Chemoproteomic profiling of protein modifications by lipid-derived electrophiles

•LDE modifications on proteins result in functional damage and signaling perturbation.•The hydrazide and oxime chemistry are exploited to capture LDE-modified proteins.•LDE-modified sites can be profiled by bioorthogonal probes and cleavable reporters.•LDE modification on cysteines can be quantitatively profiled by competitive isoTOP-ABPP.

Lipid-derived electrophiles (LDEs) are a group of endogenous reactive metabolites generated as products of lipid peroxidation when cells are under oxidative stress. LDEs are able to covalently modify nucleophilic residues in proteins to alter their structures and activities, either resulting in irreversible functional damage or triggering aberrant signaling pathways. Traditional biochemical methods have revealed individual protein targets modified by LDEs, however, deciphering the toxicity and/or signaling roles of LDEs requires systematic studies of these modifications in a high-throughput fashion. Here we survey recent progress in developing chemical proteomic strategies to globally profile protein–LDE interactions directly from complex proteomes. These powerful chemoproteomic methods have yielded a rich inventory of proteins and residue sites that are sensitive to LDE modification, serving as valuable resources to investigate mechanisms of their cellular toxicity at the molecular level.