Abstract
Glutathione is a very ancient molecule widely distributed in aerobic cells and organisms, either prokaryotes or eukaryotes. Since glutathione in not found in anaerobic cells it could have evolved in the course of the adaptation to the presence of oxygen in the atmosphere. Glutathione is the major non-protein low molecular weight antioxidant and the most important cellular thiol reducing agent. Glutathione biosynthesis occurs in the cytosol from its constituent amino acids; GSH is present also in the most important cellular districts like mitochondria and nucleus to indicate its central role in several metabolic pathways and protective mechanisms. There are several glutathione dependent enzymes involved in various steps of cell metabolism. GSH is a key antioxidant that modulates various cellular processes and therefore is determinant for redox signaling, xenobiotics’s detoxication, regulation of cell proliferation, apoptosis and immune functions. Glutathione concentration and redox state is due to a complex interaction between biosynthesis, utilization, degradation, and transport. All these factors are of great importance for understanding the significance of cellular redox balance and its correlation with pathological conditions.
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References
Aceto A, Dragani B, Melino S et al (1998) Structural characterization of human glyoxalase II as probed by limited proteolysis. Biochem Mol Biol Int 44:761–769
Aquilano K, Baldelli S, Ciriolo MR (2014) Glutathione: new roles in redox signaling for an old antioxidant. Front Pharmacol Front Pharmacol 5:196. https://doi.org/10.3389/fphar.2014.00196 eCollection 2014
Armeni T, Tomasetti M, Svegliati Baroni S et al (1997) Dietary restriction affects antioxidant levels in rat liver mitochondria during ageing. Molec Aspects Med 18:S247–S250
Armeni T, Pieri C, Marra M et al (1998) Studies on the life prolonging effect of food restriction: Glutathione levels and glyoxalase enzymes in rat liver. Mech Ageing Dev 101:101–110
Armeni T, Ghiselli R, Balercia G et al (2000) Glutathione and ultrastructural changes in inflow occlusion of rat liver. J Surg Res 88:207–214
Armeni T, Battino M, Stronati A et al (2001) Total antioxidant capacity and nuclear DNA damage in keratinocytes after exposure to H2O2. Biol Chem 382:1697–1705
Armeni T, Ercolani L, Urbanelli L et al (2012) Cellular redox imbalance and changes of protein S-glutathionylation patterns are associated with senescence induced by oncogenic H-ras. PLoS ONE 7:e52151. https://doi.org/10.1371/journal.pone.0052151
Armeni T, Cianfruglia L, Piva F et al (2014) S-D-Lactoylglutathione can be an alternative supply of mitochondrial glutathione. Free Radic Biol Med 67:451–459
Armstrong JS, Jones DP (2002) Glutathione depletion enforces the mitochondrial permeability transition and causes cell death in Bcl-2 overexpressing HL60 cells. Faseb J 16:1263–1265
Bacchetti T, Masciangelo S, Armeni T et al (2014) Glycation of human high density lipoprotein by methylglyoxal: effect on HDL-paraoxonase activity. Metabolism 63:307–311
Bartolini D, Piroddi M, Tidei C et al (2015) Reaction kinetics and targeting to cellular glutathione S-transferase of the glutathione peroxidase mimetic PhSeZnCl and its D, L-polylactide microparticle formulation. Free Radic Biol Med 78:56–65
Bartolini D, Galli F (2016) The functional interactome of GSTP: A regulatory biomolecular network at the interface with the Nrf2 adaption response to oxidative stress. J Chromatogr B Analyt Technol Biomed Life Sci 1019:29–44
Chen YR, Chen CL, Pfeiffer DR, Zweier JL (2007) Mitochondrial complex II in the post-ischemic heart: oxidative injury and the role of protein S-glutathionylation. J Biol Chem 282:32640–32654
Chen SL, Fang WH, Himo F (2009) Reaction mechanism of the binuclear zinc enzyme glyoxalase II—a theoretical study. J Inorg Biochem 103:274–281
