Science 355, 597–602 (2017)

Credit: AAAS

Methionine is one of the rarest amino acids in proteins, making it a potentially attractive handle for highly selective protein modification. However, because of a lack of robust bioorthogonal reactions for targeting methionine, it has historically been overlooked in favor of the other sulfur-containing residue, cysteine, which is more nucleophilic. Lin et al. have now developed a modification strategy that utilizes methionine's redox activity for conjugation under physiological conditions. This method, redox-activated chemical tagging (ReACT), relies on an oxaziridine reagent that converts the methionine side chain to a sulfimide conjugation product while reducing the reagent to an aldehyde. This reaction is selective for methionine over other nucleophilic amino acids and does not denature proteins, and the product is stable when exposed to reducing reagents or elevated temperatures for up to one hour. To demonstrate its utility, the authors applied the ReACT method to label proteins with alkyne- or azide-containing tags for further click chemistry and to synthesize antibody–drug conjugates. Furthermore, as methionine sulfoxide is insensitive to ReACT, the probe was applied to selectively label reactive methionines for activity-based protein profiling, leading to the identification of hyperreactive residues in enolase that have redox-active functions in vivo. With methionine now a viable choice for chemoselective bioorthogonal tagging, the options for bioconjugation are wider than ever.