TY - JOUR

T1 - Electrophile versus oxidant modification of cysteine residues

T2 - Kinetics as a key driver of protein modification

AU - Sauerland, Max B.

AU - Davies, Michael J.

N1 - Funding Information: The authors are grateful to the Novo Nordisk Foundation for financial support (grants: NNF13OC0004294 and NNF20SA0064214 to MJD). Publisher Copyright: © 2022 The Authors

PY - 2022/9/30

Y1 - 2022/9/30

N2 - 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.

AB - 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.

KW - Acrolein

KW - alpha,beta-unsaturated aldehydes

KW - Cysteine

KW - Dimethylfumarate

KW - Keap1

KW - Michael addition

KW - Protein modification

KW - Protein oxidation

KW - Quinones

KW - Soft electrophiles

UR - http://www.scopus.com/inward/record.url?scp=85133601579&partnerID=8YFLogxK

U2 - 10.1016/j.abb.2022.109344

DO - 10.1016/j.abb.2022.109344

M3 - Review

C2 - 35777524

AN - SCOPUS:85133601579

VL - 727

JO - Nitric Oxide: Biology and Chemistry

JF - Nitric Oxide: Biology and Chemistry

SN - 1089-8603

M1 - 109344

ER -