title: Biosynthesis of the antifungal haterumalide, oocydin A, in Serratia, and its regulation by quorum sensing, RpoS and Hfq.
abstract: Polyketides represent an important class of bioactive natural products with a broad range of biological activities. We identified recently a large trans-acyltransferase (AT) polyketide synthase gene cluster responsible for the biosynthesis of the antifungal, anti-oomycete and antitumor haterumalide, oocydin A (ooc). Using genome sequencing and comparative genomics, we show that the ooc gene cluster is widespread within biocontrol and phytopathogenic strains of the enterobacteria, Serratia and Dickeya. The analysis of in frame deletion mutants confirmed the role of a hydroxymethylglutaryl-coenzyme A synthase cassette, three flavin-dependent tailoring enzymes, a free-standing acyl carrier protein and two hypothetical proteins in oocydin A biosynthesis. The requirement of the three trans-acting AT domains for the biosynthesis of the macrolide was also demonstrated. Expression of the ooc gene cluster was shown to be positively regulated by an N-acyl-L-homoserine lactone-based quorum sensing system, but operating in a strain-dependent manner. At a post-transcriptional level, the RNA chaperone, Hfq, plays a key role in oocydin A biosynthesis. The Hfq-dependent regulation is partially mediated by the stationary phase sigma factor, RpoS, which was also shown to positively regulate the synthesis of the macrolide. Our results reveal differential regulation of the divergently transcribed ooc transcriptional units, highlighting the complexity of oocydin A production.
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Matilla
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Finian J
authors.initials: FJ
authors.lastname: Leeper
authors.affiliation: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QW, UK.
authors.forename: George P C
authors.initials: GP
authors.lastname: Salmond
mesh_terms: D054742:Acyl-Butyrolactones; D000935:Antifungal Agents / Q000378:metabolism*; D001426:Bacterial Proteins / Q000378:metabolism*; D001483:Base Sequence; D035001:Host Factor 1 Protein / Q000378:metabolism*; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D007783:Lactones / Q000378:metabolism*; D018942:Macrolides / Q000378:metabolism*; D005810:Multigene Family; D048630:Polyketide Synthases / Q000235:genetics / Q000378:metabolism; D053038:Quorum Sensing / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D012705:Serratia / Q000235:genetics / Q000378:metabolism*; D012808:Sigma Factor / Q000378:metabolism*
chemical_list: D054742:Acyl-Butyrolactones; D000935:Antifungal Agents; D001426:Bacterial Proteins; D035001:Host Factor 1 Protein; D007783:Lactones; D018942:Macrolides; D012808:Sigma Factor; C403892:oocydin A; C069567:sigma factor KatF protein, Bacteria; D048630:Polyketide Synthases; D006904:Hydroxymethylglutaryl-CoA Synthase