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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/07/11 11:39:34」(JST)

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Glutathione (GSH) is a tripeptide with a gamma peptide linkage between the amine group of cysteine (which is attached by normal peptide linkage to a glycine) and the carboxyl group of the glutamate side-chain. It is an antioxidant, preventing damage to important cellular components caused by reactive oxygen species such as free radicals and peroxides.^[2]

Thiol groups are reducing agents, existing at a concentration of approximately 5 mM in animal cells. Glutathione reduces disulfide bonds formed within cytoplasmic proteins to cysteines by serving as an electron donor. In the process, glutathione is converted to its oxidized form, glutathione disulfide (GSSG), also called L-(–)-glutathione.

Once oxidized, glutathione can be reduced back by glutathione reductase, using NADPH as an electron donor.^[3] The ratio of reduced glutathione to oxidized glutathione within cells is often used as a measure of cellular toxicity.^[4]

Biosynthesis[edit]

Glutathione is not an essential nutrient (meaning it does not have to be obtained via food), since it can be synthesized in the body from the amino acids L-cysteine, L-glutamic acid, and glycine. The sulfhydryl (thiol) group (SH) of cysteine serves as a proton donor and is responsible for the biological activity of glutathione. Cysteine is the rate-limiting factor in cellular glutathione synthesis, since this amino acid is relatively rare in foodstuffs.

Cells make Glutathione in two adenosine triphosphate (ATP)-dependent steps:

First, gamma-glutamylcysteine is synthesized from L-glutamate and cysteine via the enzyme gamma-glutamylcysteine synthetase (glutamate cysteine ligase, GCL). This reaction is the rate-limiting step in glutathione synthesis.^[5]
Second, glycine is added to the C-terminal of gamma-glutamylcysteine via the enzyme glutathione synthetase.

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., lacking all de novo GSH synthesis) die before birth.^[6] Mice lacking GCLM demonstrate no outward phenotype, but exhibit marked decrease in GSH and increased sensitivity to toxic insults.^[7]^[8]^[9]

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.^[10]

The plant glutamate cysteine ligase (GCL) is a redox-sensitive homodimeric enzyme, conserved in the plant kingdom.^[11] In an oxidizing environment, intermolecular disulfide bridges are formed and the enzyme switches to the dimeric active state. The midpoint 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.^[12] GCL is exclusively located in plastids, and glutathione synthetase is dual-targeted to plastids and cytosol, thus are GSH and gamma-glutamylcysteine exported from the plastids.^[13] Both glutathione biosynthesis enzymes are essential in plants; knock-outs of GCL and GS are lethal to embryo and seedling.^[14]

The biosynthesis pathway for glutathione is found in some bacteria, like cyanobacteria and proteobacteria, but is missing in many other bacteria. Most eukaryotes synthesize glutathione, including humans, but some do not, such as Leguminosae, Entamoeba, and Giardia. The only archaea that make glutathione are halobacteria.^[15]^[16]

Function[edit]

Glutathione exists in both reduced (GSH) and oxidized (GSSG) states. In the reduced state, the thiol group of cysteine is able to donate a reducing equivalent (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 (GSSG). Such a reaction is probable 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 (GSR):^[17] NADPH reduces FAD present in GSR to produce a transient FADH-anion. This anion then quickly breaks a disulfide bond (Cys58 - Cys63) and leads to Cys63's nucleophilically attacking the nearest sulfide unit in the GSSG molecule (promoted by His467), which creates a mixed disulfide bond (GS-Cys58) and a GS-anion. His467 of GSR then protonates the GS-anion to form the first GSH. Next, Cys63 nucleophilically attacks the sulfide of Cys58, releasing a GS-anion, which, in turn, picks up a solvent proton and is released from the enzyme, thereby creating the second GSH. So, for every GSSG and NADPH, two reduced GSH molecules are gained, which can again act as antioxidants scavenging reactive oxygen species in the cell.

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.^[18]
Regulation of the nitric oxide cycle, which is critical for life but can be problematic if unregulated^[19]
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.^[20]
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.^[21]

Function in animals[edit]

GSH is known as a substrate in both conjugation reactions and reduction reactions, catalyzed by glutathione S-transferase enzymes in cytosol, microsomes, 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), the reactive cytochrome P450-reactive metabolite formed by paracetamol (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 proteins, 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 preparation called Mucomyst^[22]), which is processed by cells to L-cysteine and used in the de novo synthesis of GSH.

