Subsystem: Glutathione: Redox cycle

This subsystem's description is:

Glutathione (GSH) is a tripeptide (gamma-Glu-Cys-Gly), which is present in high concentration in most living cells from microorganisms to man. The biological importance of GSH is mainly related to the free sulphydryl moiety of Cys residue. Which confers unique redox (Eo= -0.24) and nucleophilic properties. GSH servers a pivotal role in numerous and very diverse cellular functions, including free radical scavenging, redox reactions, formation of deoxyribonucleotides,
detoxication of xenobiotics, amino acid transport and leukotriene biosynthesis (in eukaryotes), and many others. Main forms of GSH include:
(i) reduced GSH,
(ii) oxidized GSSG and
(iii) mixed disulfides: mostly GSS-protein and GSSR (R = suitable residue such as cysteine or CoASH). For example, CoASSG is a major component of the CoA pool in yeast and E. coli (Loewen 1981)
(iv) thiol esters, which function as intermediates in metabolism of certain compounds, such as methylglyoxal and formaldehyde

Under unstressed physiological conditions much of the thipeptide is present in the free reduced form. In E. coli GSH content is very high and accounts for more than 1% of dry cell weight. The concentration of oxidized form is usually much smaller, with the GSH/GSSG ratio generally being greater than 50. This balance is maintained by GSH reductase (at the expense of NADPH), ensuring a cellular environment where essential sulphygryl groups of key enzymes and co-enzymes are protected. The opposite conversion of GSH to GSSH can be catalyzed by:
- GSH peroxidase, which eliminates H2O2 and organic peroxides
- GSH transhydrogenases - a group of enzymes involved in thiol-disulphide exchanges (protein disulphide isomerase, thiol-transferase, thiol-disulphide oxidoreductase). The majority of these activities have not been associated with any sequences yet, and are not encoded in this SS
- or be caused by non-enzymic processes

GSH-related enzymes can be grouped into those concerned with:

- biosynthesis and degradation (encoded in SS: “Glutathione: gamma-glutamyl cycle”)
- reduction and oxidation (encoded in this SS)
- conjugation and those in which GSH serves as a cofactor (encoded in SS: “Glutathione: Non-redox reactions”, “Glutathione-dependent pathway of formaldehyde detoxification”, and others)


Penninckx MJ, Elskens MT. 1993. Metabolism and functions of glutathione in micro-organisms. Advances in microbial physiology (Adv Microb Physiol) 1993;34:239-301. PMID: 8095770

Fahey RC, Sundquist AR. 1991. Evolution of glutathione metabolism. Advances in enzymology and related areas of molecular biology, 64:1-53. PMID: 1675828

Greer S, Perham RN. 1986. Glutathione reductase from Escherichia coli: cloning and sequence analysis of the gene and relationship to other flavoprotein disulfide oxidoreductases. Biochemistry, 25(9):2736-42

Perry AC, Ni Bhriain N, Brown NL, Rouch DA. 1991. Molecular characterization of the gor gene encoding glutathione reductase from Pseudomonas aeruginosa: determinants of substrate specificity among pyridine nucleotide-disulphide oxidoreductases. Mol Microbiol, 5(1):163-71

Gopal S, Borovok I, Ofer A, Yanku M, Cohen G, Goebel W, Kreft J, Aharonowitz Y. 2005. A multidomain fusion protein in Listeria monocytogenes catalyzes the two primary activities for glutathione biosynthesis. J Bacteriol. 2005 Jun;187(11):3839-47

Vergauwen B, Pauwels F, Vaneechoutte M, Van Beeumen JJ. Exogenous glutathione completes the defense against oxidative stress in Haemophilus influenzae. J Bacteriol. 2003 Mar;185(5):1572-81

Fernandes AP, Holmgren A; "Glutaredoxins: Glutathione-dependent redox enzymes with functions far beyond a simple thioredoxin backup system"; Antioxidants and Redox Signaling. Vol 6(1). 63-74. 2004

Fomenko, D. E. and V. N. Gladyshev (2002). "CxxS: fold-independent redox motif revealed by genome-wide searches for thiol/disulfide oxidoreductase function." Protein Sci 11(10): 2285-96

Li, K., S. Hein, et al. (2004). "The glutathione-glutaredoxin system in Rhodobacter capsulatus: part of a complex regulatory network controlling defense against oxidative stress." J Bacteriol 186(20): 6800-8

Baek, H., J. Lim, et al. (2004). "Oxidative-stress-related proteome changes in Helicobacter pylori-infected human gastric mucosa." Biochem J 379: 291-299

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