Chen CA, Wang TY, Varadharaj S et al (2010) S-glutathionylation uncouples eNOS and regulates its cellular and vascular function. Nature 468:1115–1118
Cianfruglia L, Perrelli A, Fornelli C et al (2019) KRIT loss-of-function associated with cerebral cavernous malformation disease leads to enhanced S-glutathionylation of distinct structural and regulatory proteins. Antioxidant 8(1), pii: E27. https://doi.org/10.3390/antiox8010027
Circu ML, Aw TY (2012) Glutathione and modulation of cell apoptosis. Biochim Biophys Acta 1823:1767–1777
Dalle-Donne I, Milzani A, Gagliano N et al (2008) Molecular mechanisms and potential clinical significance of S-glutathionylation. Antioxid Redox Signal 10:445–473
Damiani E, Brugè F, Cirilli I et al (2018) Modulation of oxidative status by normoxia and hypoxia on cultures of human dermal fibroblasts: how does it affect cell aging? Oxid Med Cell Longev 23(2018):5469159. https://doi.org/10.1155/2018/5469159 eCollection 2018
Ercolani L, Scirè A, Galeazzi R et al (2016) A possible S-glutathionylation of specific proteins by glyoxalase II: an in vitro and in silico study. Cell Biochem Funct 34:620–627
Fahey RC, Brown WC, Adams WB et al (1978) Occurrence of glutathione in bacteria. J Bacteriol 133:1126–1129
Fahey RC, Newton GL, Arrick B et al (1984) Entamoeba histolytica: a eukaryote without glutathione metabolism. Science 224:70–72
Ferguson G, Bridge W (2016) Glutamate cysteine ligase and the age-related decline in cellular glutathione: the therapeutic potential of γ-glutamylcysteine. Arch Biochem Biophys 593:12–23
Foster MW, Hess DT, Stamler JS (2009) Protein S-nitrosylation in health and disease: a current perspective. Trends Mol Med 15:391–404
Galeazzi R, Laudadio E, Falconi E et al (2018) Protein-protein interactions of human glyoxalase II: findings of a reliable docking protocol. Org Biomol Chem 16:5167–5177
Herszage J, dos Santos AM, Luther Luther GW (2003) Oxidation of cysteine and glutathione by soluble polymeric MnO2. Environ Sci Technol 37:3332–3338
Honek JF (2015) Glyoxalase biochemistry. Biomol Concepts 6:401–414
Janowiak BE, Griffith OW (2005) Glutathione synthesis in Streptococcus agalactiae. One protein accounts for gamma-glutamylcysteine synthetase and glutathione synthetase activities. J Biol Chem 280:11829–11839
Jassem W, Ciarimboli C, Cerioni PN et al (1996) Glyoxalase II and glutathione levels in rat liver mitochondria during cold storage in Euro-Collins and University of Wisconsin solutions. Transplantation 61:1416–1420
Jassem W, Armeni T, Quiles JL et al (2006) Protection of mitochondria during cold storage of liver and following transplantation: comparison of the two solutions, University of Wisconsin and Eurocollins. J Bioenerg Biomembr 38:49–55
Jones DP, Sies H (2015) The redox code. Antioxid Redox Signal 23:734–746
Kendall EC, Nord FF (1926) Reversible oxidation-reduction systems of cysteine-cystine and reduced and oxidized glutathione. J Biol Chem 69:295–337
Lu SC (2013) Glutathione synthesis. Biochim Biophys Acta 1830:3143–3153
Lupattelli M, Principato GB, Talesa V (1986) Glyoxalase II in germinating mung bean (Vigna radiata (l.) wilcz.). Giornale Botanico Italiano 120:110–111
Mailloux RJ, Harper ME (2011) Uncoupling proteins and the control of mitochondrial reactive oxygen species production. Free Radic Biol Med 51:1106–1115
Mailloux RJ, McBride SL, Harper ME (2013) Unearthing the secrets of mitochondrial ROS and glutathione in bioenergetics. Trends Biochem Sci 38:592–602
Mailloux RJ, Jin X, Willmore WG (2014) Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions. Redox Biol 2:123–139
Mailloux RJ, Treberg JR (2016) Protein S-glutathionlyation links energy metabolism to redox signaling in mitochondria. Redox Biol 8:110–118