Glutathione (GSH) participates in leukotriene synthesis and is a cofactor for the enzyme glutathione peroxidase. It is also important as a hydrophilic molecule that is added to lipophilic toxins and waste in the liver during biotransformation before they can become part of the bile. Glutathione is also needed for the detoxification of methylglyoxal, a toxin produced as a by-product of metabolism.

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-lactoyl-glutathione. Glyoxalase II (EC 3.1.2.6) catalyzes the hydrolysis of S-D-lactoyl-glutathione to glutathione and D-lactic acid.

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 skin 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 one hour, 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."^[23]

Function in plants[edit]

In plants, glutathione is crucial for biotic and abiotic stress management. It is a pivotal component of the glutathione-ascorbate cycle, a system that reduces poisonous hydrogen peroxide.^[24] It is the precursor of phytochelatins, glutathione oligomers that chelate heavy metals such as cadmium.^[25] Glutathione is required for efficient defence against plant pathogens such as Pseudomonas syringae and Phytophthora brassicae.^[26] APS reductase, an enzyme of the sulfur assimilation pathway uses glutathione as electron donor. Other enzymes using glutathione as substrate are glutaredoxin, these small oxidoreductases are involved in flower development, salicylic acid and plant defence signalling.^[27]

Supplementation[edit]

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."^[28]^[29] However, it is possible to increase and maintain appropriate glutathione levels by increasing the daily consumption of cysteine-rich foods and/or supplements.^[30]

Calcitriol, 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.^[31]

In addition, plasma and liver GSH concentrations can be raised by administration of certain supplements that serve as GSH precursors.

A novel prodrug for glutathione has been developed by Dr Herbert Nagasawa, that combines the fragile glutathione precursor cysteine with the monosaccharide ribose (D-ribose-L-cysteine). ^[32] D-ribose-L-cysteine is able to pass through the digestion intact and create a significant and sustained boost in systemic glutathione production. Once inside the cell, the cysteine is converted into glutathione, whilst the ribose is utilised for cellular energy in the form of Adenosine triphosphate (ATP).

Other supplements, including S-adenosylmethionine (SAMe)^[33]^[34]^[35] and whey protein^[36]^[37]^[38]^[39]^[40]^[41] 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.^[42]^[43] Melatonin has been shown to stimulate a related enzyme, glutathione peroxidase,^[44] and silymarin, an extract of the seeds of the milk thistle plant (Silybum marianum), has also demonstrated an ability to replenish glutathione levels in lab rats.^[45]^[46]

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 precursors 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,^[47]^[48]^[49] 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.^[20]^[50]

Low glutathione is also strongly implicated in wasting and negative nitrogen balance,^[51] 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.^[52] 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.^[53] Diminished GSH levels elevate cellular vulnerability towards oxidative stress; characterized by accumulating reactive oxygen species. GSH depletion has also been implicated in cellular predisposition to apoptosis.^[54] Replenishment of glutathione using N-acetyl cysteine has been shown to reduce symptoms of both disorders.^[55]

Cancer[edit]

Preliminary results indicate glutathione changes the level of reactive oxygen species in isolated cells grown in a laboratory,^[56]^[57] which may reduce cancer development.^[58] ^[59] None of these tests were performed on 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.^[60]

Pathology[edit]

Excess glutamate at synapses, which may be released in conditions such as traumatic brain injury, can prevent the uptake of cysteine, a necessary building-block of glutathione. Without the protection from oxidative injury afforded by glutathione, cells may be damaged or killed.^[61]

Methods to determine glutathione[edit]

Reduced glutathione may be visualized using Ellman's reagent or bimane derivates such as monobromobimane. The monobromobimane method is more sensitive. In this procedure, cells are lysed and thiols extracted using a HCl buffer. The thiols are then reduced with dithiothreitol (DTT) and labelled by monobromobimane. Monobromobimane becomes fluorescent after binding to GSH. The thiols are then separated by HPLC and the fluorescence quantified with a fluorescence detector. Bimane may also be used to quantify glutathione in vivo. The quantification is done by confocal laser scanning microscopy after application of the dye to living cells.^[62] 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)^[63] or redox sensitive yellow fluorescent protein (rxYFP)^[64]

Importance in winemaking[edit]

The content of glutathione in must determines the browning effect during the production of white wine by trapping the caffeoyltartaric acid quinones generated by enzymic oxidation as grape reaction product (GRP).^[65]

References[edit]

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^ Maulucci, Giuseppe; Labate, Valentina; Mele, Marina; Panieri, Emiliano; Arcovito, Giuseppe; Galeotti, Tommaso; Østergaard, H; Winther, JR et al. (2008). "High-resolution imaging of redox signaling in live cells through an oxidation-sensitive yellow fluorescent protein". Science Signaling 1 (43): pl3. doi:10.1126/scisignal.143pl3. PMID 18957692. |displayauthors= suggested (help)
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Related research[edit]

