Glutathione Explained

Glutathione (GSH,) is an organic compound with the chemical formula . It is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, peroxides, lipid peroxides, and heavy metals.[1] It is a tripeptide with a gamma peptide linkage between the carboxyl group of the glutamate side chain and cysteine. The carboxyl group of the cysteine residue is attached by normal peptide linkage to glycine.

Biosynthesis and occurrence

Glutathione biosynthesis involves two adenosine triphosphate-dependent steps:

While all animal cells are capable of synthesizing glutathione, glutathione synthesis in the liver has been shown to be essential. GCLC knockout mice die within a month of birth due to the absence of hepatic GSH synthesis.[3] [4]

The unusual gamma amide linkage in glutathione protects it from hydrolysis by peptidases.

Occurrence

Glutathione is the most abundant non-protein thiol (-containing compound) in animal cells, ranging from 0.5 to 10 mmol/L. It is present in the cytosol and the organelles. In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH), with the remainder in the disulfide form (GSSG).[5] 80-85% of cellular GSH is in the cytosol and 10-15% is in the mitochondria.

Human beings synthesize glutathione, but a few eukaryotes do not, including some members of Fabaceae, Entamoeba, and Giardia. The only known archaea that make glutathione are halobacteria. Some bacteria, such as "Cyanobacteria" and Pseudomonadota, can biosynthesize glutathione.[6] [7]

Systemic availability of orally consumed glutathione has poor bioavailability because the tripeptide is the substrate of proteases (peptidases) of the alimentary canal, and due to the absence of a specific carrier of glutathione at the level of cell membrane.[8] [9] The administration of N-acetylcysteine (NAC), a cysteine prodrug, helps replenish intracellular GSH levels.[10] The patented compound RiboCeine has been studied as a supplement that enhances production of glutathione which helps mitigate hyperglycemia.[11] [12]

Biochemical function

Glutathione exists in reduced (GSH) and oxidized (GSSG) states.[13] The ratio of reduced glutathione to oxidized glutathione within cells is a measure of cellular oxidative stress[14] [15] where increased GSSG-to-GSH ratio is indicative of greater oxidative stress.

In the reduced state, the thiol group of cysteinyl residue is a source of one reducing equivalent. Glutathione disulfide (GSSG) is thereby generated. The oxidized state is converted to the reduced state by NADPH.[16] This conversion is catalyzed by glutathione reductase:

NADPH + GSSG + H2O → 2 GSH + NADP+ + OH−

Roles

Antioxidant

GSH protects cells by neutralising (reducing) reactive oxygen species.[17] [18] This conversion is illustrated by the reduction of peroxides:

2 GSH + R2O2 → GSSG + 2 ROH (R = H, alkyl)and with free radicals:

GSH + R• → GSSG + RH

Regulation

Aside from deactivating radicals and reactive oxidants, glutathione participates in thiol protection and redox regulation of cellular thiol proteins under oxidative stress by protein S-glutathionylation, a redox-regulated post-translational thiol modification. The general reaction involves formation of an unsymmetrical disulfide from the protectable protein (RSH) and GSH:[19]

RSH + GSH + [O] → GSSR + H2O

Glutathione is also employed for the detoxification of methylglyoxal and formaldehyde, toxic metabolites produced under oxidative stress. This detoxification reaction is carried out by the glyoxalase system. Glyoxalase I (EC 4.4.1.5) catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-lactoylglutathione. Glyoxalase II (EC 3.1.2.6) catalyzes the hydrolysis of S-D-lactoylglutathione to glutathione and D-lactic acid.

It maintains exogenous antioxidants such as vitamins C and E in their reduced (active) states.[20] [21] [22]

Metabolism

Among the many metabolic processes in which it participates, glutathione is required for the biosynthesis of leukotrienes and prostaglandins. It plays a role in the storage of cysteine. Glutathione enhances the function of citrulline as part of the nitric oxide cycle.[23] It is a cofactor and acts on glutathione peroxidase.[24] Glutathione is used to produce S-sulfanylglutathione, which is part of hydrogen sulfide metabolism.[25]

Conjugation

Glutathione facilitates metabolism of xenobiotics. Glutathione S-transferase enzymes catalyze its conjugation to lipophilic xenobiotics, facilitating their excretion or further metabolism.[26] The conjugation process is illustrated by the metabolism of N-acetyl-p-benzoquinone imine (NAPQI). NAPQI is a reactive metabolite formed by the action of cytochrome P450 on paracetamol (acetaminophen). Glutathione conjugates to NAPQI, and the resulting ensemble is excreted.

