Editing Glutathione

{{Short description|Ubiquitous antioxidant compound in living organisms}}
{{Use dmy dates|date=August 2021}}
{{Chembox
| Watchedfields = changed
| verifiedrevid = 443838068
| Reference = <ref name=crc/>
| ImageFile = Glutathione-skeletal.svg
| ImageFile2 = Glutathione-from-xtal-3D-balls.png
| ImageFile3 = Glutathione-3D-vdW.png
| IUPACName = γ-Glutamylcysteinylglycine
| SystematicName = (2''S'')-2-Amino-5-({(2''R'')-1-[(carboxymethyl)amino]-1-oxo-3-sulfanylpropan-2-yl}amino)-5-oxopentanoic acid
| OtherNames = γ-<small>L</small>-Glutamyl-<small>L</small>-cysteinylglycine<br />(2''S'')-2-Amino-4-({(1''R'')-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl}carbamoyl)butanoic acid
|Section1={{Chembox Identifiers
| IUPHAR_ligand = 6737
| Abbreviations = GSH
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = GAN16C9B8O
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1543
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 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
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RWSXRVCMGQZWBV-WDSKDSINSA-N
| CASNo = 70-18-8
| CASNo_Ref = {{cascite|correct|CAS}}
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 111188
| PubChem = 124886
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00143
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16856
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = C00051
| SMILES = C(CC(=O)N[C@@H](CS)C(=O)NCC(=O)O)[C@@H](C(=O)O)N
| MeSHName = Glutathione
  }}
|Section2={{Chembox Properties
| C=10 | H=17 | N=3 | O=6 | S=1
| Appearance = 
| Density = 
| MeltingPtC = 195
| MeltingPt_ref = <ref name=crc>{{cite book | editor-last= Haynes |editor-first=William M. | name-list-style = vanc| date = 2016| title = CRC Handbook of Chemistry and Physics | edition = 97th | publisher = [[CRC Press]] | isbn = 978-1-4987-5429-3|page=3.284| title-link = CRC Handbook of Chemistry and Physics}}</ref>
| BoilingPt = 
| Solubility = Freely soluble<ref name=crc/>
| SolubleOther = Insoluble<ref name=crc/>
| Solvent = [[methanol]], [[diethyl ether]]
  }}
|Section6={{Chembox Pharmacology
| ATCCode_prefix = V03
| ATCCode_suffix = AB32
  }}
|Section7={{Chembox Hazards
| MainHazards = 
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}}

'''Glutathione''' ('''GSH''', {{IPAc-en|ˌ|ɡ|l|uː|t|ə|ˈ|θ|aɪ|əʊ|n}}) is an [[organic compound]] with the [[chemical formula]] {{chem2|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 [[Cell (biology)|cellular]] components caused by sources such as [[reactive oxygen species]], [[free radical]]s, [[peroxide]]s, [[lipid peroxidation|lipid peroxides]], and [[Toxic heavy metal|heavy metals]].<ref>{{cite journal | vauthors = Pompella A, Visvikis A, Paolicchi A, De Tata V, Casini AF | title = The changing faces of glutathione, a cellular protagonist | journal = Biochemical Pharmacology | volume = 66 | issue = 8 | pages = 1499–1503 | date = October 2003 | pmid = 14555227 | doi = 10.1016/S0006-2952(03)00504-5 }}</ref> It is a [[tripeptide]] with a [[Glutamate—cysteine ligase|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:
*First, [[Gamma-L-Glutamyl-L-cysteine|γ-glutamylcysteine]] is synthesized from <small>L</small>-[[glutamate]] and <small>L</small>-[[cysteine]].  This conversion requires the enzyme [[glutamate–cysteine ligase]] (GCL, glutamate cysteine synthase). This reaction is the rate-limiting step in glutathione synthesis.<ref>{{cite journal | vauthors = White CC, Viernes H, Krejsa CM, Botta D, Kavanagh TJ | title = Fluorescence-based microtiter plate assay for glutamate-cysteine ligase activity | journal = Analytical Biochemistry | volume = 318 | issue = 2 | pages = 175–180 | date = July 2003 | pmid = 12814619 | doi = 10.1016/S0003-2697(03)00143-X  | url = https://zenodo.org/record/1259521 }}</ref>
*Second, glycine is added to the C-terminal of γ-glutamylcysteine. This condensation is catalyzed by [[glutathione synthetase]].