Drevet, J (2006). "The antioxidant glutathione peroxidase family and spermatozoa: A complex story". Molecular and Cellular Endocrinology 250 (1–2): 70–9. doi:10.1016/j.mce.2005.12.027. PMID 16427183.
The Role of Glutathione in Cell Defense.
Wu, Guoyao; Fang, Yun-Zhong; Yang, Sheng; Lupton, Joanne R.; Turner, Nancy D. (2004). "Glutathione metabolism and its implications for health". The Journal of nutrition 134 (3): 489–92. PMID 14988435.

External links[edit]

Glutathione bound to proteins in the PDB

UpToDate Contents

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1. ヘキソースリン酸側路およびグルタチオン代謝関連疾患 related disorders of the hexose monophosphate shunt and glutathione metabolism
2. ハーブ剤および栄養補助食品による肝毒性 hepatotoxicity due to herbal medications and dietary supplements
3. 小児および思春期の患者におけるアセトアミノフェン（パラセタモール）中毒の臨床症状および診断 clinical manifestations and diagnosis of acetaminophen paracetamol poisoning in children and adolescents
4. カフェインおよびカフェイン含有飲料の利益とリスク benefits and risks of caffeine and caffeinated beverages
5. 成人におけるアセトアミノフェン（パラセタモール）中毒：病態生理、症状、および診断 acetaminophen paracetamol poisoning in adults pathophysiology presentation and diagnosis

English Journal

Effects of long-term consumption of standard diets including glucose-lysine model glycated compounds on the antioxidant status of adult rats.

Pastoriza S1, Rufián-Henares JÁ2, Delgado-Andrade C3.
Food chemistry.Food Chem.2015 Sep 15;183:283-90. doi: 10.1016/j.foodchem.2015.03.038. Epub 2015 Mar 17.
Our purpose was to evaluate the uptake of antioxidant capacity (AC) in rats fed long-term a diet containing commonly consumed Maillard reaction products (MRPs) from the glucose-lysine system. The effects on the oxidative status of liver, biceps brachii muscle and serum were also tested. The presence
PMID 25863637

Phytohormones enabled endophytic fungal symbiosis improve aluminum phytoextraction in tolerant Solanum lycopersicum: An examples of Penicillium janthinellum LK5 and comparison with exogenous GA3.

Khan AL1, Waqas M2, Hussain J3, Al-Harrasi A4, Hamayun M5, Lee IJ6.
Journal of hazardous materials.J Hazard Mater.2015 Sep 15;295:70-8. doi: 10.1016/j.jhazmat.2015.04.008. Epub 2015 Apr 4.
This work investigates the potentials of fungal-endophyte Penicillium janthinellum LK5 (PjLK5) and its inherent gibberellic acid (GA3) as reference to enhance aluminum (Al) induced toxicity in tolerant tomato (Solanum lycopersicum) plants. Initial screening showed significantly higher uptake of Al b
PMID 25885165

Antioxidant capacity automatic assay based on inline photogenerated radical species from l-glutathione-capped CdTe quantum dots.

Rodrigues DM1, Ribeiro DS1, Frigerio C1, Rodrigues SS1, Santos JL1, Prior JA2.
Talanta.Talanta.2015 Aug 15;141:220-9. doi: 10.1016/j.talanta.2015.04.013. Epub 2015 Apr 11.
This work aimed at the development of a methodology implemented in an automatic flow system for determination of the antioxidant capacity in food samples, based on the luminol oxidation by inline photogenerated radical species from cadmium telluride nanoparticles capped with l-glutathione. Radical s
PMID 25966406

Japanese Journal

Diagnostic application of recombinant equine merozoite surface antigen-1 in elisa for detection of Theileria equi specific antibodies

Kumar Sandeep,Rakha Naresh K.,Goyal Liza,Goel Parveen,Kumar Rajender,Kumar Ashok,Kumar Sanjay
Japanese Journal of Veterinary Research 63(3), 129-137, 2015-08
… The 547 bp EMA-1 gene fragment encoding high hydrophilic antigenic region was expressed with glutathione-S-transferase tag in prokaryotic system and purified protein (43 kDa) was used for development of ELISA (EMA-1t/ELISA). …
NAID 120005656350

Effects of Long-term Feeding of Graded Levels of T-2 Toxin-contaminated Diets on Performance, Some Lipid Peroxide and Glutathione Redox Status Parameters of Broiler Chickens

