Start of the Glyteine (GGC) story.
When working for a global baker's yeast manufacturer in 1997, Prof Wallace Bridge, UNSW Sydney was exploring manufacturing options for the production of glutathione as a value-added product. Through this project he developed an understanding of glutathione biochemistry which ultimately led to his interest in gamma-glutamylcysteine's (GlyteineTM) therapeutic potential.
What is glutathione and where does it come from?
Glutathione is often termed the "master antioxidant". It is produced in every cell of your body. It is a tripeptide (small protein) that mops up free radicals and toxins. Glutathione's tripeptide (small protein) structure is composed of the amino acids (protein building blocks); glutamate, cysteine, and glycine. Glutathione is synthesized in two reactions inside each of our cells. The first joins glutamate and cysteine to form gamma-glutamylcysteine (GlyteineTM) and the second adds glycine to form glutathione.
How is glutathione produced in the body?
Glutathione is produced in every cell of our bodies. The system involves two enzymes (catalysts) that sequentially join the three amino acids glutamate, cysteine and glycine to form glutathione. The first enzyme (glutamate cysteine ligase, GCL) joins glutamate and cysteine to form gamma-glutamylcysteine (GGC, GlyteineTM) and the second enzyme glutathione synthetase adds the glycine to make glutathione. Both these reactions require energy (ATP), which is provided on the most part by the mitochondria. The video explains how glutathione levels are maintained (regulated) in cells at optimum (homeostasis) levels and the implications if this system goes wrong.
Glutathione depletion and oxidative stress
Oxidative stress can occur if the capacity of our cells to produce enough glutathione is diminished. Free radicals generated during mitochondrial respiration will not be neutralized, which will potentially cause damage to the mitochondria and the cells that ultimately may lead to illness.
What about GLYTEINETM?
Animal and human studies have demonstrated that GLYTEINETM supplements can, as theoretically expected, increase cellular glutathione levels following a single dose. Clinical trials are currently underway to determine the efficacy of GLYTEINETM in numerous chronic and acute glutathione depletion related conditions.
How quickly can Glyteine (GGC) increase my glutathione levels?
Human clinical study has demonstrated that a single orally administered dose of GlyteineTM could increase cellular (lymphocytes) glutathione levels above homeostasis within hours. This observation indicated that GlyteineTM is systemically bioavailable by surviving the gastrointestinal tract, being distributed throughout the body by the vascular system, where it is taken up by cells and converted to glutathione. This finding highlights Glyteine's therapeutic potential as many chronic diseases and ageing itself are associated with glutathione homeostasis being lowered to unhealthy levels.
Why haven't we heard of GLYTEINETM before?
Unlike NAC and glutathione there is no natural source that contains sufficient GLYTEINETM from which it can be extracted and processed. Though GLYTEINETM is continuously produced in almost every oxygen using cell from bacteria, through to plants and animals, it is almost always immediately converted to glutathione. So, the main reason, you have not been able to buy GLYTEINETM containing supplements is that no one until now has been able to work out a way to produce it. Our GLYTEINETM manufacturing process was developed purposefully over the last 20 years so that it could be offered to the world to treat illness and make the world a better place and not simply as a means of value adding to existing products.
What foods contain Glyteine (GGC)?
Some foods contain gamma-glutamylcysteine (GGC), though GGC is produced in all food sources it is usually immediately converted into glutathione. The implications for developing a process for GGC (GlyteineTM) manufacture are explained in the corresponding video.
Which foods naturally contain Glyteine (GGC)?
Two major inarguable food sources in nature, egg white and whey protein, contain GGC and their provision would be of benefit to the glutathione levels of the growing baby animals.
Why should I care?
If our cells do not have enough glutathione to deal with the free radicals and toxins then they will be damaged, lose their physiological function, and perhaps even die.
When would I not produce enough glutathione?
Generally, there are two situations where you might not produce enough glutathione to protect your cells.
The first is when you have an acute glutathione deficiency due to exposure to high levels of toxins (e.g. drug overdose) or free radicals (e.g. excessive exercise).
The second is a chronic deficiency that occurs when some of your cells (e.g. specific tissues or organs) lose the ability to produce enough glutathione to protect themselves against normal levels of toxins and free radicals. This is often the case in age-related conditions such as Alzheimer's and Parkinson's diseases.
If my cells don't have enough glutathione – what can I do about it?
For acute depletion, you can assist your body restore glutathione to healthy levels by taking cysteine prodrugs (such as NAC and glutathione itself). Of the three amino acids that comprise glutathione, cysteine is the first one to run out during acute glutathione depletion. NAC is the standard antidote for acetaminophen (paracetamol) overdose.
To overcome chronic glutathione depletion, the solution is different. In these conditions, it is the cellular machinery for synthesising glutathione that has become permanently damaged. Glutathione is produced by two sequential enzyme catalyzed reactions. The first reaction combines glutamic acid with cysteine to produce GLYTEINETM (gamma-glutamylcysteine) and is catalyzed by the enzyme, glutamate cysteine ligase (GCL). The second reaction adds glycine to GLYTEINETM to make glutathione and is catalyzed by the enzyme glutathione synthetase (GS). It is the GCL enzyme that often becomes damaged in chronic conditions, which prevents the affected tissue from producing enough GLYTEINETM. The solution seems obvious! - just provide GLYTEINETM to the cells.
