Glutathione

Glutathione

Overview
Glutathione is a tripeptide
Tripeptide
A tripeptide is a peptide consisting of three amino acids joined by peptide bonds.Examples of tripeptides are:*Eisenin is a peptide with immunological activity that is isolated from the Japanese marine alga, Eisenia bicyclis, which more commonly is known as, Arame*GHK-Cu is a human copper binding...

 that contains an unusual peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 linkage between the amine group
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 (which is attached by normal peptide linkage to a glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

) and the carboxyl group of the glutamate side-chain. It is an antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

, preventing damage to important cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 components caused by reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 such as free radicals and peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

s.

Thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

 groups are reducing agents
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

, existing at a concentration of approximately 5 mM in animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...

 cells.
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Unanswered Questions
Encyclopedia
Glutathione is a tripeptide
Tripeptide
A tripeptide is a peptide consisting of three amino acids joined by peptide bonds.Examples of tripeptides are:*Eisenin is a peptide with immunological activity that is isolated from the Japanese marine alga, Eisenia bicyclis, which more commonly is known as, Arame*GHK-Cu is a human copper binding...

 that contains an unusual peptide
Peptide
Peptides are short polymers of amino acid monomers linked by peptide bonds. They are distinguished from proteins on the basis of size, typically containing less than 50 monomer units. The shortest peptides are dipeptides, consisting of two amino acids joined by a single peptide bond...

 linkage between the amine group
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...

 of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

 (which is attached by normal peptide linkage to a glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

) and the carboxyl group of the glutamate side-chain. It is an antioxidant
Antioxidant
An antioxidant is a molecule capable of inhibiting the oxidation of other molecules. Oxidation is a chemical reaction that transfers electrons or hydrogen from a substance to an oxidizing agent. Oxidation reactions can produce free radicals. In turn, these radicals can start chain reactions. When...

, preventing damage to important cellular
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....

 components caused by reactive oxygen species
Reactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....

 such as free radicals and peroxide
Peroxide
A peroxide is a compound containing an oxygen–oxygen single bond or the peroxide anion .The O−O group is called the peroxide group or peroxo group. In contrast to oxide ions, the oxygen atoms in the peroxide ion have an oxidation state of −1.The simplest stable peroxide is hydrogen peroxide...

s.

Thiol
Thiol
In organic chemistry, a thiol is an organosulfur compound that contains a carbon-bonded sulfhydryl group...

 groups are reducing agents
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

, existing at a concentration of approximately 5 mM in animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...

 cells. Glutathione reduces disulfide bond
Disulfide bond
In chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...

s formed within cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

ic protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s to cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

s by serving as an electron
Electron
The electron is a subatomic particle with a negative elementary electric charge. It has no known components or substructure; in other words, it is generally thought to be an elementary particle. An electron has a mass that is approximately 1/1836 that of the proton...

 donor. In the process, glutathione is converted to its oxidized form glutathione disulfide
Glutathione disulfide
Glutathione disulfide is a disulfide derived from two glutathione molecules.In living cells, glutathione disulfide is reduced into two molecules of glutathione with reducing equivalents from the coenzyme NADPH. This reaction is catalyzed by the enzyme glutathione reductase...

 (GSSG), also called L(-)-Glutathione.

Once oxidized, glutathione can be reduced back by glutathione reductase, using NADPH as an electron donor. The ratio of reduced glutathione to oxidized glutathione within cells is often used as a measure of cellular toxicity.

Biosynthesis


Glutathione is not an essential nutrient
Essential nutrient
An essential nutrient is a nutrient required for normal body functioning that either cannot be synthesized by the body at all, or cannot be synthesized in amounts adequate for good health , and thus must be obtained from a dietary source...

 (meaning it does not have to be obtained via food), since it can be synthesized in the body from the amino acids L-cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

, L-glutamic acid
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...

, and glycine
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...

