Electrophile versus oxidant modification of cysteine residues: Kinetics as a key driver of protein modification

Humans have widespread exposure to both oxidants, and soft electrophilic compounds such as alpha, beta-unsaturated aldehydes and quinones. Electrophilic motifs are commonly found in a drugs, industrial chemicals, pollutants and are also generated via oxidant-mediated degradation of biomolecules including lipids (e.g. formation of 4-hydroxynonenal, 4-hydroxyhexenal, prostaglandin J2). All of these classes of compounds react efficiently with Cys residues, and the particularly the thiolate anion, with this resulting in Cys modification via either oxidation or adduct formation. This can result in deleterious or beneficial effects, that are either reversible (e.g. in cell signalling) or irreversible (damaging). For example, acrolein is a well-established toxin, whereas dimethylfumarate is used in the treatment of multiple sclerosis and psoriasis. This short review discusses the targets of alpha, beta-unsaturated aldehydes, and particularly two prototypic cases, acrolein and dimethylfumarate, and the factors that control the selectivity and kinetics of reaction of these species. Comparison is made between the reactivity of oxidants versus soft electrophiles. These rate constants indicate that electrophiles can be significant thiol modifying agents in some situations, as they have rate constants similar to or greater than species such as H2O2, can be present at higher concentrations, and are less efficiently removed by protective systems when compared to H2O2. They may also induce similar or higher levels of modification than highly reactive oxidants, due to the very low concentrations of oxidants formed in most in vivo situations.

Automated summary

Humans are exposed to oxidants and soft electrophilic compounds, which can modify cysteine residues through oxidation or adduct formation. These modifications can have either reversible or irreversible effects, and can be beneficial or deleterious. This review discusses the targets of alpha, beta-unsaturated aldehydes and the factors that control their reactivity, with a focus on the examples of acrolein and dimethylfumarate. The authors compare the reactivity of oxidants and soft electrophiles, and highlight the potential significance of electrophiles as thiol modifying agents.