What are the benefits of eating glutathione rich foods?
Glutathione rich foods are simply sources of the building blocks (in particular cysteine) for glutathione synthesis. The glutathione in these foods will not however be able to directly increase the glutathione levels inside your cells above homeostasis. The implication being that if you wish to boost your glutathione levels then dietary glutathione whether in a food or a supplement is not likely to help.
How is glutathione produced?
Glutathione is manufactured industrially using baker's yeast which is analogous to how we synthesise glutathione in our cells.
What is the difference between NAC vs glutathione vs Glyteine (GGC)?
There are some supplement options for increasing glutathione levels when something has gone wrong with homeostasis; that is where our cells no longer maintain glutathione at healthy levels. Homeostasis is lowered when the regulatory enzyme responsible for the production of gamma-glutamylcysteine (GGC) becomes dysfunctional as is the case for many chronic disorders. Both NAC and glutathione (glutathione is broken down to its component amino acids by cells during cellular uptake) are simply cysteine sources for cells. This cysteine feeds into the damaged enzyme and as such cannot increase GGC or glutathione levels. Glyteine (GGC), on the other hand, can feed directly into the second enzyme where it is converted into glutathione.
Glutathione supplements – do they work?
Glutathione in the diet either through food or supplements do not increase the glutathione content of cells.
Cells have up to one thousand-fold higher levels of glutathione than that of blood plasma. To overcome this concentration gradient, cells break down extracellular glutathione to its constituent amino acids, which are then taken up by the cell. Once inside, the glutathione is resynthesised. This means, glutathione is just another source of cysteine that feeds into the damaged GCL enzyme and like NAC can do nothing to overcome the GLYTEINETM deficiency.
How does glutathione become depleted?
Acute glutathione depletion can be brought on by exposure to conditions that overwhelm the body's capacity to produce glutathione. These include toxins, overdoses with drugs such as acetaminophen/paracetamol and even excessive exercise. Chronic glutathione depletion related disorders are caused by a loss in the capacity of cells to produce enough gamma glutamyl cysteine (GlyteineTM). Cysteine prodrugs such as N-acetylcysteine are noted to be of benefit for treating acute glutathione depletion and GlyteineTM is introduced for its potential to address both acute and chronic glutathione depletion.
Is glutathione depletion a problem for athletes during strenuous exercise?
Athletes run the risk of being repeatedly exposed to acute glutathione depletion and its associated oxidative stress. They suggest that this cycle could well lead to an accumulation of cellular and tissue damage that eventually manifests as various physiological health issues for the athletes.
How does glutathione homeostasis work?
There is a complex regulatory system that controls glutathione levels inside our cells. Each cell has its own optimum level (homeostasis) which has been determined by the evolutionary processes of nature. Glutathione homeostasis is maintained by a feedback inhibition system exerted by glutathione on the enzyme responsible for gamma-glutamylcysteine (GlyteineTM) production. When glutathione is near homeostasis, the enzyme's activity is low and as the glutathione gets used up, the activity will increase.
How does low glutathione levels lead to oxidative stress?
Repeated exposure to oxidative stress can result in an accumulation of permanent damage to cells and their progeny. In many diseases and disorders, the first enzyme (glutamate cysteine ligase) involved in the synthesis of glutathione becomes dysfunctional and maintains glutathione (homeostasis) at levels too low to protect against oxidative stress. Whether accumulated oxidative stress damage may actually be one of the causes of this enzyme dysfunction is debatable and the nature of how the enzyme becomes dysfunctional is the subject of ongoing research.
Can alcohol consumption deplete glutathione levels?
Alcohol consumption can deplete glutathione and can have implications for hangovers.
Can I measure glutathione in my body?
The complexity of glutathione assays is not that straightforward as it is for testing other important chemicals such as glucose.
What diet is best for glutathione?
With a lot of discussion on calorie restriction, and the different diets in the context of glutathione and human health, the key point that is raised is the difficulty for us to know what food is good for us. We can't test the quality of our diet in animal models because the one thing that differentiates all animals is their diet. Through civilisation we have lost our natural instinct for what is good for us, and from 10,000 years of agriculture almost all our foods, in particular plants, have been purposefully evolved by us. It is quite possible that none of the many recommended diets ranging from vegan to carnivore are ideal for us and that many may even be exposing us to oxidative stress agents that we did not evolve to deal with, which would make glutathione all that more important to our health.
How safe is Glyteine (GGC) and does it have any side effects?
To test the safety of Glyteine, animal study was carried out that involved rats being fed 1 g/kg body weight (equivalent of 100 g for a 100 kg human) of Glyteine for 90 days with no observed detriment to their physiology.
Will Glyteine (GGC) effect our health/life span?