Balogh Krisztian,Bocsai Andrea,Pelyhe Csilla [他]
Journal of poultry science 52(3), 176-182, 2015-07
NAID 40020533438

グルタチオン代謝とチオールケミストリー : 病態との関係,創薬標的としての価値

渡辺文太,平竹潤
化学と生物 : 日本農芸化学会会誌 : 生命・食・環境 53(6), 354-361, 2015-06
NAID 40020489648

Related Pictures

★リンクテーブル★

リンク元	「グルタチオン」「GSH」
拡張検索	「glutathione transferase」「glutathione S-transferase pi」「lactoylglutathione lyase」「homoglutathione」

「グルタチオン」

Glutathione
	IUPAC name (2S)-2-amino-4-{[(1R)-1-[(carboxymethyl)carbamoyl]-2-sulfanylethyl]carbamoyl}butanoic acid
	Other names γ-L-Glutamyl-L-cysteinylglycine; (2S)-2-Amino-5-[[(2R)-1-(carboxymethylamino)-1-oxo- 3-sulfanylpropan-2-yl]amino]-5-oxopentanoic acid
Identifiers
Abbreviations	GSH
CAS number	70-18-8
PubChem	124886
ChemSpider	111188
UNII	GAN16C9B8O
DrugBank	DB00143
KEGG	C00051
MeSH	Glutathione
ChEBI	CHEBI:60836
ChEMBL	CHEMBL1543
ATC code	V03AB32
Jmol-3D images	Image 1
	SMILES C(CC(=O)N[C@@H](CS)C(=O)NCC(=O)O)[C@@H](C(=O)O)N ;
	InChI 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 ; Key: RWSXRVCMGQZWBV-WDSKDSINSA-N InChI=1/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; Key: RWSXRVCMGQZWBV-WDSKDSINBK ;
Properties
Molecular formula	C10H17N3O6S
Molar mass	307.32 g mol−1
Melting point	195 °C, 468 K, 383 °F
Solubility in water	Freely soluble
Solubility in methanol, diethyl ether	Insoluble
	(verify) (what is: /?); Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa)
	Infobox references

　　[★]

英: glutathione, GSH
同: γ-グルタミルシステイニルグリシン γ-glutamylcysteinylglycine、5-L-グルタミルL-システイニルグリシン
商: オペガードネオキット、タチオン、ビーエスエスプラス、ランデールチオン

概念

細菌からヒトに至るまで広く存在するチオール含有ペプチドである。
グルタチオンは細胞内の主要な抗酸化成分であり、また、毒物などを細胞外に排出することで、細胞を内的・外的な環境の変化から守る役割を果たしている。
グルタチオンは、細胞内に 0.5-10 mMという比較的高濃度で存在する。一方細胞外の濃度はその1/100から1/1000程度である。グルタチオンには還元型 (GSH) と酸化型 (glutathione disulfide, GSSG)が存在する。酸化型は、二分子の還元型グルタチオンがジスルフィド結合によってつながった分子である。細胞内のグルタチオンは、通常、ほとんど（98%以上）が還元型であり、この状態はグルタチオン還元酵素によって維持されている。

構造

グルタチオンは'グルタミン酸、システイン、グリシンが、この順番でペプチド結合したトリペプチドである (L-γ-glutamyl-L-cysteinyl-glycine)。ただし、グルタミン酸とシステインの結合は通常のペプチド結合とは異なり、グルタミン酸側鎖のγ-カルボキシ基とシステイン主鎖のα-アミノ基からなる（γ-グルタミル結合）。このためグルタチオンは、ペプチドでありながら、ほとんどのプロテアーゼに対して耐性であり、分解されない。グルタチオンを直接分解できる酵素はγ-グルタミルトランスペプチターゼや、その近縁のごく限られた酵素のみである。

http://ja.wikipedia.org/wiki/%E3%82%B0%E3%83%AB%E3%82%BF%E3%83%81%E3%82%AA%E3%83%B3)

参考

タチオン注射用100mg／*タチオン注射用200mg

http://www.info.pmda.go.jp/go/pack/3922400D1060_1_01/3922400D1060_1_01?view=body

「GSH」

　　[★]

「glutathione transferase」

　　[★]

グルタチオン転移酵素、グルタチオントランスフェラーゼ

関: glutathione S-transferase

「glutathione S-transferase pi」

　　[★]

グルタチオンS-転移酵素π、グルタチオンS-トランスフェラーゼπ

「lactoylglutathione lyase」

　　[★]

乳酸グルタチオンリアーゼ

関: glyoxalase I

「homoglutathione」

　　[★]

ホモグルタチオン

関: hGSH

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glutathione