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. 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.[5] [6] 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).[7] 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.[8] [9]

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.[10] [11] The administration of N-acetylcysteine (NAC), a cysteine prodrug, helps replenish intracellular GSH levels.[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]

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.[31] 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).[32] 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.[33] [34]

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.[35] [36]

R−S−S−R′+ 2GSH → R−SH + R′−SH + GSSGwhere 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.[37]

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

See also

Notes and References

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  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 .
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  6. Ru Cheng, Fang Feng, Fenghua Meng, Chao Deng, Jan Feijen, Zhiyuan Zhong,Glutathione-responsive nano-vehicles as a promising platform for targeted intracellular drug and gene delivery,Journal of Controlled Release,Volume 152, Issue 1,2011,Pages 2-12,ISSN 0168-3659,https://doi.org/10.1016/j.jconrel.2011.01.030.
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