Abstract
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.
Highlights
Reductive radical stress represents the other side of the redox spectrum, less studied but important compared to oxidative stress
Redox homeostasis in biology represents the variety of endogenous adaptative mechanisms to preserve physiological processes in a cell/organism and balances two sides: oxidative stress and reductive stress [1]
Reductive stress is associated with redox couples of NADH/NAD+, NADPH/NADP+ and GSH/GSSG, exploring the consequences due to exceeding reduced species, which are as harmful as oxidation products [8,9,10]
Summary
Primary reactive species e aq primary reactive species e aq, HO , and H , together with H and H2O2, as shown in Reac, without using additives. The latter species may be derived from the direct e aq attachment to the disulfide and RS−/RSH but2do not3diffuse freelyreversibly owing to the tertiary structureRS ofthe moiety Under these conditions, radical undergoes irreversible decay with formation of of the RS /RSH respectively, but do not diffuse freely owing to the tertiary structure. The reactivity of sulfur-containing amino acids in HSA under reductive radical stress conditions was investigated by γ-radiolysis coupled with Raman spectroscopy and mass spectrometry techniques [34,35]. Reactions of reactive reductive species (H atoms and e− aq ), produced by γ-irradiation of water, with ZnII –MT and CdII –MT were carried out in aqueous solutions and monitored by various spectroscopic and spectrometric techniques (Raman, CD, and ESI-MS) [37,38,39]. Substantial differences were observed in the behavior of the ZnII –MT and CdII –MT aggregates towards the reactive species, depending on the different folding of the polypeptide in these two cases
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