Glyteine is a naturally occurring dipeptide found in all mammalian life and is a key intermediate in the gamma (γ) -glutamyl cycle first described by Meister in the 1970s [1, 2]. It is the most immediate precursor to the essential antioxidant glutathione [3].

Supplementation with glutathione is incapable of increasing cellular glutathione since the glutathione 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 prevents extracellular glutathione entering cells, and it is inside the cell where glutathione performs the overwhelming majority of its essential functions.

Glyteine is not subject to such a concentration gradient as it occurs in human plasma in the range of 1 – 5 µM [2, 3] and is almost undetectable intracellularly[4].

The intracellular concentration of Glyteine is generally low, allowing it to diffuse into the cell. Once inside the cell, Glyteine is rapidly enzymatically bound to glycine to form glutathione. This second and final reaction step in glutathione biosynthesis is catalyzed by the activity of the ATP dependent glutathione synthase (GS) enzyme. Although currently unproven, Glyteine may actually be the pathway intermediate of glutathione transportation in multicellular organisms [5, 6]. That is, Glytiene could be a type of glutathione “currency” that is transported between cells to increase intracellular glutathione rapidly when needed.

A human clinical study in healthy, non-fasting adults demonstrated that orally administered Glyteine could significantly increase lymphocyte glutathione levels indicating systemic bioavailability, validating its therapeutic potential [7]. Glyteine is also capable of being a powerful antioxidant in its own right. [8-10].

Since the production of cellular Glyteine in humans slows down with age, as well as during the progression of many chronic diseases, it has been postulated that supplementation with Glyteine could offer health benefits. Glyteine supplementation may also extend to situations where glutathione has been acutely lowered below optimum such as following strenuous exercise and during trauma or poisoning episodes.

Several review articles have been published on the potential of Glyteine to replenish glutathione in age-related [11] and chronic disease states such as Alzheimer’s disease [12].

Glyteine has also been tested in in-vitro and animal studies for both the reduction of oxidant stress-induced damage in tissues including the brain [13, 14] and as a treatment for sepsis [15].

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. Wu, G., et al., Glutathione metabolism and its implications for health. Journal of Nutrition, 2004. 134(3): p. 489-92.
  6. Stark, A.A., et al., The role of gamma-glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 2003. 17(1-4): p. 139-49.
  7. 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.
  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. 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.
  12. 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.
  13. 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.
  14. Braidy, N., et al., γ-glutamylcysteine (GGC)-mediated upregulation of glutathione levels can ameliorate toxicity of natural beta-amyloid oligomers in primary adult human neurons, in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association. 2013, Elsevier. p. P854.Yang, Y., et al., γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology, 2019. 20: p. 157-166.