Glutathione[1]
Names
IUPAC name
γ-Glutamylcysteinylglycine
Systematic IUPAC name
(2S)-2-Amino-5-({(2R)-1-[(carboxymethyl)amino]-1-oxo-3-sulfanylpropan-2-yl}amino)-5-oxopentanoic acid
Other names
γ-L-Glutamyl-L-cysteinylglycine
(2S)-2-Amino-4-({(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl}carbamoyl)butanoic acid
Identifiers
3D model (JSmol)
Abbreviations GSH
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.660
KEGG
MeSH Glutathione
UNII
  • InChI=1S/C10H17N3O6S/c11-5(10(18)19)1-2-7(14)13-6(4-20)9(17)12-3-8(15)16/h5-6,20H,1-4,11H2,(H,12,17)(H,13,14)(H,15,16)(H,18,19)/t5-,6-/m0/s1 checkY
    Key: RWSXRVCMGQZWBV-WDSKDSINSA-N checkY
  • C(CC(=O)N[C@@H](CS)C(=O)NCC(=O)O)[C@@H](C(=O)O)N
Properties
C10H17N3O6S
Molar mass 307.32 g·mol−1
Melting point 195 °C (383 °F; 468 K)[1]
Freely soluble[1]
Solubility in methanol, diethyl ether Insoluble[1]
Pharmacology
V03AB32 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
checkY verify (what is checkY☒N ?)
Infobox references

Glutathione (GSH, /ˌɡluːtəˈθaɪoʊn/) 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.[2] 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.[4][5]

The unusual gamma amide linkage in glutathione protects it from hydrolysis by peptidases.[6]

Occurrence

Glutathione is the most abundant thiol in animal cells, ranging from 0.5 to 10 mmol/L. It is present in the cytosol and the organelles.[6]

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.[7][8]

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.[9][10] The administration of N-acetylcysteine (NAC), a cysteine prodrug, helps replenish intracellular GSH levels.[11] The patented compound RiboCeine has been studied as a supplement that enhances production of glutathione which helps mitigate hyperglycemia.[12][13]

Biochemical function

Glutathione exists in reduced (GSH) and oxidized (GSSG) states.[14] The ratio of reduced glutathione to oxidized glutathione within cells is a measure of cellular oxidative stress[15][16] where increased GSSG-to-GSH ratio is indicative of greater oxidative stress. 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).[17]

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.[18] 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.[19][6] This conversion is illustrated by the reduction of peroxides:

2 GSH + R2O2 → GSSG + 2 ROH  (R = H, alkyl)

and with free radicals:

GSH + R• → 1/2 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:[20]

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.[21][22][23]

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.[24] It is a cofactor and acts on glutathione peroxidase.[25] Glutathione is used to produce S-sulfanylglutathione, which is part of hydrogen sulfide metabolism.[26]

Conjugation

Glutathione facilitates metabolism of xenobiotics. Glutathione S-transferase enzymes catalyze its conjugation to lipophilic xenobiotics, facilitating their excretion or further metabolism.[27] 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.[28] It is the precursor of phytochelatins, glutathione oligomers that chelate heavy metals such as cadmium.[29] Glutathione is required for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthora brassicae.[30] 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.[31]

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.[32] Its concentration in wine can be determined by UPLC-MRM mass spectrometry.[33]

