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.
|Superclasses:||Biosynthesis → Cofactors, Prosthetic Groups, Electron Carriers Biosynthesis → Reductants Biosynthesis|
Thiols are compounds that play a major role in the detoxification of stress-inducing factors. In mammals, the major thiol is the tripeptide glutathione (γ-Glu-Cys-Gly, known as GSH). Toxins are conjugated to GSH in the liver by a dedicated enzyme, resulting in a cysteine-toxin conjugate. The conjugate is acetylated in the kidney to form mercapturate, and is then excreted [Hinchman94] (see glutathione-mediated detoxification I). In addition to oxidative stress management, low molecular weight thiols have been found to be involved in critical cellular processes including DNA synthesis and formaldehyde reduction [Patel98].
Pathogenic bacteria live in a particularly hostile environment, in which the host deliberately generates toxins, including reactive oxygen species, to destroy the invading organism. Thus thiols are particularly important for the survival of these organisms. 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
The synthesis of GSH from its three amino acid precursors L-glutamate, L-cysteine and glycine takes place in the cytosol. GSH is synthesized in all mammalian cells, many plants, and most Gram negative bacteria. In mammals, the liver is a major site of biosynthesis.
GSH is synthesized in a two-step reaction, catalyzed by γ-glutamate-cysteine ligase and by glutathione synthetase, requiring a total of two moles of ATP per mole of GSH. This ATP-dependent coupling of amino acid monomers and elongating peptides by soluble enzymes is very unusual, as oligopeptides are usually formed either by ribosomes or by nonribosomal peptide synthases. A similar mechanism is also found in the formation of the bacterial cell wall pentapeptide.
The first step in glutathione biosynthesis is controlled by negative feedback from its end product, GSH. However, feedback inhibition can be partially prevented by an excess of glutamate that blocks the regulatory site on the enzyme [Meister84, Meister83]. When GSH is consumed and feedback inhibition is lost, the availability of cysteine as a precursor can become the limiting factor [Wang98c].
Glutathione is an antioxidant that counteracts reactive oxygen species thus reducing oxidative stress [Noctor98]. It is recognized as a major player in detoxifying xenobiotics [Matringe88] by forming less reactive or storage conjugates catalyzed by GHS S-transferases [Marrs96]. Glutathione has also been reported to detoxify air pollutants such as ozone and sulfur dioxide [Madamanchi91].
GHS is discussed as important storage form of reduced sulfur regulating inter-organ sulfur allocation and its biosynthesis seems to be coupled with the sulfate assimilation pathway (see sulfate reduction II (assimilatory)) [Meyer02]. As a precursor for phytochelatin, the principal metal-binding agent in plants, glutathione is considered a vital component for the detoxification of heavy metals [Grill] [Grill89, Xiang01].
The biosynthesis of glutathione is universally catalyzed in all organisms by two enzymes, glutamate-cysteine ligase [May94] [Jez04a] regarded as the rate-limiting step of the pathway [Richman75] and glutathione synthetase [Ullmann96] [Wang96a] [Jez04].
The regulation of the plant enzymes is unlike those reported from other eucaryotes. For the glutamate-cysteine ligase a conformational change has been observed as means to modify enzyme activities in response to redox conditions. That differs from mammalian enzymes that regulate activity through a regulatory subunit of the enzyme [Jez04a].
Superpathways: γ-glutamyl cycle
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
Jez04a: Jez JM, Cahoon RE, Chen S (2004). "Arabidopsis thaliana glutamate-cysteine ligase: functional properties, kinetic mechanism, and regulation of activity." J Biol Chem 279(32);33463-70. PMID: 15180996
Matringe88: Matringe M, Scalla R (1988). "Studies on the Mode of Action of Acifluorfen-Methyl in Nonchlorophyllous Soybean Cells : Accumulation of Tetrapyrroles." Plant Physiol 86(2);619-622. PMID: 16665956
May94: May MJ, Leaver CL (1994). "Arabidopsis thaliana γ-glutamylcysteine synthetase is structurally unrelated to mammalian, yeast, and Escherichia coli homologs." Proc. Natl. Acad. Sci. USA, 91, 10059-10063.
Noctor98: Noctor G, Arisi A-CM, Jouanin L, Kunert KJ, Rennenberg H, Foyer CH (1998). "Glutathione: biosynthesis, metabolism and relationship to stress tolerance explored in transformed plants." Journal of Experimental Botany, 49(321), 623-647.
Ullmann96: Ullmann P, Gondet L, Potier S, Bach TJ (1996). "Cloning of Arabidopsis thaliana glutathione synthetase (GSH2) by functional complementation of a yeast gsh2 mutant." Eur J Biochem 236(2);662-9. PMID: 8612643
Wang96a: Wang CL, Oliver DJ (1996). "Cloning of the cDNA and genomic clones for glutathione synthetase from Arabidopsis thaliana and complementation of a gsh2 mutant in fission yeast." Plant Mol Biol 31(6);1093-104. PMID: 8914526
Xiang01: Xiang C, Werner BL, Christensen EM, Oliver DJ (2001). "The biological functions of glutathione revisited in arabidopsis transgenic plants with altered glutathione levels." Plant Physiol 126(2);564-74. PMID: 11402187
DiazMejia09: Diaz-Mejia JJ, Babu M, Emili A (2009). "Computational and experimental approaches to chart the Escherichia coli cell-envelope-associated proteome and interactome." FEMS Microbiol Rev 33(1);66-97. PMID: 19054114
Fan95: Fan C, Moews PC, Shi Y, Walsh CT, Knox JR (1995). "A common fold for peptide synthetases cleaving ATP to ADP: glutathione synthetase and D-alanine:d-alanine ligase of Escherichia coli." Proc Natl Acad Sci U S A 92(4);1172-6. PMID: 7862655
Faulkner08: Faulkner MJ, Veeravalli K, Gon S, Georgiou G, Beckwith J (2008). "Functional plasticity of a peroxidase allows evolution of diverse disulfide-reducing pathways." Proc Natl Acad Sci U S A 105(18);6735-40. PMID: 18456836
Hara95: Hara T, Tanaka T, Kato H, Nishioka T, Oda J (1995). "Site-directed mutagenesis of glutathione synthetase from Escherichia coli B: mapping of the gamma-L-glutamyl-L-cysteine-binding site." Protein Eng 8(7);711-6. PMID: 8577699
Hara96a: Hara T, Kato H, Katsube Y, Oda J (1996). "A pseudo-michaelis quaternary complex in the reverse reaction of a ligase: structure of Escherichia coli B glutathione synthetase complexed with ADP, glutathione, and sulfate at 2.0 A resolution." Biochemistry 35(37);11967-74. PMID: 8810901
Harrison09: Harrison JJ, Tremaroli V, Stan MA, Chan CS, Vacchi-Suzzi C, Heyne BJ, Parsek MR, Ceri H, Turner RJ (2009). "Chromosomal antioxidant genes have metal ion-specific roles as determinants of bacterial metal tolerance." Environ Microbiol 11(10);2491-509. PMID: 19555372
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
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