Protein thiyl radical reactions and product formation: a kinetic simulation

Protein thiyl radicals are important intermediates generated in redox processes of thiols and disulfides. Thiyl radicals efficiently react with glutathione and ascorbate, and the common notion is that these reactions serve to eliminate thiyl radicals before they can enter potentially hazardous processes. However, over the past years increasing evidence has been provided for rather efficient intramolecular hydrogen transfer processes of thiyl radicals in proteins and peptides. Based on rate constants published for these processes, we have performed kinetic simulations of protein thiyl radical reactivity. Our simulations suggest that protein thiyl radicals enter intramolecular hydrogen transfer reactions to a significant extent even under physiologic conditions, i.e., in the presence of 30µM oxygen, 1mM ascorbate, and 10mM glutathione. At lower concentrations of ascorbate and glutathione, frequently observed when tissue is exposed to oxidative stress, the extent of irreversible protein thiyl radical-dependent protein modification increases. [Display omitted] •Recent experimental evidence suggests the possibility of intramolecular hydrogen atom transfer reactions of thiyl radicals in proteins.•Kinetic simulations including experimental rate constants for hydrogen atom transfer reactions suggest that thiyl radical reactions in proteins may lead to additional products different from disulfides.•The extent to which such hydrogen atom transfer reactions may occur under physiological conditions will depend on the presence of oxygen and antioxidants.•The potential for intramolecular hydrogen atom transfer reactions will increase upon a decrease in antioxidant levels, such as is observed under conditions of oxidative stress.