See also

References

  1. 1 2 3 4 Haynes, William M., ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. p. 3.284. ISBN 9781498754293.
  2. ↑ Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF (October 2003). "The changing faces of glutathione, a cellular protagonist". Biochemical Pharmacology. 66 (8): 1499–1503. doi:10.1016/S0006-2952(03)00504-5. PMID 14555227.
  3. ↑ White CC, Viernes H, Krejsa CM, Botta D, Kavanagh TJ (July 2003). "Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity". Analytical Biochemistry. 318 (2): 175–180. doi:10.1016/S0003-2697(03)00143-X. PMID 12814619.
  4. ↑ Chen Y, Yang Y, Miller ML, Shen D, Shertzer HG, Stringer KF, Wang B, Schneider SN, Nebert DW, Dalton TP (May 2007). "Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure". Hepatology. 45 (5): 1118–1128. doi:10.1002/hep.21635. PMID 17464988. S2CID 25000753.
  5. ↑ Sies H (1999). "Glutathione and its role in cellular functions". Free Radical Biology & Medicine. 27 (9–10): 916–921. doi:10.1016/S0891-5849(99)00177-X. PMID 10569624.
  6. 1 2 3 Guoyao Wu; Yun-Zhong Fang; Sheng Yang; Joanne R. Lupton; Nancy D. Turner (2004). "Glutathione Metabolism and its Implications for Health". Journal of Nutrition. 134 (3): 489–492. doi:10.1093/jn/134.3.489. PMID 14988435.
  7. ↑ Copley SD, Dhillon JK (29 April 2002). "Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes". Genome Biology. 3 (5): research0025. doi:10.1186/gb-2002-3-5-research0025. PMC 115227. PMID 12049666.
  8. ↑ Wonisch W, Schaur RJ (2001). "Chapter 2: Chemistry of Glutathione". In Grill D, Tausz T, De Kok L (eds.). Significance of glutathione in plant adaptation to the environment. Springer. ISBN 978-1-4020-0178-9 – via Google Books.
  9. ↑ Witschi A, Reddy S, Stofer B, Lauterburg BH (1992). "The systemic availability of oral glutathione". European Journal of Clinical Pharmacology. 43 (6): 667–669. doi:10.1007/bf02284971. PMID 1362956. S2CID 27606314.
  10. ↑ "Acetylcysteine Monograph for Professionals". Drugs.com.
  11. ↑ Atkuri, K. R.; Mantovani, J. J.; Herzenberg, L. A.; Herzenberg, L. A. (2007). "N-acetylcysteine - a safe antidote for cysteine/glutathione deficiency". Current Opinion in Pharmacology. 7 (4): 355–359. doi:10.1016/j.coph.2007.04.005. PMC 4540061. PMID 17602868.
  12. ↑ Nagasawa, Herbert T. (27 November 2014). "COMPOSITIONS COMPRISING SUGAR-CYSTEINE PRODUCTS - US-20140348811-A1". ppubs.uspto.gov. United States Patent Office. p. 16. Retrieved 31 October 2023. 30. A method of increasing ATP and/or glutathione...
  13. ↑ Ukwenya VO, Alese MO, Ogunlade B, Folorunso IM, Omotuyi OI (2022). "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. doi:10.1007/s40200-022-01165-2. PMC 10225389. PMID 37255827.
  14. ↑ Iskusnykh IY, Zakharova AA, Pathak D (January 2022). "Glutathione in Brain Disorders and Aging". Molecules. 27 (1): 324. doi:10.3390/molecules27010324. PMC 8746815. PMID 35011559.
  15. ↑ Pastore A, Piemonte F, Locatelli M, Lo Russo A, Gaeta LM, Tozzi G, Federici G (August 2001). "Determination of blood total, reduced, and oxidized glutathione in pediatric subjects". Clinical Chemistry. 47 (8): 1467–1469. doi:10.1093/clinchem/47.8.1467. PMID 11468240.
  16. ↑ Lu SC (May 2013). "Glutathione synthesis". Biochimica et Biophysica Acta (BBA) - General Subjects. 1830 (5): 3143–3153. doi:10.1016/j.bbagen.2012.09.008. PMC 3549305. PMID 22995213.
  17. ↑ Halprin KM, Ohkawara A (1967). "The measurement of glutathione in human epidermis using glutathione reductase". The Journal of Investigative Dermatology. 48 (2): 149–152. doi:10.1038/jid.1967.24. PMID 6020678.
