Protein surface-exposed methionine residues

Protein surface-exposed methionine residues are sulfur-containing amino acids located on the exterior of proteins, making them highly susceptible to oxidation by reactive oxygen species (ROS) to form methionine sulfoxide (MetO). Biologically, these residues serve as an endogenous antioxidant defense system, acting as sacrificial targets that protect the protein's hydrophobic core and critical functional sites from irreversible oxidative damage (Levine et al., 1996). This process is regulated by the methionine sulfoxide reductase (Msr) system, which enzymatically reduces MetO back to methionine, thereby maintaining protein function and cellular redox balance (Stadtman et al., 2003). In various pathologies, including neurodegenerative diseases like Alzheimer's and cardiovascular conditions, the accumulation of oxidized methionine residues is linked to protein misfolding and loss of activity (Ghesquière et al., 2011). While not a traditional single-protein drug target, surface methionines are critical in the pharmaceutical industry as critical quality attributes for biologics stability and are increasingly targeted for site-specific bioconjugation using novel chemoselective reagents like oxaziridines (Lin et al., 2017). Therapeutic interventions focus on enhancing the Msr repair pathway or utilizing methionine-selective chemistry for targeted drug delivery and proteomics.

Other names

Surface methioninesExposed methionine residuesMet residuesMethionine thioether sites

Acts as a redox buffer through reversible oxidation to methionine sulfoxide; serves as a site for selective covalent labeling via electrophilic or redox-active reagents.