In plants

In plants, glutathione is involved in stress management. It is a component of the glutathione-ascorbate cycle, a system that reduces poisonous hydrogen peroxide.[27] It is the precursor of phytochelatins, glutathione oligomers that chelate heavy metals such as cadmium.[28] Glutathione is required for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthora brassicae.[29] Adenylyl-sulfate reductase, an enzyme of the sulfur assimilation pathway, uses glutathione as an electron donor. Other enzymes using glutathione as a substrate are glutaredoxins. These small oxidoreductases are involved in flower development, salicylic acid, and plant defence signalling.[30]

Uses

Winemaking

The content of glutathione in must, the first raw form of wine, determines the browning, or caramelizing effect, during the production of white wine by trapping the caffeoyltartaric acid quinones generated by enzymic oxidation as grape reaction product.[31] Its concentration in wine can be determined by UPLC-MRM mass spectrometry.[32]

See also

Notes and References

  1. Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF . The changing faces of glutathione, a cellular protagonist . Biochemical Pharmacology . 66 . 8 . 1499–1503 . October 2003 . 14555227 . 10.1016/S0006-2952(03)00504-5 .
  2. White CC, Viernes H, Krejsa CM, Botta D, Kavanagh TJ . Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity . Analytical Biochemistry . 318 . 2 . 175–180 . July 2003 . 12814619 . 10.1016/S0003-2697(03)00143-X .
  3. Chen Y, Yang Y, Miller ML, Shen D, Shertzer HG, Stringer KF, Wang B, Schneider SN, Nebert DW, Dalton TP . Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure . Hepatology . 45 . 5 . 1118–1128 . May 2007 . 17464988 . 10.1002/hep.21635 . 25000753 . free .
  4. Sies H . Glutathione and its role in cellular functions . Free Radical Biology & Medicine . 27 . 9–10 . 916–921 . 1999 . 10569624 . 10.1016/S0891-5849(99)00177-X .
  5. Halprin KM, Ohkawara A . The measurement of glutathione in human epidermis using glutathione reductase . The Journal of Investigative Dermatology . 48 . 2 . 149–152 . 1967 . 6020678 . 10.1038/jid.1967.24 . free .
  6. Copley SD, Dhillon JK . Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes . Genome Biology . 3 . 5 . research0025 . 29 April 2002 . 12049666 . 115227 . 10.1186/gb-2002-3-5-research0025 . free .
  7. Book: Significance of glutathione in plant adaptation to the environment. Wonisch. Willibald. Schaur. Rudolf J. . vanc . Springer. 2001. 978-1-4020-0178-9. Grill. D.. Chapter 2: Chemistry of Glutathione. Tausz. T.. De Kok. L.J.. https://books.google.com/books?id=aX2eJf1i67IC&pg=PA13. Google Books.
  8. Witschi A, Reddy S, Stofer B, Lauterburg BH . The systemic availability of oral glutathione . European Journal of Clinical Pharmacology . 43 . 6 . 667–669 . 1992 . 1362956 . 10.1007/bf02284971 . 27606314 .
  9. Web site: Acetylcysteine Monograph for Professionals. Drugs.com.
  10. N-acetylcysteine - a safe antidote for cysteine/glutathione deficiency. 2007 . 4540061 . Atkuri . K. R. . Mantovani . J. J. . Herzenberg . L. A. . Herzenberg . L. A. . Current Opinion in Pharmacology . 7 . 4 . 355–359 . 10.1016/j.coph.2007.04.005 . 17602868 .
  11. Web site: COMPOSITIONS COMPRISING SUGAR-CYSTEINE PRODUCTS - US-20140348811-A1 . Nagasawa . Herbert T. . November 27, 2014 . ppubs.uspto.gov . United States Patent Office . 16 . October 31, 2023 . "30. A method of increasing ATP and/or glutathione...".
  12. Ukwenya VO, Alese MO, Ogunlade B, Folorunso IM, Omotuyi OI . Anacardium occidentale leaves extract and riboceine mitigate hyperglycemia through anti-oxidative effects and modulation of some selected genes associated with diabetes . J Diabetes Metab Disord . 22 . 1 . 455–468 . 2022 . 37255827 . 10.1007/s40200-022-01165-2 . 10225389 .
  13. Iskusnykh IY, Zakharova AA, Pathak D . Glutathione in Brain Disorders and Aging . Molecules . 27 . 1 . January 2022 . 324 . 35011559 . 8746815 . 10.3390/molecules27010324 . free .
  14. Pastore A, Piemonte F, Locatelli M, Lo Russo A, Gaeta LM, Tozzi G, Federici G . Determination of blood total, reduced, and oxidized glutathione in pediatric subjects . Clinical Chemistry . 47 . 8 . 1467–1469 . August 2001 . 11468240 . 10.1093/clinchem/47.8.1467. free .
