Γ-L-Glutamyl-L-cysteine explained

γ-L-Glutamyl-L-cysteine, also known as γ-glutamylcysteine (GGC), is a dipeptide found in animals, plants, fungi, some bacteria, and archaea. It has a relatively unusual γ-bond between the constituent amino acids, L-glutamic acid and L-cysteine and is a key intermediate in the γ-glutamyl cycle first described by Meister in the 1970s.[1] [2] It is the most immediate precursor to the antioxidant glutathione.[3]

Biosynthesis

GGC is synthesized from L-glutamic acid and L-cysteine in the cytoplasm of virtually all cells in an adenosine triphosphate (ATP) requiring reaction catalysed by the enzyme glutamate-cysteine ligase (GCL, EC 6.3.2.2; formerly γ-glutamylcysteine synthetase).  The production of GGC is the rate limiting step in glutathione synthesis.

Occurrence

GGC occurs in human plasma in the range of 1 to 5 μM and intracellularly at 5 to 10 μM.[4] The intracellular concentration is generally low because GGC is rapidly bonded with a glycine to form glutathione.  This second and final reaction step in glutathione biosynthesis is catalysed by the activity of the ATP dependent glutathione synthetase enzyme.

Importance

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 GGC is vital for the biosynthesis of glutathione. Since the production of cellular GGC in humans slows down with age, as well as during the progression of many chronic diseases, it has been postulated that supplementation with GGC could offer health benefits. Such GGC supplementation may also be of benefit in situations where glutathione has been acutely lowered below optimum, such as following strenuous exercise, during trauma or episodes of poisoning.

Several review articles have been published exploring the therapeutic potential of GGC to replenish glutathione in age-related[6] and chronic disease states such as Alzheimer's disease.[7]

GGC is also capable of being a powerful antioxidant in its own right.[8] [9] [10]

Availability

GGC synthesis for commercial use is exceedingly difficult and, until recently, no commercially viable process for large scale production had been developed. The major drawback preventing the commercial success of chemical synthesis of GGC is the number of steps involved due to the three reactive groups on L-glutamic acid and L-cysteine molecules, which must be masked to achieve the correct regioisomer.  Similarly, there have been numerous attempts at biological production of GGC by fermentation over the years and none have been successfully commercialised.[11] [12] [13] [14]

Towards the end of 2019, a biocatalytic process was successfully commercialized. GGC is now available as a supplement in the US under the trademarked name of Glyteine and Continual-G.

Bioavailability and supplementation

A human clinical study in healthy, non-fasting adults demonstrated that orally administered GGC can significantly increase lymphocyte GSH levels indicating systemic bioavailability, validating the therapeutic potential of GGC.[15]

Animal model studies with GGC have supported a potential therapeutic role for GGC in both the reduction of oxidative stress induced damage in tissues, including the brain[16] and as a treatment for sepsis.[17]

In contrast, supplementation with glutathione is incapable of increasing cellular glutathione since the 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 from entering cells.  Although currently unproven, GGC may be the pathway intermediate of glutathione transportation in multicellular organisms.[18] [19]

Safety

Safety assessment of GGC sodium salt in rats has shown that orally administered (gavage) GGC was not acutely toxic at the limit single dosage of 2000 mg/kg (monitored over 14 days) and demonstrated no adverse effects following repeated daily doses of 1000 mg/kg over 90 days.[20]

History

In 1983, pioneers of glutathione research, Mary E. Anderson and Alton Meister, were the first to report on the ability of GGC to augment cellular GSH levels in a rat model. Intact GGC, which was synthesised in their own laboratory, was shown to be taken up by cells, bypassing the rate-limiting step of the GCL enzyme to be converted to glutathione. Control experiments with combinations of the constituent amino acids that make up GGC, including L-glutamic acid and L-cysteine, were ineffective. Since this initial work, only a few studies using GGC were performed due to the fact that there was no commercial source of GGC on the market. Subsequently, GGC has become commercially available and studies investigating its efficacy have commenced.[21]

