Glutathione

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Glutathione [1]
Glutathione-skeletal.svg
Glutathione-from-xtal-3D-balls.png
Glutathione-3D-vdW.png
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)
AbbreviationsGSH
ChEBI
ChEMBL
ChemSpider
DrugBank
ECHA InfoCard 100.000.660 OOjs UI icon edit-ltr-progressive.svg
KEGG
MeSH Glutathione
PubChem CID
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 Yes check.svgY
    Key: RWSXRVCMGQZWBV-WDSKDSINSA-N Yes check.svgY
  • 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).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Glutathione (GSH, /ˌɡluːtəˈθaɪoʊn/ ) is an organic compound with the chemical formula HOCOCH(NH2)CH2CH2CONHCH(CH2SH)CONHCH2COOH. 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. [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 non-protein thiol (R−SH-containing compound) in animal cells, ranging from 0.5 to 10 mmol/L. It is present in the cytosol and the organelles. [6] The concentration of glutathione in the cytoplasm is significantly higher (ranging from 0.5-10 mM) compared to extracellular fluids (2-20 μM), reaching levels up to 1000 times greater. [7] [8] 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). [9] The cytosol holds 80-85% of cellular GSH and the mitochondria hold 10-15%. [10]

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. [11] [12]

Systemic availability of orally consumed glutathione is poor. It had low 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. [13] [14] The administration of N-acetylcysteine (NAC), a cysteine prodrug, helps replenish intracellular GSH levels. [15]

Biochemical function

Glutathione exists in reduced (GSH) and oxidized (GSSG) states. [16] The ratio of reduced glutathione to oxidized glutathione within cells is a measure of cellular oxidative stress [17] [10] 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. [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]

In degradation of drug delivery systems

Among various types of cancer, lung cancer, larynx cancer, mouth cancer, and breast cancer exhibit higher concentrations (10-40 mM) of GSH compared to healthy cells. [32] Thus, drug delivery systems containing disulfide bonds, typically cross-linked micro-nanogels, stand out for their ability to degrade in the presence of high concentrations of glutathione (GSH). [33] This degradation process releases the drug payload specifically into cancerous or tumorous tissue, leveraging the significant difference in redox potential between the oxidizing extracellular environment and the reducing intracellular cytosol. [34] [35]

When internalized by endocytosis, nanogels encounter high concentrations of GSH inside the cancer cell. GSH, a potent reducing agent, donates electrons to disulfide bonds in the nanogels, initiating a thiol-disulfide exchange reaction. This reaction breaks the disulfide bonds, converting them into two thiol groups, and facilitates targeted drug release where it is needed most. This reaction is called a thiol-disulfide exchange reaction. [36] [37]

R−S−S−R′+ 2GSH → R−SH + R′−SH + GSSG

where R and R' are parts of the micro-nanogel structure, and GSSG is oxidized glutathione (glutathione disulfide).

The breaking of disulfide bonds causes the nanogel to degrade into smaller fragments. This degradation process leads to the release of encapsulated drugs. The released drug molecules can then exert their therapeutic effects, such as inducing apoptosis in cancer cells. [38]

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. [39] Its concentration in wine can be determined by UPLC-MRM mass spectrometry. [40]

