title: Structure of the epimerization domain of tyrocidine synthetase A.
abstract: 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.
authors.affiliation: Biomedical Research Centre/FB15, Philipps Universität, Hans-Meerwein-Strasse 4, 35032 Marburg, Germany.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Samel
authors.affiliation: Computational Chemistry, Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Czodrowski
authors.affiliation: Biomedical Research Centre/FB15, Philipps Universität, Hans-Meerwein-Strasse 4, 35032 Marburg, Germany.
authors.forename: Lars-Oliver
authors.initials: LO
authors.lastname: Essen
mesh_terms: D001407:Bacillus / Q000201:enzymology; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D018698:Glutamic Acid / Q000737:chemistry; D008958:Models, Molecular; D010453:Peptide Synthases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D018698:Glutamic Acid; D010453:Peptide Synthases; C035180:tyrocidine synthetase
keywords: cofactor-independent epimerization; enzymology; nonribosomal peptide synthesis; tyrocidine antibiotics