Post-translational modification of ribosomally synthesized peptides by a radical SAM epimerase in Bacillus subtilis

Ribosomally synthesized peptides are built out of L- amino acids, whereas D- amino acids are generally the hallmark of non-ribosomal synthetic processes. Here we show that the model bacterium Bacillus subtilis is able to produce a novel type of ribosomally synthesized and post-translationally modified peptide that contains D- amino acids, and which we propose to call epipeptides. We demonstrate that a two [4Fe–4S]-cluster radical S -adenosyl- L- methionine (SAM) enzyme converts L- amino acids into their D- counterparts by catalysing C α -hydrogen-atom abstraction and using a critical cysteine residue as the hydrogen-atom donor. Unexpectedly, these D- amino acid residues proved to be essential for the activity of a peptide that induces the expression of LiaRS, a major component of the bacterial cell envelope stress-response system. Present in B. subtilis and in several members of the human microbiome, these epipeptides and radical SAM epimerases broaden the landscape of peptidyl structures accessible to living organisms. Radical SAM enzymes are versatile enzymes catalysing chemically challenging reactions. Now, a radical SAM enzyme that post-translationally modifies ribosomally synthesized peptides to contain D-amino acids has been discovered in Bacillus subtilis , and its mechanism has been deciphered. These peptides, called epipeptides, efficiently inhibit bacterial growth.