While all animal cells are capable of synthesizing glutathione, synthesis in the liver has been shown to be essential. [[GCLC]] [[Knockout mouse|knockout mice]] die within a month of birth due to the absence of hepatic GSH synthesis.<ref>{{cite journal | vauthors = Chen Y, Yang Y, Miller ML, Shen D, Shertzer HG, Stringer KF, Wang B, Schneider SN, Nebert DW, Dalton TP | title = Hepatocyte-specific Gclc deletion leads to rapid onset of steatosis with mitochondrial injury and liver failure | journal = Hepatology | volume = 45 | issue = 5 | pages = 1118–28 | date = May 2007 | pmid = 17464988 | doi = 10.1002/hep.21635 | s2cid = 25000753 | doi-access = free }}</ref><ref name="Sies 916–921">{{cite journal | vauthors = Sies H | title = Glutathione and its role in cellular functions | journal = Free Radical Biology & Medicine | volume = 27 | issue = 9–10 | pages = 916–921 | year = 1999 | pmid = 10569624 | doi = 10.1016/S0891-5849(99)00177-X }}</ref>

The unusual gamma amide linkage in glutathione protects it from hydrolysis by peptidases.<ref name=Wu/>

===Occurrence===
Glutathione is the most abundant non-protein [[thiol]] ({{chem2|R\sSH}}-containing compound) in animal cells, ranging from 0.5 to 10&nbsp;mmol/L. It is present in the [[cytosol]] and the [[organelle]]s.<ref name=Wu/> 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.<ref>{{cite journal |vauthors=Giustarini D, Milzani A, Dalle-Donne I, Rossi R |title=How to Increase Cellular Glutathione |journal=Antioxidants |volume=12 |issue=5 |date=May 2023 |page=1094 |pmid=37237960 |pmc=10215789 |doi=10.3390/antiox12051094 |doi-access=free }}</ref><ref>{{cite journal |vauthors=Cheng R, Feng F, Meng F, Deng C, Feijen J, Zhong Z |title=Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery |journal=J Control Release |volume=152 |issue=1 |pages=2–12 |date=May 2011 |pmid=21295087 |doi=10.1016/j.jconrel.2011.01.030 }}
</ref>  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).<ref name="pmid6020678">{{cite journal | vauthors = Halprin KM, Ohkawara A | title = The measurement of glutathione in human epidermis using glutathione reductase | journal = The Journal of Investigative Dermatology | volume = 48 | issue = 2 | pages = 149–152 | year = 1967 | pmid = 6020678 | doi = 10.1038/jid.1967.24 | doi-access = free }}</ref> The cytosol holds 80-85% of cellular GSH and the [[mitochondria]] hold 10-15%.<ref name="pmid22995213" />

Human beings synthesize glutathione, but a few [[eukaryote]]s do not, including some members of [[Fabaceae]], ''[[Entamoeba]]'', and ''[[Giardia]]''. The only known [[archaea]] that make glutathione are [[Haloarchaea|halobacteria]]. Some [[bacteria]], such as "[[Cyanobacteria]]" and [[Pseudomonadota]], can biosynthesize glutathione.<ref>{{cite journal | vauthors = Copley SD, Dhillon JK | title = Lateral gene transfer and parallel evolution in the history of glutathione biosynthesis genes | journal = Genome Biology | volume = 3 | issue = 5 | pages = research0025 | date = 29 April 2002 | pmid = 12049666 | pmc = 115227 | doi = 10.1186/gb-2002-3-5-research0025 | doi-access = free }}</ref><ref>{{Cite book|url=https://books.google.com/books?id=aX2eJf1i67IC|title=Significance of glutathione in plant adaptation to the environment|last1=Wonisch|first1=Willibald|last2=Schaur|first2=Rudolf J. | name-list-style = vanc | publisher=Springer|year=2001|isbn=978-1-4020-0178-9|editor-last=Grill|editor-first=D.|chapter=Chapter 2: Chemistry of Glutathione|editor-last2=Tausz|editor-first2=T.|editor-last3=De Kok|editor-first3=L.J.|chapter-url=https://books.google.com/books?id=aX2eJf1i67IC&pg=PA13|via=Google Books}}</ref>

