Thiyl radicals and induction of protein degradation

Abstract

Thiyl radicals are important intermediates in the redox biology and chemistry of thiols. These radicals can react via hydrogen transfer with various C-H bonds in peptides and proteins, leading to the generation of carbon-centered radicals, and, potentially, to irreversible protein damage. This review summarizes quantitative information on reaction kinetics and product formation, and discusses the significance of these reactions for protein degradation induced by thiyl radical formation.

Reactivity of disulfide bonds is markedly affected by structure and environment: implications for protein modification and stability

“…Proteins are major targets for these oxidants as a result of their abundance, and high rate constants for reaction, with sulfur-containing amino acids being particularly prone to modification due to the presence of the reactive sulfur center (reviewed)151718. Oxidation of cysteine (Cys) and methionine (Met) residues is relatively well understood (reviewed)1920, but modification of disulfides (e.g. cystine), and the factors that control this, are less well characterized, despite the critical importance of such bonds in maintaining protein structures.…”

Protein cysteine oxidation in redox signaling: Caveats on sulfenic acid detection and quantification

“…as a result of hydrogen atom abstraction from the weak RS-H bond. The chemistry of such thiyl radicals has been discussed in detail in a number of excellent reviews and will not be addressed further in this paper [1,2]. It should be noted however, that one electron reactions involving freely diffusible radicals (as opposed to radicals formed in the active site of an enzyme, or on a protein during enzyme catalysis) are very unlikely to participate in signal transduction, which involves regulated enzymatic processes.…”

Special issue on “Free Radical and Redox Biochemistry of Thiols”

“…A more profound discussion on thiyl radical fates under biological conditions, taking into account published kinetic data, can be found in the review presented by Schoneich [6]. Those include thiyl radical repair by ascorbate and glutathione as well as reaction with oxygen, together with hydrogen abstraction from C-H bonds in peptides and proteins to form carbon-centered radicals that could result in protein damage [6].…”

“…Those include thiyl radical repair by ascorbate and glutathione as well as reaction with oxygen, together with hydrogen abstraction from C-H bonds in peptides and proteins to form carbon-centered radicals that could result in protein damage [6]. Mechanisms leading to such protein damage include generation of peroxyl radicals at the a C position followed by additional hydrogen and electron transfer processes and fragmentation reactions as well as thiyl radical elimination promoting the electrophilic dehydroalanine formation, which can further react with nucleophilic protein residues [7,8].…”

“…They are reversible processes that occur through SN2 nucleophilic substitution mechanisms. Different oxido-reductases, such as thioredoxins, glutaredoxins and protein disulfide isomerase, catalyze thioldisulfide exchange reactions by factors of up to 10 6 . The factors conferring specificity in enzymatic thiol/disulfide exchange reactions are reviewed by Netto et al in this issue [14].…”