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

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.

A Diet Supplemented with Polyphenols, Prebiotics and Omega-3 Fatty Acids Modulates the Intestinal Microbiota and Improves the Profile of Metabolites Linked with Anxiety in Dogs

“…2-aminobutyrate, which was significantly higher in plasma following consumption of the control or test foods in this study, appears to protect against oxidative stress by increasing cellular levels of reduced glutathione [ 49 ]. In addition to oxidative stress, 2-aminobutyrate plays a role in decreasing reductive stress, as the attack of a hydrogen atom on a sulfur atom in methionine leads to formation of 2-aminobutyrate [ 50 ]. Thus, the increased plasma levels of 2-aminobutyrate observed here following consumption of the control or test foods may indicate an increased ability to withstand oxidative and reductive stress.…”

Lipid Peroxidation and Antioxidant Protection

“…Interestingly, in parallel to the influence of lipid oxidation products in the structure and functions of proteins, oxidative damage to peptides and proteins, particularly concerning cysteine and methionine residues, would cause radical damage to lipids, altering their stucture and functions [ 70 , 71 , 72 , 73 ].…”

Evaluation of Hydroxyl Radical Reactivity by Thioether Group Proximity in Model Peptide Backbone: Methionine versus S-Methyl-Cysteine

“…It is well documented from previous studies on Met derivatives that the sulfoxide 3 is formed from the in-situ generation of hydrogen peroxide [ 11 , 12 ], whereas the H • addition to the sulfur center ( k = 1.7 × 10 9 M −1 s −1 ) with the formation of a sulfuranyl radical intermediate affords compound 4 and the CH 3 S • radical ( Scheme 6 ) [ 24 , 25 ]. In analogy, we expected the same reactions with starting material 2 giving 5 and 6 , respectively.…”