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 GHS 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
(v) another interesting derivative is the covalent addict GSH-spermidine formed at the end of exponential growth in E. coli (Tabor and Tabor, 1979) and in trypanosomatids (encoded in Subsystem: Glutathionylspermidine and Trypanothione)

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.

In higher eukaryotes glutathione metabolism proceeds through gamma-glutamyl cycle. Complete core cycle involves six enzymes (see Tab "Illustrations"): gamma-glutamyl cysteine synthetase, GSH synthetase, gamma-glutamyl transpeptidase, gamma-glutamyl cyclotransferase, 5-oxoprolinase, and dipeptidase (and additional peptidases in some organisms) (Meister, 1985). However, gamma-glutamyl cycle in microbes apparently differs from that in mammals in that activities of gamma-glutamyl cyclotransferase and 5-oxoprolinase are excluded and bypassed by gamma-glutamyl transpeptidase. This truncated version of the cycle involves:
(i) the biosynthetic enzymes (encoded also in SS: Glutathione Biosynthesis”)
(ii) Gamma-glutamyltranspeptidase,
(iii) Cystein-glycine dipeptidase (or other peptidases)

Gamma-glutamyl-cyclotransferase and 5-oxoprolinase are probably NOT present in lower euks (yeast) and microbes, but the issue is still being debated (for example, see review by (Penninckx and Elkens, 1993)

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

- biosynthesis and degradation (encoded in this SS)
- reduction and oxidation (encoded in SS: Glutathione: Redox cycle)
- 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)

Most eukaryotes, cyanobacteria, and α,β,γ-proteobacteria synthesize glutathione. Yet the evolutionary history of glutathione biosynthesis is convoluted, and other aerobic microorganisms use different thiol cofactors to resist oxidative damage (Fahey RC. 2001). For example, low G+C Gram-positive bacteria produce excess amounts of CoASH for this purpose, whereas high G+C Gram-positive bacteria produce mycothiol or ergothioneine (Fahey RC. 2001). Gamma-glutamyl-cysteine is produced by Halobacteria (Newton, Javor, 1985; Malki et al., 2009), and trypanothione – by trypanosomatids (Oza et al., 2003). Methanogenic archaea contain significant amounts of coenzyme M, a thiol cofactor that like glutathione has been recruited into pathways to degrade oxidized metabolites (Allen et al., 1999).

The presence in Actinobacteria of the hypothetical protein family currently annotated in SEED as "Similar to Glutamate--cysteine ligase (EC 6.3.2.2), function unknown" is puzzling, since glutathione is NOT produced in these organisms (e.g. fig|246196.1.peg.6211)

References

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. 2001. Novel thiols of prokaryotes. Annu Rev Microbiol. 2001;55:333-56

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

Malki L, Yanku M, Borovok I, Cohen G, Mevarech M, Aharonowitz Y. 2009. Identification and characterization of gshA, a gene encoding the glutamate-cysteine ligase in the halophilic archaeon Haloferax volcanii. J Bacteriol, 191(16):5196-204

Ellinor Ristoff, Agne Larsson. 1998. Patients with genetic defects in the gamma-glutamyl
Cycle. Chemico-Biological Interactions 111 – 121

Kimura K, Tran LS, Uchida I, Itoh Y. 2004. Characterization of Bacillus subtilis gamma-glutamyltransferase and its involvement in the degradation of capsule poly-gamma-glutamate. Microbiology, 150(Pt 12): 4115-23

Ye GJ, Breslow EB, Meister A. 1996. The amino acid sequence of rat kidney 5-oxo-L-prolinase determined by cDNA cloning. J Biol Chem, 271(50): 32293-300

Ishiye M, Yamashita M, Niwa M. 1993. Molecular cloning of the gamma-glutamyltranspeptidase gene from a Pseudomonas strain. Biotechnol Prog, 9(3):323-31

Xu K, Strauch MA. 1996. Identification, sequence, and expression of the gene encoding gamma-glutamyltranspeptidase in Bacillus subtilis. J Bacteriol, 178(14):4319-22

Griffith, O. W., R. J. Bridges, et al. (1981). "Formation of gamma-glutamycyst(e)ine in vivo is catalyzed by gamma-glutamyl transpeptidase." Proc Natl Acad Sci U S A 78(5): 2777-81

Mehdi, K., J. Thierie, et al. (2001). "gamma-Glutamyl transpeptidase in the yeast Saccharomyces cerevisiae and its role in the vacuolar transport and metabolism of glutathione." Biochem J 359(Pt 3): 631-7

Meierjohann, S., R. D. Walter, et al. (2002). "Glutathione synthetase from Plasmodium falciparum." Biochem J 363(Pt 3): 833-8

Muller, S. (2003). "Thioredoxin reductase and glutathione synthesis in Plasmodium falciparum." Redox Rep 8(5): 251-5

Anderson, M. E. and A. Meister (1983). "Transport and direct utilization of gamma-glutamylcyst(e)ine for glutathione synthesis." Proc Natl Acad Sci U S A 80(3): 707-11