Mari M, Morales A, Colell A et al (2009) Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 11:2685–2700
Mieyal JJ, Gallogly MM, Qanungo S et al (2008) Molecular mechanisms and clinical implications of reversible protein S-glutathionylation. Antioxid Redox Signal 10:1941–1988
Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1–13
Norton SJ, Principato GB, Talesa V et al (1989) Glyoxalase II from Zea mays: properties and inhibition study of the enzyme purified by use of a new affinity ligand. Enzyme 42:189–196
Norton SJ, Talesa V, Yuan W-J et al (1990) Glyoxalase I and glyoxalase II from Aloe vera: purification, characterization and comparison with animal glyoxalases. Biochem Int 22:411–418
Principato GB, Rosi G, Talesa V et al (1984) Purification of S-2-hydroxyacylglutathione hydrolase (glyoxalase II) from calf brain. Biochem Int 9:351–359
Principato GB, Rosi G, Talesa V et al (1985) Purification and characterization of S-2-hydroxyacylglutathione hydrolase (glyoxalase II) from human brain. IRCS Med Sci 13:952–953
Principato GB, Rosi G, Talesa V et al (1987) A comparative study on glyoxalase II from vertebrata. Enzyme 37:164–168
Raftos JE, Whillier S, Kuchel PW (2010) Glutathione synthesis and turnover in the human erythrocyte: alignment of a model based on detailed enzyme kinetics with experimental data. J Biol Chem 285:23557–23567
Requejo R, Hurd TR, Costa NJ et al (2010) Cysteine residues exposed on protein surfaces are the dominant intramitochondrial thiol and may protect against oxidative damage. FEBS J 277:1465–1480
Ridderström M, Saccucci F, Hellman U et al (1996) Molecular cloning, heterologous expression, and characterization of human glyoxalase II. J Biol Chem 271:319–323
Schafer FQ, Buettner GR (2001) Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 30:1191–1212
Scirè A, Cianfruglia L, Minnelli C et al (2018) Glutathione compartmentalization and its role in glutathionylation and other regulatory processes of cellular pathways. BioFactors. https://doi.org/10.1002/biof.1476
Smirnova GV, Oktyabrsky ON (2005) Glutathione in Bacteria. Biochemistry (Mosc) 70:1199–1211
Sundquist AR, Fahey RC (1989) The function of gamma-glutamylcysteine and bis-gamma-glutamylcystine reductase in Halobacterium halobium. J Biol Chem 15:719–725
Szajewski RP, Whitesides GM (1980) Rate constants and equilibrium constants for thiol-disulfide interchange reactions involving oxidized glutathione. J Am Chem Soc 102:2011–2026
Taylor ER, Hurrell F, Shannon RJ et al (2003) Reversible glutathionylation of complex I increases mitochondrial superoxide formation. J Biol Chem 278:19603–19610
Thauer RK, Jungermann K, Decker K (1977) Energy conservation in chemotrophic anaerobic bacteria. Bacteriol Rev 41:100–180
Toppo S, Flohe L, Ursini F et al (2009) Catalytic mechanisms and specificities of glutathione peroxidases: variations of a basic scheme. Biochim Biophys Acta 1790:1486–1500
Townsend DM (2007) S-glutathionylation: indicator of cell stress and regulator of the unfolded protein response. Mol Interv 7:313–324
Woodward W, Fischer JH, Johnson JE (2016) Evolution of oxygenic photosynthesis. Annual Rev Earth and Planetary Sciences 44:647–683
Zhang H, Forman HJ, Choi J (2005) Gamma-glutamyl transpeptidase in glutathione biosynthesis. Meth Enzymol 401:468–483
Zhong Q, Putt DA, Xu F et al (2008) Hepatic mitochondrial transport of glutathione: studies in isolated rat liver mitochondria and H4IIE rat hepatoma cells. Arch Biochem Biophys 474:119–127
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Armeni, T., Principato, G. (2020). Glutathione, an Over One Billion Years Ancient Molecule, Is Still Actively Involved in Cell Regulatory Pathways. In: Longhi, S., et al. The First Outstanding 50 Years of “Università Politecnica delle Marche”. Springer, Cham. https://doi.org/10.1007/978-3-030-33832-9_28
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