. The sulfhydryl (thiol) group (SH) of cysteine serves as a proton donor and is responsible for the biological activity of glutathione. Provision of this amino acid is the rate-limiting factor in glutathione synthesis by the cells, since cysteine is relatively rare in foodstuffs. Furthermore, if released as the free amino acid, cysteine is toxic and spontaneously catabolized in the gastrointestinal tract and blood plasma.

Glutathione is synthesized in two adenosine triphosphate
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

-dependent steps:
  • First, gamma-glutamylcysteine is synthesized from L-glutamate and cysteine via the enzyme gamma-glutamylcysteine synthetase
    Gamma-glutamylcysteine synthetase
    Gamma-glutamylcysteine synthetase is the first enzyme in the glutathione biosynthesis pathway.-Function:...

     (a.k.a. glutamate cysteine ligase, GCL). This reaction is the rate-limiting step in glutathione synthesis.
  • Second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase
    Glutathione synthetase
    Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione.In eukaryotes, this is a homodimeric enzyme...

    .


Animal glutamate cysteine ligase (GCL) is a heterodimeric enzyme composed of a catalytic (GCLC) and modulatory (GCLM) subunit. GCLC constitutes all the enzymatic activity, whereas GCLM increases the catalytic efficiency of GCLC. Mice lacking GCLC (i.e., all de novo GSH synthesis) die before birth. Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.

While all cells in the human body are capable of synthesizing glutathione, liver glutathione synthesis has been shown to be essential. Mice with genetically-induced loss of GCLC (i.e., GSH synthesis) only in the liver die within 1 month of birth.

The plant glutamate cysteine ligase (GCL) is a redox-sensitive homodimeric enzyme, conserved in the plant kingdom. In an oxidizing environment, intermolecular disulfide bridges are formed and the enzyme switches to the dimeric active state. The mid-point potential of the critical cysteine pair is -318 mV. In addition to the redox-dependent control is the plant GCL enzyme feedback inhibited by GSH. GCL is exclusively located in plastids, and glutathione synthetase
Glutathione synthetase
Glutathione synthetase is the second enzyme in the glutathione biosynthesis pathway. It catalyses the condensation of gamma-glutamylcysteine and glycine, to form glutathione.In eukaryotes, this is a homodimeric enzyme...

 is dual-targeted to plastids and cytosol, thus are GSH and gamma-glutamylcysteine
Gamma-Glutamylcysteine
γ-Glutamylcysteine is a precursor of glutathione. It is formed by gamma-glutamylcysteine synthetase and used by glutathione synthetase to form glutathione....

 exported from the plastids. Both glutathione biosynthesis enzymes are essential in plants; knock-outs of GCL and GS are lethal to embryo and seedling.

The biosynthesis pathway for glutathione is found in some bacteria, like cyanobacteria and proteobacteria
Proteobacteria
The Proteobacteria are a major group of bacteria. They include a wide variety of pathogens, such as Escherichia, Salmonella, Vibrio, Helicobacter, and many other notable genera....

, but is missing in many other bacteria. Most eukaryotes synthesize glutathione, including humans, but some do not, such as Leguminosae, Entamoeba
Entamoeba
Entamoeba is a genus of Amoebozoa found as internal parasites or commensals of animals.In 1875, Fedor Lösch described the first proven case of amoebic dysentery in St Petersburg, Russia. He referred to the amoeba he observed microscopically as 'Amoeba coli'; however it is not clear whether he was...

, and Giardia
Giardia
Giardia is a genus of anaerobic flagellated protozoan parasites of the phylum Metamonada in the supergroup "Excavata" that colonise and reproduce in the small intestines of several vertebrates, causing giardiasis, commonly known as Beaver fever...

. The only archaea that make glutathione are halobacteria
Halobacteria
In taxonomy, the Halobacteria are a class of the Euryarchaeota, found in water saturated or nearly saturated with salt. They are also called halophiles, though this name is also used for other organisms which live in somewhat less concentrated salt water...

.

