**3. Conclusion**

A single Cys residue can form a potential redox-sensitive site on a protein because a second cysteine can be introduced into the sequence with a disulfide formation and oxidation of the cytosolic molecule. The formation of disulfide bridges between two Cys molecules is important in stabilizing protein conformation; therefore sulfur atoms in Cys are responsible for the major covalent cross-links in protein structures. Disulfide bonds between Cys residues are generally thought to confer extra rigidity and stability to their resident protein, forming a type of proteinaceous spot weld. Conformational changes are generally small, involving protein backbone, and are often accompanied by a local increase in protein disorder [28, 37]. Surface modification of proteins by GSH results in significant disorder of the GSH distal to the covalent bond [37]. GSH plays important roles in nutrient metabolism and regulation of cellular processes, including cell differentiation, proliferation, and apoptosis [38]. DNA-binding activity of transcription factors often involves critical Cys residues, and the maintenance of these residues in a reduced form, at least in the nuclear compartment, is necessary. The reversible thiolation of proteins is known to regulate several metabolic processes including enzyme activity, signal transduction, and gene expression through redox-sensitive nuclear transcription factors such as AP-1, NF-kB, and p53 protein [39]. GSH is involved in a variety of cell functions such as DNA repair, cell cycle, regulation of cell signaling, and transcription factors, GSH therefore can modulate the genes of cell proliferation, differentiation, and apoptosis. The molecular mechanism of how GSH modulates cell proliferation remains largely speculative. A key mechanism for GSH's role in DNA synthesis relates to the maintenance of reduced glutaredoxin or thioredoxin, which is required for the

activity of ribonucleotide reductase, the rate-limiting enzyme in DNA synthesis [32].

disorders, cystic fibrosis, HIV, and aging [30, 40].

based sites and are known to be redox regulated.

**2.3. Modular redox switches in life evolution**

22 Glutathione in Health and Disease

Due to different roles of ROS in cell signaling and many human pathological processes, imbalance of GSH is observed in a wide range of pathologies including cancer, neurodegenerative

It is generally believed that before multiple genome sequences were complete, the increased complexity of organisms correlated with the gene number. Hence, after completion of the first genomes, the small differences in gene number between simple unicellular eukaryotes and mammals forced revision of how complexity is encoded. Additional complexity at the organismal level is likely encoded at the molecular level by noncoding DNA [41]. Hence, increased complexity may also be encoded at the protein level. It is recognized that concatenation of existing domains through gene fusion, also known as protein domain mosaicism, encodes new functions in more complex organisms [42]. Studies on the changing amino acid content of proteins show that domains are also not static structures. Additional complexity added to protein domains in the form of redox and other switches likely increases the signaling capabilities of individual domains. In other words, nature is continually tinkering with these independent folding units: a domain from archaea may not have the same sophisticated set of switches as the homologous domain from a mammalian protein. Thus, two modes of acquisition of increased protein complexity have been demonstrated to date: protein domain mosaicism [42] and acquisition of allosteric control sites. Babu et al. [43] showed that Zn finger allosteric control sites are added to protein sequences via retrotransposons. Both are CysThe sulfur cycle participation in life evolution comes from ancient anoxygenic elemental sulfur reduction generating environmental sulfide incorporated as mitochondrial Fe-S for the electron-transport chains. Sulfur compounds that contributed for electron leakage and oxidative stress have counteractions by thiol participation either as antioxidant defensors and/or as redox-modulators or cell functions, influencing life evolution and contemporary diseases.