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.<ref>{{cite journal | vauthors = Witschi A, Reddy S, Stofer B, Lauterburg BH | title = The systemic availability of oral glutathione | journal = European Journal of Clinical Pharmacology | volume = 43 | issue = 6 | pages = 667–9 | year = 1992 | pmid = 1362956 | doi = 10.1007/bf02284971 | s2cid = 27606314 }}</ref><ref>{{Cite web|url=https://www.drugs.com/monograph/acetylcysteine.html|title=Acetylcysteine Monograph for Professionals|website=Drugs.com}}</ref> The administration of N-acetylcysteine (NAC), a cysteine prodrug, helps replenish intracellular GSH levels.<ref>{{Cite journal|title=N-acetylcysteine — a safe antidote for cysteine/glutathione deficiency|date=2007 |pmc=4540061 |last1=Atkuri |first1=K. R. |last2=Mantovani |first2=J. J. |last3=Herzenberg |first3=L. A. |last4=Herzenberg |first4=L. A. |journal=Current Opinion in Pharmacology |volume=7 |issue=4 |pages=355–9 |doi=10.1016/j.coph.2007.04.005 |pmid=17602868 }}</ref>

==Biochemical function==
Glutathione exists in reduced (GSH) and oxidized ([[Glutathione disulfide|GSSG]]) states.<ref name="Iskusnykh">{{cite journal |vauthors=Iskusnykh IY, Zakharova AA, Pathak D |title=Glutathione in Brain Disorders and Aging |journal=Molecules |volume=27 |issue=1 |date=January 2022 |page=324 |pmid=35011559 |pmc=8746815 |doi=10.3390/molecules27010324 |url= |doi-access=free }}</ref> The ratio of reduced glutathione to oxidized glutathione within cells is a measure of cellular [[oxidative stress]]<ref>{{cite journal | vauthors = Pastore A, Piemonte F, Locatelli M, Lo Russo A, Gaeta LM, Tozzi G, Federici G | title = Determination of blood total, reduced, and oxidized glutathione in pediatric subjects | journal = Clinical Chemistry | volume = 47 | issue = 8 | pages = 1467–9 | date = August 2001 | pmid = 11468240 | doi =  10.1093/clinchem/47.8.1467| url = http://www.clinchem.org/content/47/8/1467.long | doi-access = free }}</ref><ref name="pmid22995213">{{cite journal | author = Lu SC | title = Glutathione synthesis | journal =  Biochimica et Biophysica Acta (BBA) - General Subjects| volume = 1830 | issue = 5 | pages = 3143–53 | date = May 2013 | pmid = 22995213 | pmc = 3549305 | doi = 10.1016/j.bbagen.2012.09.008  }}</ref> 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]].<ref name="Couto2013">{{cite journal | vauthors = Couto N, Malys N, Gaskell SJ, Barber J | title = Partition and turnover of glutathione reductase from Saccharomyces cerevisiae: a proteomic approach | journal = Journal of Proteome Research | volume = 12 | issue = 6 | pages = 2885–94 | date = June 2013 | pmid = 23631642 | doi = 10.1021/pr4001948 | url = https://pure.manchester.ac.uk/ws/files/27512240/POST-PEER-REVIEW-PUBLISHERS.PDF }}</ref> This conversion is catalyzed by [[glutathione reductase]]:
:NADPH +  GSSG + H<sub>2</sub>O →  2 GSH  +  NADP<sup>+</sup>  +  OH<sup>−</sup>

==Roles==

===Antioxidant===
GSH protects cells by neutralising (reducing) [[reactive oxygen species]].<ref name=Brownlee>{{cite journal|title=The pathobiology of diabetic complications: A unifying mechanism|journal=Diabetes|year=2005|volume=54|issue=6|pages=1615–25|doi=10.2337/diabetes.54.6.1615|pmid=15919781|author=Michael Brownlee|doi-access=free}}</ref><ref name=Wu>{{cite journal |author=Guoyao Wu |author2=Yun-Zhong Fang |author3=Sheng Yang |author4=Joanne R. Lupton |author5=Nancy D. Turner |title=Glutathione Metabolism and its Implications for Health|journal=Journal of Nutrition|year=2004|volume=134|issue=3|pages=489–492|doi=10.1093/jn/134.3.489|pmid=14988435|doi-access=free}}</ref> This conversion is illustrated by the reduction of peroxides:
:2 GSH  +  R<sub>2</sub>O<sub>2</sub> →  GSSG  +  2 ROH {{pad|2em}}(R = H, alkyl)
and with free radicals:
:GSH  +  R<sup>•</sup> →  {{sfrac|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:<ref>{{cite journal|title=Protein ''S''-glutathionylation: a regulatory device from bacteria to humans |author=Dalle-Donne, Isabella |author2=Rossi, Ranieri |author3=Colombo, Graziano |author4=Giustarini, Daniela |author5=Milzani, Aldo |journal=Trends in Biochemical Sciences|year=2009|volume=34|issue=2|pages=85–96|doi=10.1016/j.tibs.2008.11.002|pmid=19135374}}</ref>
:RSH  +  GSH  + [O]  →  GSSR   +  H<sub>2</sub>O

