Harnessing the Versatility of SAM‐Dependent Enzymes: From Mechanism to Application

2 methyl transfer, SAM-dependent enzymes could initiate radical-mediated chemistry via reductive SAM cleavage, enabling versatile reactions from methyl transfer to alkylation, isomerization, and decarboxylation. Despite their extraordinary catalytic plasticity and potential for sustainable industrial synthesis, SAM-dependent enzymes are often limited by insufficient activity, stability, and substrate scope, necessitating further engineering. In this review, we summarize SAM-dependent enzymes into methylation and nonmethylation catalytic systems, and systematically summarize recent protein engineering efforts aimed at enhancing activity, selectivity, and stability. Together, these advances establish a unified framework for unlocking the full catalytic potential of SAM-dependent enzymes, paving the way for their integration as versatile and sustainable biocatalysts in modern chemical synthesis.