Cellular proteins containing reactive cysteine thiols

Cellular proteins containing reactive cysteine thiols constitute a functional subset of the proteome where specific cysteine residues exhibit enhanced nucleophilicity, often due to a lowered pKa influenced by the surrounding protein environment (Weerapana et al., 2010). These reactive sites are essential for various biological processes, including enzymatic catalysis, redox-mediated signaling, and the maintenance of protein structural integrity through disulfide bond formation (Backus et al., 2016). In the context of human disease, reactive cysteines are frequently found in the active or allosteric sites of proteins involved in oncogenesis, inflammation, and neurodegeneration. Therapeutic strategies often leverage these residues by designing covalent inhibitors that form stable, irreversible bonds, providing high selectivity and prolonged pharmacodynamic effects for targets like BTK, EGFR, and KRAS (Chung et al., 2023). Despite their therapeutic utility, targeting reactive cysteines carries risks of off-target reactivity and the formation of drug-protein adducts that can trigger immune-mediated toxicities (Boike et al., 2022). Consequently, modern drug discovery emphasizes the use of activity-based protein profiling (ABPP) to map the cysteine-reactive proteome and ensure target specificity.

Other names

Cysteine-reactive proteomeCovalent proteomeNucleophilic cysteinesThiol-containing proteins

Covalent modification of nucleophilic cysteine residues via Michael addition or other electrophilic reactions, resulting in irreversible or slowly reversible inhibition of protein function.