Bacterial Biosynthetic Gene Clusters Encoding the Anti-cancer Haterumalide Class of Molecules BIOGENESIS OF THE BROAD SPECTRUM ANTIFUNGAL AND ANTI-OOMYCETE COMPOUND, OOCYDIN A

Haterumalides are halogenated macrolides with strong anti- tumor properties, making them attractive targets for chemical synthesis. Unfortunately, current synthetic routes to these mol- ecules are inefficient. The potent haterumalide, oocydin A, was previously identified from two plant-associated bacteria through its high bioactivity against plant pathogenic fungi and oomycetes. In this study, we describe oocydin A (ooc) biosyn- thetic gene clusters identified by genome sequencing, compara- tive genomics, and chemical analysis in four plant-associated enterobacteria of the Serratia and Dickeya genera. Disruption of the ooc gene cluster abolished oocydin A production and bioac- tivity against fungi and oomycetes. The ooc gene clusters span between 77 and 80 kb and encode five multimodular polyketide synthase (PKS) proteins, a hydroxymethylglutaryl-CoA syn- thase cassette and three flavin-dependent tailoring enzymes. The presence of two free-standing acyltransferase proteins clas- sifies the oocydin A gene cluster within the growing family of trans-AT PKSs. The amino acid sequences and organization of the PKS domains are consistent with the chemical predictions and functional peculiarities associated with trans-acyltrans- ferase PKS. Based on extensive in silico analysis of the gene clus- ter, we propose a biosynthetic model for the production of oocy- din A and, by extension, for other members of the haterumalide family of halogenated macrolides exhibiting anti-cancer, anti- fungal, and other interesting biological properties.

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