Catalytic promiscuity of a bacterial α‐ N ‐methyltransferase

The posttranslational methylation of N‐terminal α‐amino groups (α‐N‐methylation) is a ubiquitous reaction found in all domains of life. Although this modification usually occurs on protein substrates, recent studies have shown that it also takes place on ribosomally synthesized natural products. Here we report an investigation of the bacterial α‐ N ‐methyltransferase CypM involved in the biosynthesis of the peptide antibiotic cypemycin. We demonstrate that CypM has low substrate selectivity and methylates a variety of oligopeptides, cyclic peptides such as nisin and haloduracin, and the ε‐amino group of lysine. Hence it may have potential for enzyme engineering and combinatorial biosynthesis. Bayesian phylogenetic inference of bacterial α‐ N ‐methyltransferases suggests that they have not evolved as a specific group based on the chemical transformations they catalyze, but that they have been acquired from various other methyltransferase classes during evolution.