This view shows enzymes only for those organisms listed below, in the list of taxa known to possess the pathway. If an enzyme name is shown in bold, there is experimental evidence for this enzymatic activity.
Synonyms: glutathione metabolism
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Reductants Biosynthesis|
Thiols play several major roles in the cell; they help maintain the redox balance, keeping a reduced environment (see the pathway glutathione-glutaredoxin redox reactions), they fight reactive oxygen and nitrogen species, and they are involved in the detoxification of many other toxins and stress-inducing factors.
In most organisms the major thiol is the tripeptide glutathione (γ-Glu-Cys-Gly, known as GSH). The intracellular concentration of GSH ranges from 0.5-10 mM. Most of the non-protein cysteine is stored in the form of GSH, since free L-cysteine auto-oxidizes rapidly to L-cystine, producing potentially toxic oxygen radicals [Ritz01].
In the process of reducing other molecules (such as peroxides) two molecules of GSH are condensed into a single molecule of the oxidized form glutathione disulfide (see glutathione-glutaredoxin redox reactions). In eukaryotes this reaction is catalyzed by the enzyme glutathione peroxidase (for example, see glutathione peroxidase 1). Recently, glutathione-dependent peroxidases have been discovered in several prokaryotes as well [Vergauwen01, Pauwels03]. The disulfide is reduced back to GSH by the action of glutathione reductase. Most of the glutathione pool is kept in the reduced form. In Escherichia coli, the ratio of reduced to oxidized glutathione is 200:1 [Ritz01].
GSH is active against toxins by a process that involves multiple enzyme, and in the case of eukaryotes, occurs across multiple organs. Toxins are conjugated to GSH by a dedicated enzyme, resulting in a cysteine-toxin conjugate (this occurs in the liver in eukaryotes). The conjugate is acetylated (in the kidney), and cleaved, resulting in a part of the glutatione molecule and a mercapturate form of the toxin, which is excreted out of the cell (see glutathione-mediated detoxification I) [Hinchman94].
In addition, low molecular weight thiols have been found to be involved in a few other cellular process, including DNA synthesis [Suthanthiran90] and formaldehyde reduction (see formaldehyde oxidation II (glutathione-dependent) [Patel98].
While GSH is the major thiol in eukaryotic organisms, Gram negative bacteria and the majority of Gram positive bacteria, it is not universal. In some organisms other thiols have taken its role, including coenzyme M, trypanothione, ergothioneine, mycothiol and the ovothiols.
About This Pathway
In mammals, the intracellular synthesis of glutathione and its utilization are linked by the γ-glutamyl cycle, which is composed of six enzyme-catalyzed reactions. The first two reactions are responsible for GSH biosynthesis - in the first step, which is catalyzed by glutamate--cysteine ligase, an amide linkage is formed between L-cysteine and L-glutamate. glutathione synthetase then catalyzes the reaction between glycine and the cysteine carboxyl of the γ-L-glutamyl-L-cysteine dipeptide to form GSH.
The second part of the pathway consists of glutathione degradation, and occurs outside of the cell. The enzymes that catalyze its breakdown are γ-glutamyltransferase 1 and different dipeptidases, which are membrane-bound proteins located predominantly on the apical surface of epithelial tissues in mammals. γ-glutamyltransferase 1 is the only enzyme that can remove the γ-glutamyl moiety from GSH under physiological conditions, while the dipeptidases (EC 184.108.40.206) remove the glycyl moiety. The breakdown products (glutamate, glycine, and cysteine) can be reabsorbed into the cell and used for additional GSH synthesis (by EC 6.3.22 and EC 220.127.116.11) [Meister76, Wang98f].