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''-<small>D</small>-lactoylglutathione. [[Glyoxalase II]] (EC 3.1.2.6) catalyzes the hydrolysis of ''S''-<small>D</small>-lactoylglutathione to glutathione and [[lactic acid|<small>D</small>-lactic acid]].

It maintains exogenous antioxidants such as [[vitamin C|vitamins C]] and [[Vitamin E|E]] in their reduced (active) states.<ref>{{cite journal | vauthors = Dringen R | title = Metabolism and functions of glutathione in brain | journal = Progress in Neurobiology | volume = 62 | issue = 6 | pages = 649–671 | date = December 2000 | pmid = 10880854 | doi = 10.1016/s0301-0082(99)00060-x | s2cid = 452394 }}</ref><ref>{{cite journal | vauthors = Scholz RW, Graham KS, Gumpricht E, Reddy CC | year = 1989 | title = Mechanism of interaction of vitamin E and glutathione in the protection against membrane lipid peroxidation | journal = Annals of the New York Academy of Sciences | volume = 570 | issue = 1| pages = 514–7 | doi=10.1111/j.1749-6632.1989.tb14973.x| bibcode = 1989NYASA.570..514S | s2cid = 85414084 }}</ref><ref>{{cite journal | vauthors = Hughes RE | name-list-style = vanc | year = 1964 | title = Reduction of dehydroascorbic acid by animal tissues | journal = Nature | volume = 203 | issue = 4949| pages = 1068–9 | doi=10.1038/2031068a0 | pmid = 14223080 | bibcode = 1964Natur.203.1068H | s2cid = 4273230 }}</ref>

===Metabolism===
Among the many metabolic processes in which it participates, glutathione is required for the biosynthesis of [[leukotriene]]s and [[prostaglandin]]s. It plays a role in the storage of cysteine. Glutathione enhances the function of [[citrulline]] as part of the [[nitric oxide]] cycle.<ref>{{cite journal | vauthors = Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS | title = Phytochelatin synthase genes from Arabidopsis and the yeast ''Schizosaccharomyces pombe'' | journal = The Plant Cell | volume = 11 | issue = 6 | pages = 1153–64 | date = June 1999 | pmid = 10368185 | pmc = 144235 | doi = 10.1105/tpc.11.6.1153 | jstor = 3870806 }}</ref> It is a [[cofactor (biochemistry)|cofactor]] and acts on [[glutathione peroxidase]].<ref name="Grant_2001">{{cite journal | vauthors = Grant CM | title = Role of the glutathione/glutaredoxin and thioredoxin systems in yeast growth and response to stress conditions | journal = Molecular Microbiology | volume = 39 | issue = 3 | pages = 533–541 | year = 2001 | pmid = 11169096 | doi = 10.1046/j.1365-2958.2001.02283.x | s2cid = 6467802 | doi-access = free }}</ref> Glutathione is used to produce S-sulfanylglutathione, which is part of [[hydrogen sulfide]] metabolism.<ref>{{cite journal |last1=Melideo |first1=SL |last2=Jackson |first2=MR |last3=Jorns |first3=MS |title=Biosynthesis of a central intermediate in hydrogen sulfide metabolism by a novel human sulfurtransferase and its yeast ortholog. |journal=Biochemistry |date=22 July 2014 |volume=53 |issue=28 |pages=4739–53 |doi=10.1021/bi500650h |pmid=24981631|pmc=4108183 }}</ref>

===Conjugation===
Glutathione facilitates [[Xenobiotic metabolism#Phase II – conjugation|metabolism of xenobiotics]]. [[Glutathione S-transferase|Glutathione ''S''-transferase]] enzymes catalyze its conjugation to [[lipophilic]] xenobiotics, facilitating their excretion or further metabolism.<ref>{{cite journal|title=Glutathione transferases |author=Hayes, John D. |author2=Flanagan, Jack U. |author3=Jowsey, Ian R. |journal=Annual Review of Pharmacology and Toxicology|year=2005|volume=45|pages=51–88|doi=10.1146/annurev.pharmtox.45.120403.095857|pmid=15822171}}</ref> The conjugation process is illustrated by the metabolism of [[NAPQI|''N''-acetyl-''p''-benzoquinone imine]] (NAPQI). NAPQI is a reactive [[metabolite]] formed by the action of [[cytochrome P450 oxidase|cytochrome P450]] on [[paracetamol]] (acetaminophen). Glutathione conjugates to NAPQI, and the resulting ensemble is excreted. As a result of this reaction cellular glutathione concentration tends to be depleted in presence of acetaminophen.

