012. 64(1): p. 17-25.
  22. Braidy, N., et al., The Precursor to Glutathione (GSH), γ-Glutamylcysteine (GAMMA-GLUTAMYLCYSTEINE), Can Ameliorate Oxidative Damage and Neuroinflammation Induced by Aβ40 Oligomers in Human Astrocytes. Frontiers in Aging Neuroscience, 2019. 11(177).

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