title: Hexaene derivatives of nystatin produced as a result of an induced rearrangement within the nysC polyketide synthase gene in S. noursei ATCC 11455.
abstract: Genetic manipulation of the polyketide synthase (PKS) gene nysC involved in the biosynthesis of the tetraene antifungal antibiotic nystatin yielded a recombinant strain producing hexaene nystatin derivatives. Analysis of one such compound, S48HX, by LC-MS/MS suggested that it comprises a 36-membered macrolactone ring completely decorated by the post-PKS modification enzymes. Further characterization by bioassay has shown that S48HX exhibits antifungal activity. Genetic analysis of the hexaene-producing mutant revealed an in-frame deletion within the nysC gene via recombination between two homologous ketoreductase domain-encoding sequences. Apparently, this event resulted in the elimination of one complete module from NysC PKS, subsequently leading to the production of the nystatin derivative with a contracted macrolactone ring. These results represent the first example of manipulation of a PKS gene for the biosynthesis of a polyene antibiotic.
authors.affiliation: Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway.
authors.forename: Trygve
authors.initials: T
authors.lastname: Brautaset
authors.forename: Per
authors.initials: P
authors.lastname: Bruheim
authors.forename: Håvard
authors.initials: H
authors.lastname: Sletta
authors.forename: Lars
authors.initials: L
authors.lastname: Hagen
authors.forename: Trond E
authors.initials: TE
authors.lastname: Ellingsen
authors.forename: Arne R
authors.initials: AR
authors.lastname: Strøm
authors.forename: Svein
authors.initials: S
authors.lastname: Valla
authors.forename: Sergey B
authors.initials: SB
authors.lastname: Zotchev
mesh_terms: D000935:Antifungal Agents / Q000096:biosynthesis*; D017353:Gene Deletion; D005798:Genes, Bacterial; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics*; D009761:Nystatin / Q000031:analogs & derivatives* / Q000096:biosynthesis*; D013302:Streptomyces / Q000201:enzymology / Q000235:genetics*
chemical_list: D000935:Antifungal Agents; D009097:Multienzyme Complexes; D009761:Nystatin