Haterumalides are halogenated macrolides with strong antitumor properties, making them attractive targets for chemical synthesis. Unfortunately, current synthetic routes to these molecules 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) biosynthetic gene clusters identified by genome sequencing, comparative 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 bioactivity against fungi and oomycetes. The ooc gene clusters span between 77- and 80-kb and encode five multimodular polyketide synthase (PKS) proteins, a hydroxy-methylglutaryl-CoA synthase cassette and three flavin-dependent tailoring enzymes. The presence of two free-standing acyltransferase (AT) proteins classifies the oocydin A gene cluster within the growing family of trans-AT PKSs. The amino acid sequences and organization of the PKS domains is consistent with the chemical predictions and functional peculiarities associated with trans-AT PKS. Based on extensive in silico analysis of the gene cluster, we propose a biosynthetic model for the production of oocydin A, and by extension, for other members of the haterumalide family of halogenated macrolides exhibiting anti-cancer, antifungal and other interesting biological properties.
Department of Chemistry
University of Cambridge