From bacteria to plants and humans, the glutathione system plays a pleiotropic role in cell defense against metabolic, oxidative and metal stresses. Glutathione (GSH), the γ-L-glutamyl-L-cysteinyl-glycine nucleophile tri-peptide, is the central player of this system that acts in redox homeostasis, detoxification and iron metabolism in most living organisms. GSH directly scavenges diverse reactive oxygen species (ROS), such as singlet oxygen, superoxide anion, hydrogen peroxide, hydroxyl radical, nitric oxide and carbon radicals. It also serves as a cofactor for various enzymes, such as glutaredoxins (Grxs), glutathione peroxidases (Gpxs), glutathione reductase (GR) and glutathione-S-transferases (GSTs), which play crucial roles in cell detoxication. This review summarizes what is known concerning the GSH-system (GSH, GSH-derived metabolites and GSH-dependent enzymes) in selected model organisms (Escherichia coli, Saccharomyces cerevisiae, Arabidopsis thaliana and human), emphasizing cyanobacteria for the following reasons. Cyanobacteria are environmentally crucial and biotechnologically important organisms that are regarded as having evolved photosynthesis and the GSH system to protect themselves against the ROS produced by their active photoautotrophic metabolism. Furthermore, cyanobacteria synthesize the GSH-derived metabolites, ergothioneine and phytochelatin, that play crucial roles in cell detoxication in humans and plants, respectively. Cyanobacteria also synthesize the thiol-less GSH homologs ophthalmate and norophthalmate that serve as biomarkers of various diseases in humans. Hence, cyanobacteria are well-suited to thoroughly analyze the role/specificity/redundancy of the players of the GSH-system using a genetic approach (deletion/overproduction) that is hardly feasible with other model organisms (E.coli and S. cerevisiae do not synthesize ergothioneine, while plants and humans acquire it from their soil and their diet, respectively).
Most life forms are continuously challenged with toxic reactive oxygen species (ROS) present in our oxygenic atmosphere (ozone, O 3), and/or generated by respiration and cell metabolism and photosynthesis in cyanobacteria, algae and plants. In addition, photosynthetic organisms are exposed to solar UV that also generate ROS.
ROS molecules encompass singlet oxygens (1 O 2), superoxide anions (O 2●−), hydrogen peroxides (H 2 O 2), and hydroxyl radicals (●OH) that cause damages to target molecules, namely: lipids, nucleic acids and proteins, thereby generating cell death in microorganisms and multiple disorders and diseases in humans that reduce longevity.
Superoxide anions and hydrogen peroxides can both react with proteins containing iron-sulfur [Fe-S] clusters, liberating their Fe ions. Free or complexed Fe 2+ ions reduce H 2 O 2, yielding hydroxyl radicals that modify all kinds of biomolecules at a diffusion-limited rate. Hence, radicals, sulfenic acids, disulfides and (hydro)peroxides are directly or indirectly formed by ROS. ROS also oxidize cysteines to form thiyl (sulfenyl) radical (-S●) by one-electron transition; sulfenic acid (-SOH) and disulfide (-S-S-) by a two-electrons transition; sulfinic acid (-SO 2 H) by a four-electrons transition; and eventually sulfonic acid (-SO 3 H) by a six-electrons transition. Concerning disulfides, two types can be distinguished considering whether they link two cysteinyl residues from either the same or different proteins (intra- or inter-molecular disulfide bridges), or from a protein and a molecule of glutathione (glutathionylation). Glutathione is the γ-L-glutamyl-L-cysteinyl-glycine tri-peptide (hereafter designated as GSH) that plays a prominent role in ROS detoxification from bacteria to higher eukaryotes. It directly scavenges ROS and also serves as a redox cofactor for various antioxidant enzymes, such as glutaredoxins (Grxs), glutathione peroxidases (Gpxs), glutathione reductase (GR) and glutathione S-transferases (GSTs). The above-mentioned glutathionylation can protect cysteinyl residues against irreversible oxidation (generation of sulfinic and sulfonic acids), and/or act in regulation, as shown in Figure 1.
Figure 1. Schematic representation of the oxidation of the cysteinyl residue of protein to sulfenic (-SOH), sulfinic (-SO 2 H) and sulfonic (-SO 3 H); and disulfide (-S-S-) with another cysteinyl residue from the same or another protein, or a molecule of glutathione.
ROS can also be detoxified by various metabolites (ascorbate, carotenoids, vitamins, etc.) and several enzymes. The superoxide dismutase (SOD) converts O 2●− to H 2 O 2, which is then detoxified to H 2 O by the catalase and peroxidase enzymes. H 2 O 2 can also be detoxified by the hydroperoxide activity of some glutaredoxins. The protein disulfides and glutathione-protein mixed disulfides are repaired by thioredoxins, glutaredoxins and glutathione-S-transferases.
ROS-removing systems are usually viewed as beneficial antioxidants that maintain damaging ROS below dangerous levels. However, ROS are also a necessary part of subcellular and intercellular communication in living organisms. Indeed ROS species can serve as signal mediators in the redox regulation of cell metabolism, as they are enzymatically produced and degraded by NADPH-oxidases, which generate superoxide anions, SOD, which generates H 2 O 2, and catalase and peroxidase, which detoxify H 2 O 2 into H 2 O. Furthermore, H 2 O 2 oxidizes protein thiols in disulfides or sulfenic acids, which can be reduced back to thiols, and are thereby good thiol redox switches for signaling. Consequently, it has been proposed that “redox biology” or “ROS processing systems” would be a more accurate term than “(anti)oxidative systems” to describe cellular components that interact with ROS.
This review presents what is known concerning the evolutionary-conserved glutathione-system in selected model organisms, E. coli, S. cerevisiae, A. thaliana and human, emphasizing cyanobacteria for several reasons (See the next paragraphs for details and references). Cyanobacteria are environmentally crucial prokaryotes regarded as having evolved the oxygenic photosynthesis process, the chloroplast of algae and plants, and the glutathione-system to protect themselves against the ROS produced by their active photoautotrophic metabolism. Furthermore, cyanobacteria synthesize the thiol-less GSH homologs, ophthalmate and norophthalmate, and the ergothioneine antioxidant that operates in signaling and/or detoxication in humans. Moreover, cyanobacteria combine several important properties, such as (i) a simple nutritional requirement, (ii) a great physiological robustness, (iii) an important metabolic plasticity and (iv) the powerful genetics of some model strains. Hence, they are regarded as promising “low-cost” microbial factories for (i) the sustainable production of food and high-value chemicals for health and energy, (ii) the bioremediation of polluted waters and (iii) the fertilization of cultures.
Cyanobacteria are primordial prokaryotes regarded as the “inventor” of oxygenic photosynthesis, which played an important role in the evolution of Early Earth and the biosphere by absorbing a huge amount of the greenhouse gas carbon dioxide (CO 2), and evolving a huge amount of dioxygen (O 2). Indeed, cyanobacteria are regarded as responsible for the oxygenation (and oxidation) of the atmosphere since the Great Oxidation Event around 2.4 Ga.
As a consequence, cyanobacteria have long been challenged by ROS 1 O 2, O 2●−, H 2 O 2 and OH, which are generated by their active photosynthesis and, sometimes, their respiration.
