Wolfgang M Müller

Publications (4)26.78 Total impact

• Article: Deuterium labeled peptides give insights into the directionality of class III lantibiotic synthetase LabKC.

  Bartlomiej Krawczyk, Paul Ensle, Wolfgang M Müller, Roderich D Süssmuth
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  ABSTRACT: The biosynthesis of a considerable number of ribosomally synthesized peptide antibiotics involves the modification of Ser and Thr residues of a precursor peptide. This post-translational processing is performed by one or multiple modifying enzymes encoded in the biosynthetic gene cluster. We present a deuterium-label based enzyme assay, utilizing a series of peptide substrates with α-deuterated Ser, for the determination of the dehydration order during the biosynthesis of class III lantibiotic labyrinthopeptin A2. Remarkably, the data show that, in contrast to other modifying enzymes of class I and II lantibiotics, LabKC has a C- to N-terminal processing mode. This surprising finding, which we consider relevant for the biosyntheses of other class III lantibiotics, underlines significant differences of this class of modifying enzymes compared to other investigated systems.
  Journal of the American Chemical Society 06/2012; 134(24):9922-5. · 9.91 Impact Factor
• Article: Leader peptide-directed processing of labyrinthopeptin A2 precursor peptide by the modifying enzyme LabKC.

  Wolfgang M Müller, Paul Ensle, Bartlomiej Krawczyk, Roderich D Süssmuth
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  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.
  Biochemistry 09/2011; 50(39):8362-73. · 3.42 Impact Factor
• Article: In‐vitro‐Biosynthese des Typ‐III‐Lantibiotikums Prä‐Labyrinthopeptin A2 unter C‐C‐Bindungsknüpfung als posttranslationaler Modifizierung

  Wolfgang M. Müller, Timo Schmiederer, Paul Ensle, Roderich D. Süssmuth
  Angewandte Chemie 02/2010; 122(13):2486 - 2490.
• Article: In vitro biosynthesis of the prepeptide of type-III lantibiotic labyrinthopeptin A2 including formation of a C-C bond as a post-translational modification.

  Wolfgang M Müller, Timo Schmiederer, Paul Ensle, Roderich D Süssmuth
  Angewandte Chemie International Edition 02/2010; 49(13):2436-40. · 13.45 Impact Factor