title: Reprogramming the Biosynthesis of Cyclodepsipeptide Synthetases to Obtain New Enniatins and Beauvericins.
abstract: Non-ribosomal peptide synthetases are complex multimodular biosynthetic machines that assemble various important and medically relevant peptide antibiotics. An interesting subgroup comprises the cyclodepsipeptide synthetases from fungi synthesizing cyclohexa- and cyclo-octadepsipeptides with antibacterial, anthelmintic, insecticidal, and anticancer properties; some are marketed drugs. We exploit the modularity of these highly homologous synthetases by fusing the hydroxy-acid-activating module of PF1022 synthetase with the amino-acid-activating modules of enniatin and beauvericin synthetase, thus yielding novel hybrid synthetases. The artificial synthetases expressed in Escherichia coli and the fungus Aspergillus niger yielded new cyclodepsipeptides, thus paving the way for the exploration of these derivatives for their bioactivity.
authors.affiliation: Fachgebiet Biologische Chemie, Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623, Berlin, Germany.
authors.forename: Sophia
authors.initials: S
authors.lastname: Zobel
authors.affiliation: Fachgebiet Biologische Chemie, Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623, Berlin, Germany.|Fachgebiet Angewandte und Molekulare Mikrobiologie, Institut für Biotechnologie, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355, Berlin, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Boecker
authors.affiliation: Global Drug Discovery, Bayer Animal Health GmbH, Bayer HealthCare Animal Health, Monheim, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Kulke
authors.affiliation: Global Drug Discovery, Bayer Animal Health GmbH, Bayer HealthCare Animal Health, Monheim, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heimbach
authors.affiliation: Fachgebiet Angewandte und Molekulare Mikrobiologie, Institut für Biotechnologie, Technische Universität Berlin, Gustav-Meyer-Allee 25, 13355, Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Meyer
authors.affiliation: Fachgebiet Biologische Chemie, Institut für Chemie, Technische Universität Berlin, Strasse des 17. Juni 124, 10623, Berlin, Germany. roderich.suessmuth@tu-berlin.de.
authors.forename: Roderich D
authors.initials: RD
authors.lastname: Süssmuth
mesh_terms: D000818:Animals; D000871:Anthelmintics / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001234:Aspergillus niger / Q000235:genetics; D003001:Cloning, Molecular; D047630:Depsipeptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D004183:Dirofilaria immitis / Q000187:drug effects; D004184:Dirofilariasis / Q000188:drug therapy; D004926:Escherichia coli / Q000235:genetics; D005658:Fungi / Q000737:chemistry / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007218:Industrial Microbiology; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000871:Anthelmintics; D047630:Depsipeptides; D011993:Recombinant Fusion Proteins; C100264:enniatins; C004456:beauvericin; D010453:Peptide Synthases; C055861:beauvericin synthetase
keywords: biosynthesis; cyclodepsipeptides; enniatin; module exchange; non-ribosomal peptide synthetase; protein engineering