Function


Glutathione exists in reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent
Reducing equivalent
In biochemistry, the term reducing equivalent refers to any of a number of chemical species which transfer the equivalent of one electron in redox reactions...

 (H++ e-) to other unstable molecules, such as reactive oxygen species. In donating an electron, glutathione itself becomes reactive, but readily reacts with another reactive glutathione to form glutathione disulfide
Glutathione disulfide
Glutathione disulfide is a disulfide derived from two glutathione molecules.In living cells, glutathione disulfide is reduced into two molecules of glutathione with reducing equivalents from the coenzyme NADPH. This reaction is catalyzed by the enzyme glutathione reductase...

 (GSSG). Such a reaction is possible due to the relatively high concentration of glutathione in cells (up to 5 mM in the liver). GSH can be regenerated from GSSG by the enzyme glutathione reductase
Glutathione reductase
Glutathione reductase, also known as GSR or GR, is an enzyme that reduces glutathione disulfide to the sulfhydryl form GSH, which is an important cellular antioxidant....

.

In healthy cells and tissue, more than 90% of the total glutathione pool is in the reduced form (GSH) and less than 10% exists in the disulfide form (GSSG). An increased GSSG-to-GSH ratio is considered indicative of oxidative stress.

Glutathione has multiple functions:
  • It is the major endogenous antioxidant produced by the cells, participating directly in the neutralization of free radicals and reactive oxygen compounds, as well as maintaining exogenous antioxidants such as vitamins C and E in their reduced (active) forms.
  • Regulation of the nitric oxide
    Nitric oxide
    Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...

     cycle, which is critical for life but can be problematic if unregulated
  • It is used in metabolic and biochemical reactions such as DNA synthesis and repair, protein synthesis, prostaglandin synthesis, amino acid transport, and enzyme activation. Thus, every system in the body can be affected by the state of the glutathione system, especially the immune system, the nervous system, the gastrointestinal system and the lungs.
  • It has a vital function in iron metabolism. Yeast cells depleted of or containing toxic levels of GSH show an intense iron starvation-like response and impairment of the activity of extra-mitochondrial ISC enzymes, followed by death.


Function in animals


GSH is known as a substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...

 in both conjugation reactions and reduction
Redox
Redox reactions describe all chemical reactions in which atoms have their oxidation state changed....

 reactions, catalyzed by glutathione S-transferase
Glutathione S-transferase
Enzymes of the glutathione S-transferase family are composed of many cytosolic, mitochondrial, and microsomal proteins. GSTs are present in eukaryotes and in prokaryotes, where they catalyze a variety of reactions and accept endogenous and xenobiotic substrates.GSTs can constitute up to 10% of...

 enzymes in cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....

, microsome
Microsome
In cell biology, microsomes are vesicle-like artifacts re-formed from pieces of the endoplasmic reticulum when eukaryotic cells are broken-up in the laboratory; by definition, microsomes are not ordinarily present in living cells....

s, and mitochondria. However, it is also capable of participating in non-enzymatic conjugation with some chemicals.

In the case of N-acetyl-p-benzoquinone imine
NAPQI
NAPQI is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol...

 (NAPQI), the reactive cytochrome P450
Cytochrome P450 oxidase
The cytochrome P450 superfamily is a large and diverse group of enzymes. The function of most CYP enzymes is to catalyze the oxidation of organic substances. The substrates of CYP enzymes include metabolic intermediates such as lipids and steroidal hormones, as well as xenobiotic substances...

-reactive metabolite
Metabolite
Metabolites are the intermediates and products of metabolism. The term metabolite is usually restricted to small molecules. A primary metabolite is directly involved in normal growth, development, and reproduction. Alcohol is an example of a primary metabolite produced in large-scale by industrial...

 formed by paracetamol
Paracetamol
Paracetamol INN , or acetaminophen USAN , is a widely used over-the-counter analgesic and antipyretic . It is commonly used for the relief of headaches and other minor aches and pains and is a major ingredient in numerous cold and flu remedies...

