Structure of the epimerization domain of tyrocidine synthetase A

Tyrocidine, a macrocyclic decapeptide from Bacillus brevis, is nonribosomally assembled by a set of multimodular peptide synthetases, which condense two D‐amino acids and eight L‐amino acids to produce this membrane‐disturbing antibiotic. D‐Phenylalanine, the first amino acid incorporated into tyrocidine, is catalytically derived from enzyme‐bound L‐Phe by the C‐terminal epimerization (E) domain of tyrocidine synthetase A (TycA). The 1.5 Å resolution structure of the cofactor‐independent TycA E domain reveals an intimate relationship to the condensation (C) domains of peptide synthetases. In contrast to the latter, the TycA E domain uses an enlarged bridge region to plug the active‐site canyon from the acceptor side, whereas at the donor side a latch‐like floor loop is suitably extended to accommodate the αIII helix of the preceding peptide‐carrier domain. Additionally, E domains exclusively harbour a conserved glutamate residue, Glu882, that is opposite the active‐site residue His743. This active‐site topology implies Glu882 as a candidate acid–base catalyst, whereas His743 stabilizes in the protonated state a transient enolate intermediate of the L↔D isomerization.