Chembiochem. 2026 Jun 15;27(11):e70416. doi: 10.1002/cbic.70416.
ABSTRACT
S-Adenosyl-L-methionine (SAM) is a central biological cofactor that supplied activated methyl groups and enables a broad-spectrum biochemical transformation. Beyond canonical SN2 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.
PMID:42298833 | DOI:10.1002/cbic.70416