 (or acetaminophen as it is known in the US), which becomes toxic when GSH is depleted by an overdose of acetaminophen, glutathione is an essential antidote to overdose. Glutathione conjugates to NAPQI and helps to detoxify it. In this capacity, it protects cellular protein thiol groups, which would otherwise become covalently modified; when all GSH has been spent, NAPQI begins to react with the cellular protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s, killing the cells in the process. The preferred treatment for an overdose of this painkiller is the administration (usually in atomized form) of N-acetyl-L-cysteine (often as a trademarked preparation called Mucomyst® http://www.rxmed.com/b.main/b2.pharmaceutical/b2.1.monographs/CPS-%20Monographs/CPS-%20%28General%20Monographs-%20M%29/MUCOMYST.html), which is processed by cells to L-cysteine and used in the de novo synthesis of GSH.

Glutathione (GSH) participates in leukotriene
Leukotriene
Leukotrienes are fatty signaling molecules. They were first found in leukocytes . One of their roles is to trigger contractions in the smooth muscles lining the trachea; their overproduction is a major cause of inflammation in asthma and allergic rhinitis...

 synthesis and is a cofactor
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....

 for the enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...

 glutathione peroxidase
Glutathione peroxidase
Glutathione peroxidase is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage...

. It is also important as a hydrophilic molecule that is added to lipophilic
Lipophilic
Lipophilicity, , refers to the ability of a chemical compound to dissolve in fats, oils, lipids, and non-polar solvents such as hexane or toluene. These non-polar solvents are themselves lipophilic — the axiom that like dissolves like generally holds true...

 toxins and waste in the liver during biotransformation
Biotransformation
Biotransformation is the chemical modification made by an organism on a chemical compound. If this modification ends in mineral compounds like CO2, NH4+, or H2O, the biotransformation is called mineralisation....

 before they can become part of the bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...

. Glutathione is also needed for the detoxification of methylglyoxal
Methylglyoxal
Methylglyoxal, also called pyruvaldehyde or 2-oxopropanal is the aldehyde form of pyruvic acid. It has two carbonyl groups, so it is a dicarbonyl compound. Methylglyoxal is both an aldehyde and a ketone....

, a toxin produced as a by-product of metabolism.

This detoxification reaction is carried out by the glyoxalase system
Glyoxalase system
The glyoxalase system is a set of enzymes that carry out the detoxification of methylglyoxal and the other reactive aldehydes that are produced as a normal part of metabolism...

. Glyoxalase I (EC 4.4.1.5) catalyzes the conversion of methylglyoxal and reduced glutathione to S-D-lactoyl-glutathione. Glyoxalase II (EC 3.1.2.6) catalyzes the hydrolysis of S-D-lactoyl-glutathione to glutathione and D-lactic acid
Lactic acid
Lactic acid, also known as milk acid, is a chemical compound that plays a role in various biochemical processes and was first isolated in 1780 by the Swedish chemist Carl Wilhelm Scheele. Lactic acid is a carboxylic acid with the chemical formula C3H6O3...

.

Glutathione has recently been used as an inhibitor of melanin in the cosmetics industry. In countries like Japan and the Philippines, this product is sold as a whitening soap. Glutathione competitively inhibits melanin synthesis in the reaction of tyrosinase and L-DOPA by interrupting L-DOPA's ability to bind to tyrosinase during melanin synthesis. The inhibition of melanin synthesis was reversed by increasing the concentration of L-DOPA, but not by increasing tyrosinase. Although the synthesized melanin was aggregated within 1 h, the aggregation was inhibited by the addition of glutathione. These results indicate that glutathione inhibits the synthesis and agglutination of melanin by interrupting the function of L-DOPA."

Function in plants


In plants, glutathione is crucial for biotic and abiotic stress management. It is a pivotal component of the glutathione-ascorbate cycle
Glutathione-ascorbate cycle
The glutathione-ascorbate cycle is a metabolic pathway that detoxifies hydrogen peroxide , which is a reactive oxygen species that is produced as a waste product in metabolism...