Subpathways: glutathione biosynthesis
Pauwels03: Pauwels F, Vergauwen B, Vanrobaeys F, Devreese B, Van Beeumen JJ (2003). "Purification and characterization of a chimeric enzyme from Haemophilus influenzae Rd that exhibits glutathione-dependent peroxidase activity." J Biol Chem 278(19);16658-66. PMID: 12606554
Suthanthiran90: Suthanthiran M, Anderson ME, Sharma VK, Meister A (1990). "Glutathione regulates activation-dependent DNA synthesis in highly purified normal human T lymphocytes stimulated via the CD2 and CD3 antigens." Proc Natl Acad Sci U S A 87(9);3343-7. PMID: 1970635
Vergauwen01: Vergauwen B, Pauwels F, Jacquemotte F, Meyer TE, Cusanovich MA, Bartsch RG, Van Beeumen JJ (2001). "Characterization of glutathione amide reductase from Chromatium gracile. Identification of a novel thiol peroxidase (Prx/Grx) fueled by glutathione amide redox cycling." J Biol Chem 276(24);20890-7. PMID: 11399772
AlLahham99: Al-Lahham A, Rohde V, Heim P, Leuchter R, Veeck J, Wunderlich C, Wolf K, Zimmermann M (1999). "Biosynthesis of phytochelatins in the fission yeast. Phytochelatin synthesis: a second role for the glutathione synthetase gene of Schizosaccharomyces pombe." Yeast 15(5);385-96. PMID: 10219997
Anderson82: Anderson ME, Allison RD, Meister A (1982). "Interconversion of leukotrienes catalyzed by purified gamma-glutamyl transpeptidase: concomitant formation of leukotriene D4 and gamma-glutamyl amino acids." Proc Natl Acad Sci U S A 79(4);1088-91. PMID: 6122208
Arisi97: Arisi AC, Noctor G, Foyer CH, Jouanin L (1997). "Modification of thiol contents in poplars (Populus tremula x P. alba) overexpressing enzymes involved in glutathione synthesis." Planta 203(3);362-72. PMID: 9431683
Bodnaryk73: Bodnaryk, R. P., McGirr, L. (1973). "Purification, properties and function of a unique γ-glutamyl cyclotransferase from the house fly, Musca domestica L." Bioch. Biophys. Acta 315:352-362.
Ganguli07: Ganguli D, Kumar C, Bachhawat AK (2007). "The alternative pathway of glutathione degradation is mediated by a novel protein complex involving three new genes in Saccharomyces cerevisiae." Genetics 175(3);1137-51. PMID: 17179087
Gipp92: Gipp JJ, Chang C, Mulcahy RT (1992). "Cloning and nucleotide sequence of a full-length cDNA for human liver gamma-glutamylcysteine synthetase." Biochem Biophys Res Commun 185(1);29-35. PMID: 1350904
Gipp95: Gipp JJ, Bailey HH, Mulcahy RT (1995). "Cloning and sequencing of the cDNA for the light subunit of human liver gamma-glutamylcysteine synthetase and relative mRNA levels for heavy and light subunits in human normal tissues." Biochem Biophys Res Commun 206(2);584-9. PMID: 7826375
Grill89: Grill E, Loffler S, Winnacker EL, Zenk MH (1989). "Phytochelatins, the heavy-metal-binding peptides of plants, are synthesized from glutathione by a specific gamma-glutamylcysteine dipeptidyl transpeptidase (phytochelatin synthase)." Proc Natl Acad Sci U S A 86(18);6838-6842. PMID: 16594069
Harth05: Harth G, Maslesa-Galic S, Tullius MV, Horwitz MA (2005). "All four Mycobacterium tuberculosis glnA genes encode glutamine synthetase activities but only GlnA1 is abundantly expressed and essential for bacterial homeostasis." Mol Microbiol 58(4);1157-72. PMID: 16262797
Heisterkamp91: Heisterkamp N, Rajpert-De Meyts E, Uribe L, Forman HJ, Groffen J (1991). "Identification of a human gamma-glutamyl cleaving enzyme related to, but distinct from, gamma-glutamyl transpeptidase." Proc Natl Acad Sci U S A 88(14);6303-7. PMID: 1676842
Hibi93: Hibi T, Kato H, Nishioka T, Oda J, Yamaguchi H, Katsube Y, Tanizawa K, Fukui T (1993). "Use of adenosine (5')polyphospho(5')pyridoxals to study the substrate-binding region of glutathione synthetase from Escherichia coli B." Biochemistry 32(6);1548-54. PMID: 8431434
Hiratake02: Hiratake J, Irie T, Tokutake N, Oda J (2002). "Recognition of a cysteine substrate by E. coli gamma-glutamylcysteine synthetase probed by sulfoximine-based transition-state analogue inhibitors." Biosci Biotechnol Biochem 66(7);1500-14. PMID: 12224634
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