===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]].<ref name=Noctor >{{cite journal | vauthors = Noctor G, Foyer CH | title = Ascorbate and Glutathione: Keeping Active Oxygen Under Control | journal = Annual Review of Plant Physiology and Plant Molecular Biology | volume = 49 | issue = 1 | pages = 249–279 | date = June 1998 | pmid = 15012235 | doi = 10.1146/annurev.arplant.49.1.249 }}</ref> It is the precursor of [[phytochelatins]], glutathione [[oligomer]]s that [[chelate]] heavy metals such as [[cadmium]].<ref>{{cite journal | vauthors = Ha SB, Smith AP, Howden R, Dietrich WM, Bugg S, O'Connell MJ, Goldsbrough PB, Cobbett CS | title = Phytochelatin synthase genes from Arabidopsis and the yeast Schizosaccharomyces pombe | journal = The Plant Cell | volume = 11 | issue = 6 | pages = 1153–64 | date = June 1999 | pmid = 10368185 | pmc = 144235 | doi = 10.1105/tpc.11.6.1153 }}</ref> Glutathione is required for efficient defence against plant pathogens such as ''[[Pseudomonas syringae]]'' and ''[[Phytophthora]] brassicae''.<ref name=Parisy >{{cite journal | vauthors = Parisy V, Poinssot B, Owsianowski L, Buchala A, Glazebrook J, Mauch F | title = Identification of PAD2 as a gamma-glutamylcysteine synthetase highlights the importance of glutathione in disease resistance of Arabidopsis | journal = The Plant Journal | volume = 49 | issue = 1 | pages = 159–172 | date = January 2007 | pmid = 17144898 | doi = 10.1111/j.1365-313X.2006.02938.x | url = http://doc.rero.ch/record/6306/files/mauch_ipg.pdf | doi-access = free }}</ref> [[Adenylyl-sulfate reductase]], an enzyme of the [[sulfur assimilation]] pathway, uses glutathione as an electron donor. Other enzymes using glutathione as a substrate are [[glutaredoxin]]s. These small [[oxidoreductases]] are involved in flower development, [[salicylic acid]], and plant defence signalling.<ref name=Rouhier >{{cite journal | vauthors = Rouhier N, Lemaire SD, Jacquot JP | title = The role of glutathione in photosynthetic organisms: emerging functions for glutaredoxins and glutathionylation | journal = Annual Review of Plant Biology | volume = 59 | issue = 1 | pages = 143–166 | year = 2008 | pmid = 18444899 | doi = 10.1146/annurev.arplant.59.032607.092811 | bibcode = 2008AnRPB..59..143R | url = https://hal.inrae.fr/hal-02660326/file/2008%20Rouhier%20Jacquot%20ARPB.pdf }}</ref>

==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.<ref>{{cite journal |vauthors=Gamcsik MP, Kasibhatla MS, Teeter SD, Colvin OM |title=Glutathione levels in human tumors |journal=Biomarkers |volume=17 |issue=8 |pages=671–91 |date=December 2012 |pmid=22900535 |pmc=3608468 |doi=10.3109/1354750X.2012.715672 }}</ref> Thus, [[drug delivery systems]] containing [[disulfide bond]]s, typically cross-linked micro-nanogels, stand out for their ability to degrade in the presence of high concentrations of glutathione (GSH).<ref>{{cite journal |vauthors=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 |title=Nano based drug delivery systems: recent developments and future prospects |journal=J Nanobiotechnology |volume=16 |issue=1 |pages=71 |date=September 2018 |pmid=30231877 |pmc=6145203 |doi=10.1186/s12951-018-0392-8 |doi-access=free}}</ref> 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.<ref>{{cite journal |vauthors=Li Y, Maciel D, Rodrigues J, Shi X, Tomás H |title=Biodegradable Polymer Nanogels for Drug/Nucleic Acid Delivery |journal=Chem Rev |volume=115 |issue=16 |pages=8564–8608 |date=August 2015 |pmid=26259712 |doi=10.1021/cr500131f }}</ref><ref>{{cite journal |vauthors=Adamo G, Grimaldi N, Campora S, Sabatino MA, Dispenza C, Ghersi G |title=Glutathione-Sensitive Nanogels for Drug Release |journal=Chemical Engineering Transactions |volume=38 |pages=457–462 |date=2014 |doi= |url=https://www.cetjournal.it/index.php/cet/article/view/5682}}</ref>