, a system that reduces poisonous hydrogen peroxide
Hydrogen peroxide
Hydrogen peroxide is the simplest peroxide and an oxidizer. Hydrogen peroxide is a clear liquid, slightly more viscous than water. In dilute solution, it appears colorless. With its oxidizing properties, hydrogen peroxide is often used as a bleach or cleaning agent...

. It is the precursor of phytochelatins, glutathione oligomeres that chelate heavy metals such as cadmium
Cadmium
Cadmium is a chemical element with the symbol Cd and atomic number 48. This soft, bluish-white metal is chemically similar to the two other stable metals in group 12, zinc and mercury. Similar to zinc, it prefers oxidation state +2 in most of its compounds and similar to mercury it shows a low...

. Glutathione is required for efficient defence against plant pathogens such as Pseudomonas syringae
Pseudomonas syringae
Pseudomonas syringae is a rod shaped, Gram-negative bacterium with polar flagella. It is a plant pathogen which can infect a wide range of plant species, and exists as over 50 different pathovars, all of which are available to legitimate researches via international culture collections such as the...

and Phytophthora
Phytophthora
Phytophthora is a genus of plant-damaging Oomycetes , whose member species are capable of causing enormous economic losses on crops worldwide, as well as environmental damage in natural ecosystems. The genus was first described by Heinrich Anton de Bary in 1875...

 brassicae
. APS reductase, an enzyme of the sulfur assimilation
Sulfur assimilation
Sulfur is an essential element for growth and physiological functioning of plants. However, its content strongly varies between plant species and it ranges from 0.1 to 6 % of the plants' dry weight. Sulfates taken up by the roots are the major sulfur source for growth, though it has to be reduced...

 pathway uses glutathione as electron donor. Other enzymes using glutathione as substrate are glutaredoxin
Glutaredoxin
Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no...

, these small oxidoreductases are involved in flower development, salicylic acid
Salicylic acid
Salicylic acid is a monohydroxybenzoic acid, a type of phenolic acid and a beta hydroxy acid. This colorless crystalline organic acid is widely used in organic synthesis and functions as a plant hormone. It is derived from the metabolism of salicin...

 and plant defence signalling.

Supplementation


Raising GSH levels through direct supplementation of glutathione is difficult. Research suggests that glutathione taken orally is not well absorbed across the gastrointestinal tract. In a study of acute oral administration of a very large dose (3 grams) of oral glutathione, Witschi and coworkers found "it is not possible to increase circulating glutathione to a clinically beneficial extent by the oral administration of a single dose of 3 g of glutathione."

Calcitriol
Calcitriol
Calcitriol , also called 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3, is the hormonally active form of vitamin D with three hydroxyl groups...

, the active metabolite of vitamin D synthesized in the kidney, increases glutathione levels in the brain and appears to be a catalyst for glutathione production.

In addition, plasma and liver GSH concentrations can be raised by administration of certain supplements that serve as GSH precursors. N-acetylcysteine, commonly referred to as NAC, is the most bioavailable precursor of glutathione. Other supplements, including S-adenosylmethionine
S-Adenosyl methionine
S-Adenosyl methionine is a common cosubstrate involved in methyl group transfers. SAM was first discovered in Italy by G. L. Cantoni in 1952. It is made from adenosine triphosphate and methionine by methionine adenosyltransferase . Transmethylation, transsulfuration, and aminopropylation are the...

 (SAMe) and whey protein
Whey protein
Whey protein is a mixture of globular proteins isolated from whey, the liquid material created as a by-product of cheese production. Some preclinical studies in rodents have suggested that whey protein may possess anti-inflammatory or anti-cancer properties; however, human data is lacking...

 have also been shown to increase glutathione content within the cell.