See also

References

  1. 1 2 3 4 Haynes WM, ed. (2016). CRC Handbook of Chemistry and Physics (97th ed.). CRC Press. p. 3.284. ISBN   978-1-4987-5429-3.
  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): 1118–28. 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. ↑ Giustarini D, Milzani A, Dalle-Donne I, Rossi R (May 2023). "How to Increase Cellular Glutathione". Antioxidants (Basel). 12 (5): 1094. doi: 10.3390/antiox12051094 . PMC   10215789 . PMID   37237960.
  8. ↑ Cheng R, Feng F, Meng F, Deng C, Feijen J, Zhong Z (May 2011). "Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery". J Control Release. 152 (1): 2–12. doi:10.1016/j.jconrel.2011.01.030. PMID   21295087.
  9. ↑ 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.
  10. 1 2 Lu SC (May 2013). "Glutathione synthesis". Biochimica et Biophysica Acta (BBA) - General Subjects. 1830 (5): 3143–53. doi:10.1016/j.bbagen.2012.09.008. PMC   3549305 . PMID   22995213.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ Witschi A, Reddy S, Stofer B, Lauterburg BH (1992). "The systemic availability of oral glutathione". European Journal of Clinical Pharmacology. 43 (6): 667–9. doi:10.1007/bf02284971. PMID   1362956. S2CID   27606314.
  14. ↑ "Acetylcysteine Monograph for Professionals". Drugs.com.
  15. ↑ 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): 355–9. doi:10.1016/j.coph.2007.04.005. PMC   4540061 . PMID   17602868.
  16. ↑ 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.
  17. ↑ 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): 1467–9. doi: 10.1093/clinchem/47.8.1467 . PMID   11468240.
  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): 2885–94. doi:10.1021/pr4001948. PMID   23631642.
  19. ↑ Michael Brownlee (2005). "The pathobiology of diabetic complications: A unifying mechanism". Diabetes. 54 (6): 1615–25. 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): 514–7. 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): 1068–9. 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): 1153–64. 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): 1153–64. 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. Bibcode:2008AnRPB..59..143R. doi:10.1146/annurev.arplant.59.032607.092811. PMID   18444899.
  32. ↑ Gamcsik MP, Kasibhatla MS, Teeter SD, Colvin OM (December 2012). "Glutathione levels in human tumors". Biomarkers. 17 (8): 671–91. doi:10.3109/1354750X.2012.715672. PMC   3608468 . PMID   22900535.
  33. ↑ Patra JK, Das G, Fraceto LF, Campos EV, Rodriguez-Torres MD, Acosta-Torres LS, Diaz-Torres LA, Grillo R, Swamy MK, Sharma S, Habtemariam S, Shin HS (September 2018). "Nano based drug delivery systems: recent developments and future prospects". J Nanobiotechnology. 16 (1): 71. doi: 10.1186/s12951-018-0392-8 . PMC   6145203 . PMID   30231877.
  34. ↑ Li Y, Maciel D, Rodrigues J, Shi X, Tomás H (August 2015). "Biodegradable Polymer Nanogels for Drug/Nucleic Acid Delivery". Chem Rev. 115 (16): 8564–8608. doi:10.1021/cr500131f. PMID   26259712.
  35. ↑ Adamo G, Grimaldi N, Campora S, Sabatino MA, Dispenza C, Ghersi G (2014). "Glutathione-Sensitive Nanogels for Drug Release". Chemical Engineering Transactions. 38: 457–462.
  36. ↑ Gilbert, H.F. (1990). "Molecular and Cellular Aspects of Thiol–Disulfide Exchange". Advances in Enzymology and Related Areas of Molecular Biology. Vol. 63. pp. 69–172. doi:10.1002/9780470123096.ch2. ISBN   978-0-470-12309-6. PMID   2407068.
  37. ↑ Gilbert, H.F. (1995). "Thiol/disulfide exchange equilibria and disulfide bond stability". Biothiols, Part A: Monothiols and Dithiols, Protein Thiols, and Thiyl Radicals. Methods in Enzymology. Vol. 251. pp. 8–28. doi:10.1016/0076-6879(95)51107-5. ISBN   978-0-12-182152-4. PMID   7651233.
  38. ↑ Elkassih SA, Kos P, Xiong H, Siegwart DJ (January 2019). "Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization". Biomater Sci. 7 (2): 607–617. doi:10.1039/c8bm01120f. PMC   7031860 . PMID   30462102.
  39. ↑ 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.
  40. ↑ 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): 142–9. Bibcode:2015JAFC...63..142V. doi:10.1021/jf504383g. PMID   25457918.
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