Lysine post-translational modifications (PTMs) play crucial roles in regulating protein structures, interactions, and cellular signaling. Precise study of PTM functions requires homogeneous proteins with modifications at defined sites; however, selective chemical modification is challenging because multiple lysines undergo similar chemistry yet exhibit variable reactivity depending on their local environments. Early chemical strategies exploited intrinsic reactivity differences, which are effective for exposed lysines but limited for low-reactivity or sterically hindered sites. In contrast, enzymes achieve high selectivity through substrate recognition and spatial organization. Inspired by this enzymatic principle, chemical approaches have been developed, including ligand-directed chemistry, proximity-enabled modification, and on-demand generation of highly reactive electrophiles. Recent advances in ligand-guided catalysis now enable regioselective and catalytic installation of biorelevant, authentic PTMs, providing a platform for programmable lysine modification and synthetic epigenetics.
Onoda et al. (Fri,) studied this question.