NAC is available both as a drug and as a generic supplement. Alpha lipoic acid has also been shown to restore intracellular glutathione. Melatonin has been shown to stimulate a related enzyme, glutathione peroxidase, and silymarin, an extract of the seeds of the milk thistle
Milk thistle
The milk thistle is a thistle of the genus Silybum Adans., a flowering plant of the daisy family . They are native to the Mediterranean regions of Europe, North Africa and the Middle East...

 plant (Silybum marianum), has also demonstrated an ability to replenish glutathione levels.

Glutathione is a tightly regulated intracellular constituent, and is limited in its production by negative feedback inhibition of its own synthesis through the enzyme gamma-glutamylcysteine synthetase, thus greatly minimizing any possibility of overdosage. Glutathione augmentation using presursors of glutathione synthesis or intravenous glutathione is a strategy developed to address states of glutathione deficiency, high oxidative stress, immune deficiency, and xenobiotic overload in which glutathione plays a part in the detoxification of the xenobiotic in question (especially through the hepatic route). Glutathione deficiency states include, but are not limited to, HIV/AIDS, chemical and infectious hepatitis, myalgic encephalomyelitis chronic fatigue syndrome ME / CFS, prostate and other cancers, cataracts, Alzheimer's disease, Parkinson's disease, chronic obstructive pulmonary disease, asthma, radiation poisoning, malnutritive states, arduous physical stress, and aging, and has been associated with suboptimal immune response. Many clinical pathologies are associated with oxidative stress and are elaborated upon in numerous medical references.,

Low glutathione is also strongly implicated in wasting and negative nitrogen balance, as seen in cancer, AIDS, sepsis, trauma, burns and even athletic overtraining. Glutathione supplementation can oppose this process, and in AIDS, for example, result in improved survival rates. However, studies in many of these conditions have not been able to differentiate between low glutathione as a result of acutely (as in septic patients) or chronically (as in HIV) increased oxidative stress, and increased pathology as a result of preexisting deficiencies.

Schizophrenia and bipolar disorder are associated with lowered glutathione. Accruing data suggest that oxidative stress may be a factor underlying the pathophysiology of bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). Glutathione (GSH) is the major free radical scavenger in the brain. Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. Replenishment of glutathione using N-acetyl cysteine has been shown to reduce symptoms of both disorders.

Cancer


Preliminary results indicate glutathione changes the level of reactive oxygen species in isolated cells grown in a laboratory, which may reduce cancer development.
None of these tests were performed in humans.

However, once a cancer has already developed, by conferring resistance to a number of chemotherapeutic drugs, elevated levels of glutathione in tumour cells are able to protect cancerous cells in bone marrow, breast, colon, larynx, and lung cancers.

Pathology


Excess glutamate at synapse
Synapse
In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another cell...

s, which may be released in conditions such as traumatic brain injury
Traumatic brain injury
Traumatic brain injury , also known as intracranial injury, occurs when an external force traumatically injures the brain. TBI can be classified based on severity, mechanism , or other features...

, can prevent the uptake of cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...

, a necessary building-block of glutathione. Without the protection from oxidative injury afforded by glutathione, cells may be damaged or killed.

Methods to determine glutathione


Reduced glutathione may be visualized using Ellman's reagent
Ellman's reagent
Ellman's reagent is a chemical used to quantify the number or concentration of thiol groups in a sample.-Preparation:...

 or bimane
Bimane
Bimane is a heterocyclic chemical compound. Bimane forms the core of a class of fluorescent dyes known as bimane dyes....

 derivates such as monobromobimane
Bromobimane
Bromobimane is a heterocyclic compound and bimane dye that is used as a reagent in biochemistry. It alkylates thiol groups, replacing the H with a fluorescent tag . Its alkylating properties are comparable to iodoacetamide....