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.<ref>{{cite book |first=H.F. |last=Gilbert |chapter=Molecular and Cellular Aspects of Thiol–Disulfide Exchange |title=Advances in Enzymology and Related Areas of Molecular Biology |publisher= |volume=63 |date=1990 |isbn=978-0-470-12309-6 |pages=69–172 |doi=10.1002/9780470123096.ch2 |pmid=2407068}}</ref><ref>{{cite book |first=H.F. |last=Gilbert |chapter=Thiol/disulfide exchange equilibria and disulfide bond stability |title=Biothiols, Part A: Monothiols and Dithiols, Protein Thiols, and Thiyl Radicals |series=Methods in Enzymology |publisher= |volume=251 |date=1995 |isbn=978-0-12-182152-4 |pages=8–28 |doi=10.1016/0076-6879(95)51107-5 |pmid=7651233}}</ref>
:::::::::::''R−S−S−R′''+ 2''GSH'' → ''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.<ref>{{cite journal |vauthors=Elkassih SA, Kos P, Xiong H, Siegwart DJ |title=Degradable redox-responsive disulfide-based nanogel drug carriers via dithiol oxidation polymerization |journal=Biomater Sci |volume=7 |issue=2 |pages=607–617 |date=January 2019 |pmid=30462102 |pmc=7031860 |doi=10.1039/c8bm01120f }}</ref>

== Uses ==
===Winemaking===
The content of glutathione in [[must]], the first raw form of wine, determines the [[browning (biochemistry)|browning]], or caramelizing effect, during the production of [[white wine]] by trapping the [[caffeoyltartaric acid]] quinones generated by enzymic oxidation as [[grape reaction product]].<ref>{{cite journal | vauthors = Rigaud J, Cheynier V, Souquet JM, Moutounet M | name-list-style = vanc | year = 1991 | title = Influence of must composition on phenolic oxidation kinetics | journal = Journal of the Science of Food and Agriculture | volume = 57 | issue = 1| pages = 55–63 | doi = 10.1002/jsfa.2740570107 | title-link = must | bibcode = 1991JSFA...57...55R }}</ref> Its concentration in wine can be determined by UPLC-MRM mass spectrometry.<ref>{{cite journal | vauthors = Vallverdú-Queralt A, Verbaere A, Meudec E, Cheynier V, Sommerer N | title = Straightforward method to quantify GSH, GSSG, GRP, and hydroxycinnamic acids in wines by UPLC-MRM-MS | journal = Journal of Agricultural and Food Chemistry | volume = 63 | issue = 1 | pages = 142–9 | date = January 2015 | pmid = 25457918 | doi = 10.1021/jf504383g | bibcode = 2015JAFC...63..142V }}</ref>

== See also ==
* [[Reductive stress]]
* [[Glutathione synthetase deficiency]]
* [[Ophthalmic acid]]
* [[roGFP]], a tool to measure the cellular glutathione redox potential
* [[Glutathione-ascorbate cycle]]
* [[Bacterial glutathione transferase]]
* [[Thioredoxin]], a cysteine-containing small proteins with very similar functions as reducing agents
* [[Glutaredoxin]], an antioxidant protein that uses reduced glutathione as a cofactor and is reduced nonenzymatically by it
* [[Bacillithiol]]
* [[Mycothiol]]
* [[Gamma-L-Glutamyl-L-cysteine|γ-<small>L</small>-Glutamyl-<small>L</small>-cysteine]]

== References ==
{{reflist}}

{{Antioxidants}}
{{Antidotes}}
{{Enzyme cofactors}}
{{Amino acid metabolism intermediates}}
{{Glutamatergics}}
{{Authority control}}

[[Category:Thiols]]
[[Category:Tripeptides]]
[[Category:Antioxidants]]
[[Category:Skin whitening]]