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Biosynthesis of the antifungal haterumalide, oocydin A, in Serratia, and its regulation by quorum sensing, RpoS and Hfq.


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Authors

Matilla, Miguel A 
Leeper, Finian J 
Salmond, George PC 

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.

Description

Keywords

Acyl-Butyrolactones, Antifungal Agents, Bacterial Proteins, Base Sequence, Host Factor 1 Protein, Hydroxymethylglutaryl-CoA Synthase, Lactones, Macrolides, Multigene Family, Polyketide Synthases, Quorum Sensing, Sequence Deletion, Serratia, Sigma Factor

Journal Title

Environ Microbiol

Conference Name

Journal ISSN

1462-2912
1462-2920

Volume Title

17

Publisher

Wiley
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/G000298/1)
Biotechnology and Biological Sciences Research Council (BB/E015581/1)
Biotechnology and Biological Sciences Research Council (BB/F009666/1)
European Commission (298003)
This research was supported by the EU Marie-Curie Intra-European Fellowship for Career Development (FP7-PEOPLE-2011-IEF) Grant No. 298003. The Salmond laboratory is supported by funding through the Biotechnology and Biological Sciences Research Council, BBSRC (UK). Work with plant pathogens was carried out under DEFRA Licence No. 50864/197900/1.