Reductive Stress of Sulfur-Containing Amino Acids within Proteins and Implication of Tandem Protein-Lipid Damage

Reductive radical stress represents the other side of the redox spectrum, less studied but equally important compared to oxidative stress. The reactivity of hydrogen atoms (H^•) and hydrated electrons (e^-_aq) connected with peptides/proteins is summarized, focusing on the chemical transformations of methionine (Met) and cystine (CysS-SCys) residues into α-aminobutyric acid and alanine, respectively. Chemical and mechanistic aspects of desulfurization processes with formation of diffusible sulfur-centered radicals, such as methanethiyl (CH₃S^•) and sulfhydryl (HS^•) radicals, are discussed. These findings are further applied to biomimetic radical chemistry, modeling the occurrence of tandem protein-lipid damages in proteo-liposomes and demonstrating that generation of sulfur-centered radicals from a variety of proteins is coupled with the cis-trans isomerization of unsaturated lipids in membranes. Recent applications to pharmaceutical and pharmacological contexts are described, evidencing novel perspectives in the stability of formulations and mode of action of drugs, respectively.