GLUTATHIONE: ADVANCES IN PROTEIN-PEPTIDE CHEMISTRY, BIOTECHNOLOGY, AND NATURAL PRODUCTS

Glutathione (GSH) is a low-molecular-weight, sulfur-containing tripeptide that serves as a central regulator of intracellular redox homeostasis and cellular defense mechanisms across all aerobic life forms. Structurally composed of L-glutamate, L-cysteine, and glycine, glutathione possesses a distinctive γ-glutamyl peptide linkage that confers resistance to proteolytic degradation and underpins its biochemical stability. The thiol group of the cysteine residue imparts potent nucleophilic and reducing properties, enabling glutathione to function as a major endogenous antioxidant and a key modulator of redox-dependent signaling pathways. Intracellular glutathione exists predominantly in its reduced form (GSH), while the oxidized disulfide form (GSSG) accumulates under conditions of oxidative stress; the GSH/GSSG ratio is therefore widely recognized as a sensitive indicator of cellular redox status and oxidative stress. This chapter presents a comprehensive and integrative overview of glutathione biology, including its chemical structure, physicochemical characteristics, cellular distribution, biosynthesis, degradation, transport, and recycling via the γ-glutamyl cycle. Special emphasis is placed on the enzymatic regulation of glutathione synthesis and its tight coupling with cellular metabolic and redox networks. The multifaceted biological functions of glutathione, including reactive oxygen and nitrogen species scavenging, maintenance of protein thiol redox state, conjugation and detoxification of xenobiotics through glutathione S-transferases, and modulation of immune responses, apoptosis, and gene expression, are critically examined. We also explore the central role of glutathione dysregulation in the pathogenesis of human diseases, including neurodegenerative disorders, cancer, cardiovascular diseases, metabolic syndromes, and aging-related conditions. Current and emerging therapeutic strategies aimed at restoring or modulating glutathione homeostasis, including dietary interventions, pharmacological precursors, targeted delivery systems, and nanotechnology-based formulations, are discussed in detail. Advances in analytical methodologies for glutathione quantification, along with biotechnological approaches for its microbial and industrial production, are also highlighted.