  18. ↑ Couto N, Malys N, Gaskell SJ, Barber J (June 2013). "Partition and turnover of glutathione reductase from Saccharomyces cerevisiae: a proteomic approach" (PDF). Journal of Proteome Research. 12 (6): 2885–2894. doi:10.1021/pr4001948. PMID 23631642.
  19. ↑ Michael Brownlee (2005). "The pathobiology of diabetic complications: A unifying mechanism". Diabetes. 54 (6): 1615–1625. doi:10.2337/diabetes.54.6.1615. PMID 15919781.
  20. ↑ Dalle-Donne, Isabella; Rossi, Ranieri; Colombo, Graziano; Giustarini, Daniela; Milzani, Aldo (2009). "Protein S-glutathionylation: a regulatory device from bacteria to humans". Trends in Biochemical Sciences. 34 (2): 85–96. doi:10.1016/j.tibs.2008.11.002. PMID 19135374.
  21. ↑ Dringen R (December 2000). "Metabolism and functions of glutathione in brain". Progress in Neurobiology. 62 (6): 649–671. doi:10.1016/s0301-0082(99)00060-x. PMID 10880854. S2CID 452394.
  22. ↑ 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. Bibcode:1989NYASA.570..514S. doi:10.1111/j.1749-6632.1989.tb14973.x. S2CID 85414084.
  23. ↑ Hughes RE (1964). "Reduction of dehydroascorbic acid by animal tissues". Nature. 203 (4949): 1068–1069. Bibcode:1964Natur.203.1068H. doi:10.1038/2031068a0. PMID 14223080. S2CID 4273230.
  24. ↑ Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS (June 1999). "Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe". The Plant Cell. 11 (6): 1153–1164. doi:10.1105/tpc.11.6.1153. JSTOR 3870806. PMC 144235. PMID 10368185.
  25. ↑ Grant CM (2001). "Role of the glutathione/glutaredoxin and thioredoxin systems in yeast growth and response to stress conditions". Molecular Microbiology. 39 (3): 533–541. doi:10.1046/j.1365-2958.2001.02283.x. PMID 11169096. S2CID 6467802.
  26. ↑ Melideo, SL; Jackson, MR; Jorns, MS (22 July 2014). "Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog". Biochemistry. 53 (28): 4739–53. doi:10.1021/bi500650h. PMC 4108183. PMID 24981631.
  27. ↑ Hayes, John D.; Flanagan, Jack U.; Jowsey, Ian R. (2005). "Glutathione transferases". Annual Review of Pharmacology and Toxicology. 45: 51–88. doi:10.1146/annurev.pharmtox.45.120403.095857. PMID 15822171.
  28. ↑ Noctor G, Foyer CH (June 1998). "Ascorbate and Glutathione: Keeping Active Oxygen Under Control". Annual Review of Plant Physiology and Plant Molecular Biology. 49 (1): 249–279. doi:10.1146/annurev.arplant.49.1.249. PMID 15012235.
  29. ↑ Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS (June 1999). "Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe". The Plant Cell. 11 (6): 1153–1164. doi:10.1105/tpc.11.6.1153. PMC 144235. PMID 10368185.
  30. ↑ Parisy V, Poinssot B, Owsianowski L, Buchala A, Glazebrook J, Mauch F (January 2007). "Identification of PAD2 as a gamma-glutamylcysteine synthetase highlights the importance of glutathione in disease resistance of Arabidopsis" (PDF). The Plant Journal. 49 (1): 159–172. doi:10.1111/j.1365-313X.2006.02938.x. PMID 17144898.
  31. ↑ Rouhier N, Lemaire SD, Jacquot JP (2008). "The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation" (PDF). Annual Review of Plant Biology. 59 (1): 143–166. doi:10.1146/annurev.arplant.59.032607.092811. PMID 18444899.
  32. ↑ Rigaud J, Cheynier V, Souquet JM, Moutounet M (1991). "Influence of must composition on phenolic oxidation kinetics". Journal of the Science of Food and Agriculture. 57 (1): 55–63. Bibcode:1991JSFA...57...55R. doi:10.1002/jsfa.2740570107.
  33. ↑ Vallverdú-Queralt A, Verbaere A, Meudec E, Cheynier V, Sommerer N (January 2015). "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. doi:10.1021/jf504383g. PMID 25457918.
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