  15. Lu SC . Glutathione synthesis . Biochimica et Biophysica Acta (BBA) - General Subjects . 1830 . 5 . 3143–3153 . May 2013 . 22995213 . 3549305 . 10.1016/j.bbagen.2012.09.008 .
  16. Couto N, Malys N, Gaskell SJ, Barber J . Partition and turnover of glutathione reductase from Saccharomyces cerevisiae: a proteomic approach . Journal of Proteome Research . 12 . 6 . 2885–2894 . June 2013 . 23631642 . 10.1021/pr4001948 .
  17. The pathobiology of diabetic complications: A unifying mechanism. Diabetes. 2005. 54. 6. 1615–1625. 10.2337/diabetes.54.6.1615. 15919781. Michael Brownlee. free.
  18. Guoyao Wu . Yun-Zhong Fang . Sheng Yang . Joanne R. Lupton . Nancy D. Turner . Glutathione Metabolism and its Implications for Health. Journal of Nutrition. 2004. 134. 3. 489–492. 10.1093/jn/134.3.489. 14988435. free.
  19. Protein S-glutathionylation: a regulatory device from bacteria to humans . Dalle-Donne, Isabella . Rossi, Ranieri . Colombo, Graziano . Giustarini, Daniela . Milzani, Aldo . Trends in Biochemical Sciences. 2009. 34. 2. 85–96. 10.1016/j.tibs.2008.11.002. 19135374.
  20. Dringen R . Metabolism and functions of glutathione in brain . Progress in Neurobiology . 62 . 6 . 649–671 . December 2000 . 10880854 . 10.1016/s0301-0082(99)00060-x . 452394 .
  21. Scholz RW, Graham KS, Gumpricht E, Reddy CC . 1989 . Mechanism of interaction of vitamin E and glutathione in the protection against membrane lipid peroxidation . Annals of the New York Academy of Sciences . 570 . 1. 514–517 . 10.1111/j.1749-6632.1989.tb14973.x. 1989NYASA.570..514S . 85414084 .
  22. Hughes RE . vanc . 1964 . Reduction of dehydroascorbic acid by animal tissues . Nature . 203 . 4949. 1068–1069 . 10.1038/2031068a0 . 14223080 . 1964Natur.203.1068H . 4273230 .
  23. Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS . Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe . The Plant Cell . 11 . 6 . 1153–1164 . June 1999 . 10368185 . 144235 . 10.1105/tpc.11.6.1153 . 3870806 .
  24. Grant CM . Role of the glutathione/glutaredoxin and thioredoxin systems in yeast growth and response to stress conditions . Molecular Microbiology . 39 . 3 . 533–541 . 2001 . 11169096 . 10.1046/j.1365-2958.2001.02283.x . 6467802 . free .
  25. Melideo . SL . Jackson . MR . Jorns . MS . Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog. . Biochemistry . 22 July 2014 . 53 . 28 . 4739–53 . 10.1021/bi500650h . 24981631. 4108183 .
  26. Glutathione transferases . Hayes, John D. . Flanagan, Jack U. . Jowsey, Ian R. . Annual Review of Pharmacology and Toxicology. 2005. 45. 51–88. 10.1146/annurev.pharmtox.45.120403.095857. 15822171.
  27. Noctor G, Foyer CH . Ascorbate and Glutathione: Keeping Active Oxygen Under Control . Annual Review of Plant Physiology and Plant Molecular Biology . 49 . 1 . 249–279 . June 1998 . 15012235 . 10.1146/annurev.arplant.49.1.249 .
  28. Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS . Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe . The Plant Cell . 11 . 6 . 1153–1164 . June 1999 . 10368185 . 144235 . 10.1105/tpc.11.6.1153 .
  29. Parisy V, Poinssot B, Owsianowski L, Buchala A, Glazebrook J, Mauch F . Identification of PAD2 as a gamma-glutamylcysteine synthetase highlights the importance of glutathione in disease resistance of Arabidopsis . The Plant Journal . 49 . 1 . 159–172 . January 2007 . 17144898 . 10.1111/j.1365-313X.2006.02938.x . free .
  30. Rouhier N, Lemaire SD, Jacquot JP . The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation . Annual Review of Plant Biology . 59 . 1 . 143–166 . 2008 . 18444899 . 10.1146/annurev.arplant.59.032607.092811 .
  31. Rigaud J, Cheynier V, Souquet JM, Moutounet M . vanc . 1991 . Influence of must composition on phenolic oxidation kinetics . Journal of the Science of Food and Agriculture . 57 . 1. 55–63 . 10.1002/jsfa.2740570107 . must . 1991JSFA...57...55R .
  32. Vallverdú-Queralt A, Verbaere A, Meudec E, Cheynier V, Sommerer N . Straightforward method to quantify GSH, GSSG, GRP, and hydroxycinnamic acids in wines by UPLC-MRM-MS . Journal of Agricultural and Food Chemistry . 63 . 1 . 142–149 . January 2015 . 25457918 . 10.1021/jf504383g .

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