title: Leader peptide-directed processing of labyrinthopeptin A2 precursor peptide by the modifying enzyme LabKC.
abstract: Lantibiotics are peptide antibiotics, realizing their unique secondary structure by posttranslational modifications, the most important one being the formation of the characteristic amino acid lanthionine. Like other ribosomal peptide antibiotics, they are synthesized with an N-terminal leader peptide important for posttranslational processing by modifying enzymes; after peptide maturation, the leader peptide is proteolytically cleaved off. Numerous studies of the leader peptides of class I and II lantibiotics already showed their crucial role in recognition, self-immunity, and extracellular transport. The recently described labyrinthopeptins, members of the family of class III lantibiotics, exhibit the characteristic novel amino acid labionin, which was revealed by elucidation of the structure of labyrinthopeptin A2. The assembly of the labionin motif in the linear peptide chain is mediated by the lyase-kinase-cyclase-type enzyme LabKC through a serine side chain phosphorylation with GTP, elimination of the phosphate group, and a subsequent 2-fold Michael-type addition cyclization. In this work, we systematically investigated for the first time the importance of the leader peptide in the processing of class III lantibiotics using the example of the labyrinthopeptin A2 precursor peptide. In vitro studies with synthetic leader peptide analogues revealed that a conserved N-terminal hydrophobic patch on a putative helical structure is required for the proper peptide processing by the modifying enzyme LabKC. On the other hand, studies showed that the C-terminal part of the leader peptide serves as a spacer between the binding site and active sites for phosphorylation and elimination, thus restricting the number of hydroxy amino acid side chains that could undergo dehydration. Finally, a model for the peptide recognition and processing by the LabKC has been postulated.
authors: Fakultät II-Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623 Berlin, Germany.
authors: Wolfgang M
authors: WM
authors: Müller
authors: Paul
authors: P
authors: Ensle
authors: Bartlomiej
authors: B
authors: Krawczyk
authors: Roderich D
authors: RD
authors: Süssmuth
mesh_terms: D020816:Amino Acid Motifs / Q000502:physiology; D000595:Amino Acid Sequence; D001430:Bacteriocins / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D009097:Multienzyme Complexes / Q000378:metabolism*; D019761:Phosphorus-Oxygen Lyases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021382:Protein Sorting Signals / Q000235:genetics / Q000502:physiology*
chemical_list: D001430:Bacteriocins; D009097:Multienzyme Complexes; D021382:Protein Sorting Signals; C550284:labyrinthopeptin A2; D017346:Protein Serine-Threonine Kinases; D019761:Phosphorus-Oxygen Lyases