Notes and References

  1. Orlowski. M.. Meister. A.. 1970-11-01. The Gamma-Glutamyl Cycle: A Possible Transport System for Amino Acids. Proceedings of the National Academy of Sciences. 67. 3. 1248–1255. 10.1073/pnas.67.3.1248. 5274454. 283344. 1970PNAS...67.1248O. 0027-8424. free.
  2. Meister. A. Anderson. M E. 1983. Glutathione. Annual Review of Biochemistry. 52. 1. 711–760. 10.1146/annurev.bi.52.070183.003431. 6137189. 0066-4154.
  3. Anderson. M. E.. Meister. A.. 1983-02-01. Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis.. Proceedings of the National Academy of Sciences. 80. 3. 707–711. 10.1073/pnas.80.3.707. 6572362. 393448. 1983PNAS...80..707A. 0027-8424. free.
  4. Mårtensson. Johannes. 1987. 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. 420. 1. 152–157. 10.1016/0378-4347(87)80166-4. 3667817. 0378-4347.
  5. Dalton. Timothy P.. Chen. Ying. Schneider. Scott N.. Nebert. Daniel W.. Daniel W. Nebert. Shertzer. Howard G.. 2004. Genetically altered mice to evaluate glutathione homeostasis in health and disease. Free Radical Biology and Medicine. 37. 10. 1511–1526. 10.1016/j.freeradbiomed.2004.06.040. 15477003. 0891-5849.
  6. Ferguson. Gavin. Bridge. Wallace. 2016. Glutamate cysteine ligase and the age-related decline in cellular glutathione: The therapeutic potential of γ-glutamylcysteine. Archives of Biochemistry and Biophysics. 593. 12–23. 10.1016/j.abb.2016.01.017. 26845022. 0003-9861.
  7. Braidy. Nady. Zarka. Martin. Welch. Jeffrey. Bridge. Wallace. 2015-04-27. Therapeutic Approaches to Modulating Glutathione Levels as a Pharmacological Strategy in Alzheimer's Disease. Current Alzheimer Research. 12. 4. 298–313. 10.2174/1567205012666150302160308. 25731620. 1567-2050.
  8. Quintana-Cabrera. Ruben. Bolaños. Juan. 2013-01-29. Glutathione and γ-glutamylcysteine in the antioxidant and survival functions of mitochondria. Biochemical Society Transactions. 41. 1. 106–110. 10.1042/bst20120252. 23356267. 0300-5127.
  9. Quintana Cabrera. Rubén. Fernández Fernández. Seila. Bobo Jiménez. Veronica. Escobar. Javier. Sastre. Juan. Almeida. Ángeles. Bolaños. Juan P.. 2012. γ-Glutamylcysteine detoxifies reactive oxygen species by acting as glutathione peroxidase-1 cofactor. Nature Communications. 3. 1. 718. 10.1038/ncomms1722. 22395609. 3316877. 2012NatCo...3..718Q. 2041-1723. free.
  10. Nakamura. Yukiko K.. Dubick. Michael A.. Omaye. Stanley T.. 2012. γ-Glutamylcysteine inhibits oxidative stress in human endothelial cells. Life Sciences. 90. 3–4. 116–121. 10.1016/j.lfs.2011.10.016. 22075492. 0024-3205.
  11. Microorganism and method for overproduction of gamma-glutamylcysteine and derivatives of this dipeptide by fermentation. 2014-11-20. US. 2014342399. Wacker Chemie AG. Thoen . Marcel. Schloesser . Thomas.
  12. Candida utilis containing gamma-glutamylcysteine. 2004-12-22. EP. 1489173. Ajinomoto KK. Nishiuchi . Hiroaki. Nishimura . Yasushi. Kuroda . Motonaka.
  13. gamma-Glutamylcysteine-producing yeast and method of screening the same. 2002-11-21. EP. 1452585. 2004-09-01. Ajinomoto KK. Nishiuchi . Hiroaki. Suehiro . Mariko. Sugimoto . Reiko. NISHIMURA YASUSHI ; KURODA MOTONAKA.
  14. Method for producing γ-glutamylcysteine. 2003-12-11. US. 7410790. 2008-08-12. Ajinomoto KK. Suehiro . Mariko. Nishiuchi . Hiroaki. Nishimura . Yasushi.
  15. Zarka. Martin Hani. Bridge. Wallace John. 2017. Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology. 11. 631–636. 10.1016/j.redox.2017.01.014. 28131081. 5284489. 2213-2317. free.
  16. Le. Truc M.. Jiang. Haiyan. Cunningham. Gary R.. Magarik. Jordan A.. Barge. William S.. Cato. Marilyn C.. Farina. Marcelo. Rocha. Joao B.T.. Milatovic. Dejan. Lee. Eunsook. Aschner. Michael. 2011. γ-Glutamylcysteine ameliorates oxidative injury in neurons and astrocytes in vitro and increases brain glutathione in vivo. NeuroToxicology. 32. 5. 518–525. 10.1016/j.neuro.2010.11.008. 21159318. 0161-813X. 3079792.
  17. Yang. Yang. Li. Ling. Hang. Qiyun. Fang. Yuan. Dong. Xiaoliang. Cao. Peng. Yin. Zhimin. Luo. Lan. 2019. γ-glutamylcysteine exhibits anti-inflammatory effects by increasing cellular glutathione level. Redox Biology. 20. 157–166. 10.1016/j.redox.2018.09.019. 30326393. 6197438. 2213-2317. free.
  18. Wu. Guoyao. Fang. Yun-Zhong. Yang. Sheng. Lupton. Joanne R.. Turner. Nancy D.. 2004-03-01. Glutathione Metabolism and Its Implications for Health. The Journal of Nutrition. 134. 3. 489–492. 10.1093/jn/134.3.489. 14988435. 0022-3166. free.
  19. Stark. Avishay-Abraham. Porat. Noga. Volohonsky. Gloria. Komlosh. Arthur. Bluvshtein. Evgenia. Tubi. Chen. Steinberg. Pablo. 2003. The role of γ-glutamyl transpeptidase in the biosynthesis of glutathione. BioFactors. 17. 1–4. 139–149. 10.1002/biof.5520170114. 12897436. 86244588. 0951-6433.
  20. Chandler. S.D.. Zarka. M.H.. Vinaya Babu. S.N.. Suhas. Y.S.. Raghunatha Reddy. K.R.. Bridge. W.J.. 2012. Safety assessment of gamma-glutamylcysteine sodium salt. Regulatory Toxicology and Pharmacology. 64. 1. 17–25. 10.1016/j.yrtph.2012.05.008. 22698997. 0273-2300.
  21. Braidy. Nady. Zarka. Martin. Jugder. Bat-Erdene. Welch. Jeffrey. Jayasena. Tharusha. Chan. Daniel K. Y.. Sachdev. Perminder. Bridge. Wallace. 2019-08-08. 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. 11. 177. 10.3389/fnagi.2019.00177. 31440155. 6694290. 1663-4365. free.

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