title: New Simocyclinones: Surprising Evolutionary and Biosynthetic Insights.
abstract: Simocyclinone D8 (1, SD8) has attracted attention due to its highly complex hybrid structure and the unusual way it inhibits bacterial DNA gyrase by preventing DNA binding to the enzyme. Although a hypothesis explaining simocyclinone biosynthesis has been previously proposed, little was proven in vivo due to the genetic inaccessibility of the producer strain. Herein, we report discovery of three new D-type simocyclinones (D9, D10, and D11) produced by Kitasatospora sp. and Streptomyces sp. NRRL B-24484, as well as the identification and annotation of their biosynthetic gene clusters. Unexpectedly, the arrangement of the newly discovered biosynthetic gene clusters is starkly different from the previously published one, despite the nearly identical structures of D8 and D9 simocyclinones. The gene inactivation and expression studies have disproven the role of a modular polyketide synthase (PKS) system in the assembly of the linear dicarboxylic acid. Instead, the new stand-alone ketosynthase genes were shown to be involved in the biosynthesis of the tetraene chain. Additionally, we identified the gene responsible for the conversion of simocyclinone D9 (2, SD9) into D8.
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus , Building C2.3, 66123 Saarbrücken, Germany.
authors.forename: Oksana
authors.initials: O
authors.lastname: Bilyk
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus , Building C2.3, 66123 Saarbrücken, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Brötz
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus , Building C2.3, 66123 Saarbrücken, Germany.
authors.forename: Bogdan
authors.initials: B
authors.lastname: Tokovenko
authors.affiliation: University of Freiburg , Institute for Pharmaceutical Sciences, Department for Pharmaceutical Biology and Biotechnology, Stefan-Meier-Straße 14, 79104 Freiburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bechthold
authors.affiliation: University of Siegen , Faculty 4, Organic Chemistry 2, Adolf-Reichwein-Straße 2, 57068 Siegen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Paululat
authors.affiliation: Helmholtz-Institute for Pharmaceutical Research Saarland, Saarland University Campus , Building C2.3, 66123 Saarbrücken, Germany.|Universität des Saarlandes , Pharmazeutische Biotechnologie, Building C2.3, 66123 Saarbrücken, Germany.
authors.forename: Andriy
authors.initials: A
authors.lastname: Luzhetskyy
mesh_terms: D001551:Benz(a)Anthracenes / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000737:chemistry*; D019143:Evolution, Molecular; D006027:Glycosides / Q000096:biosynthesis* / Q000737:chemistry* / Q000235:genetics; D015394:Molecular Structure; D005810:Multigene Family / Q000235:genetics; D017422:Sequence Analysis, DNA; D013302:Streptomyces / Q000145:classification / Q000235:genetics / Q000378:metabolism*
chemical_list: D001551:Benz(a)Anthracenes; D003374:Coumarins; D006027:Glycosides