. The monobromobimane method is more sensitive. In this procedure, cells are lysed and thiols extracted using a HCl
HCL
HCL or HCl can stand for:* Hairy cell leukemia, an uncommon and slowly progressing B cell leukemia* Hardware compatibility list...

 buffer
Buffer solution
A buffer solution is an aqueous solution consisting of a mixture of a weak acid and its conjugate base or a weak base and its conjugate acid. It has the property that the pH of the solution changes very little when a small amount of strong acid or base is added to it. Buffer solutions are used as a...

. The thiols are then reduced with dithiothreitol
Dithiothreitol
Dithiothreitol is the common name for a small-molecule redox reagent known as Cleland's reagent. DTT's formula is C4H10O2S2 and the molecular structure of its reduced form is shown at the right; its oxidized form is a disulfide-bonded 6-membered ring . Its name derives from the four-carbon...

 (DTT) and labelled by monobromobimane. Monobromobimane becomes fluorescent after binding to GSH. The thiols are then separated by HPLC
High-performance liquid chromatography
High-performance liquid chromatography , HPLC, is a chromatographic technique that can separate a mixture of compounds and is used in biochemistry and analytical chemistry to identify, quantify and purify the individual components of the mixture.HPLC typically utilizes different types of stationary...

 and the fluorescence quantified with a fluorescence detector. Bimane may also be used to quantify glutathione in vivo
In vivo
In vivo is experimentation using a whole, living organism as opposed to a partial or dead organism, or an in vitro controlled environment. Animal testing and clinical trials are two forms of in vivo research...

. The quantification is done by confocal laser scanning microscopy
Confocal laser scanning microscopy
Confocal laser scanning microscopy is a technique for obtaining high-resolution optical images with depth selectivity. The key feature of confocal microscopy is its ability to acquire in-focus images from selected depths, a process known as optical sectioning...

 after application of the dye to living cells. Another approach, which allows to measure the glutathione redox potential at a high spatial and temporal resolution in living cells is based on redox imaging using the redox-sensitive green fluorescent protein (roGFP) or redox sensitive yellow fluorescent protein (rxYFP)

See also

  • Glutathione synthetase deficiency
    Glutathione synthetase deficiency
    Glutathione synthetase deficiency is a rare autosomal recessive metabolic disorder that prevents the production of glutathione. Glutathione helps prevent damage to cells by neutralizing harmful molecules generated during energy production...

  • Ophthalmic acid
    Ophthalmic acid
    Ophthalmic acid, also known as ophthalmate , is a tripeptide analogue of glutathione in which the cysteine group is replaced by L-2-aminobutyrate...

  • roGFP
    RoGFP
    The reduction-oxidation sensitive green fluorescent protein is a redox sensitive biosensor. Two cysteines were introduced into the beta barrel structure of the GFP, the oxidation state of the engineered thiols determines the fluorescence properties of the sensor...

    , a tool to measure the cellular glutathione redox potential
  • Glutathione-ascorbate cycle
    Glutathione-ascorbate cycle
    The glutathione-ascorbate cycle is a metabolic pathway that detoxifies hydrogen peroxide , which is a reactive oxygen species that is produced as a waste product in metabolism...

  • Bacterial glutathione transferase
    Bacterial glutathione transferase
    Bacterial glutathione transferases are part of a superfamily of enzymes that play a crucial role in cellular detoxification...

  • Thioredoxin
    Thioredoxin
    Thioredoxin is a class of small redox proteins known to be present in all organisms. It plays a role in many important biological processes. In humans, it is encoded by the TXN gene. Loss-of-function mutation of either of the two human thioredoxin genes is lethal at the four-cell stage of the...

     Cysteine-containing small proteins with very similar functions as reducing agents
  • Glutaredoxin
    Glutaredoxin
    Glutaredoxins are small redox enzymes of approximately one hundred amino-acid residues that use glutathione as a cofactor. Glutaredoxins are oxidized by substrates, and reduced non-enzymatically by glutathione. In contrast to thioredoxins, which are reduced by thioredoxin reductase, no...

    Antioxidant protein that uses reduced glutathione as a cofactor and is reduced nonenzymatically by it

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