Prof Wallace Bridge, UNSW Sydney; explains the greatest benefit of Glyteine (GGC) is likely to be an improved health span, where we may not necessarily live longer but will stay healthier throughout the later stages of life.
- Chandler, S. D., Zarka, M. H., Vinaya Babu, S. N., Suhas, Y. S., Raghunatha Reddy, K. R., and Bridge, W. J. (2012) Safety assessment of gamma-glutamylcysteine sodium salt. Regulatory Toxicology and Pharmacology 64, 17-25
- Zarka, M. H., and Bridge, W. J. (2017) Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology 11, 631-636
- Braidy, N., Zarka, M., Judger, B., Welch, J., Jayasena T. and Bridge W. (2019) The precursor to glutathione (GSH), ?-glutamylcysteine (GGC), can ameliorate oxidative damage and neuroinflammation induced by amyloid-beta oligomers in primary adult human brain cells. Frontiers in Aging Neuroscience (in press)
- Le, T. M., Jiang, H., Cunningham, G. R., Magarik, J. A., Barge, W. S., Cato, M. C., Farina, M., Rocha, J. B., Milatovic, D., Lee, E., Aschner, M., and Summar, M. L. (2011) gamma-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. Neurotoxicology 32, 518-525
- Pileblad, E., and Magnusson, T. (1992) Increase in rat brain glutathione following intracerebroventricular administration of gamma-glutamylcysteine. Biochemical Pharmacology 44, 895-903
- Dringen, R., Kranich, O., Loeschmann, P.-A., and Hamprecht, B. (1997) Use of dipeptides for the synthesis of glutathione by astroglia-rich primary cultures. Journal of Neurochemistry 69, 868-874
- Dringen, R., Gutterer, J. M., and Hirrlinger, J. (2000) Glutathione metabolism in brain. European Journal of Biochemistry 267, 4912-4916
- Salama, S. A., Arab, H. H., Maghrabi, I. A., Hassan, M. H., and AlSaeed, M. S. (2016) Gamma-Glutamyl Cysteine Attenuates Tissue Damage and Enhances Tissue Regeneration in a rat Model of Lead-Induced Nephrotoxicity. Biological Trace Element Research 173, 96-107
- Salama, S. A., Al-Harbi, M. S., Abdel-Bakky, M. S., and Omar, H. A. (2015) Glutamyl cysteine dipeptide suppresses ferritin expression and alleviates liver injury in iron-overload rat model. Biochimie 115, 203-211
- Chen, Y., Shertzer, H. G., Schneider, S. N., Nebert, D. W., and Dalton, T. P. (2005) Glutamate cysteine ligase catalysis: dependence on ATP and modifier subunit for regulation of tissue glutathione levels. J Biol Chem 280, 33766-33774
- Lu, S. C. (2009) Regulation of glutathione synthesis. Mol Aspects Med 30, 42-59
- Townsend, D. M., Tew, K. D., and Tapiero, H. (2003) The importance of glutathione in human disease. Biomedicine & Pharmacotherapy 57, 145-155
- Liu, R., and Choi, J. (2000) Age-associated decline in gamma-glutamylcysteine synthetase gene expression in rats. Free Radic Biol Med 28, 566-574
- Liu, R. M. (2002) Down-regulation of γ-glutamylcysteine synthetase regulatory subunit gene expression in rat brain tissue during aging. Journal of Neuroscience Research 68, 344-351
- Liu, R. M., and Dickinson, D. A. (2003) Decreased synthetic capacity underlies the age-associated decline in glutathione content in Fisher 344 rats. Antioxid Redox Signal 5, 529-536
- Liu, H., Wang, H., Shenvi, S., Hagen, T. M., and Liu, R.-M. (2004) Glutathione Metabolism during Aging and in Alzheimer Disease. Annals of the New York Academy of Sciences 1019, 346-349
- Lee, J. I., Kang, J., and Stipanuk, M. H. (2006) Differential regulation of glutamate-cysteine ligase subunit expression and increased holoenzyme formation in response to cysteine deprivation. Biochem J 393, 181-190
- Rae, C. D., and Williams, S. R. (2017) Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy. Anal Biochem 529, 127-143
- Griffith, O. W. (1999) Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radical Biology & Medicine 27, 922-935
- Lu, S. C. (2009) Regulation of glutathione synthesis. Mol Aspects Med 30, 42-59
- Franco, R., Schoneveld, O. J., Pappa, A., and Panayiotidis, M. I. (2007) The central role of glutathione in the pathophysiology of human diseases. Archives of Physiology and Biochemistry 113, 234-258
- Schafer, F. Q., and Buettner, G. R. (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radical Bio Med 30, 1191-1212
- Stark, A. A., Porat, N., Volohonsky, G., Komlosh, A., Bluvshtein, E., Tubi, C., & Steinberg, P. (2003). The role of γ‐glutamyl transpeptidase in the biosynthesis of glutathione. Biofactors, 17(1‐4), 139-149.
- Zhang, H., Forman, H. J., & Choi, J. (2005). γ‐Glutamyl transpeptidase in glutathione biosynthesis. Methods in enzymology, 401, 468-483