IRON ACQUISITION IN PLAGUE - MODULAR LOGIC IN ENZYMATIC BIOGENESIS OFYERSINIABACTIN BY YERSINIA-PESTIS

Background: Virulence in the pathogenic bacterium Yersinia pestis, cau sative agent of bubonic plague, has been correlated with the biosynthe sis and transport of an iron-chelating siderophore, yersiniabactin, wh ich is induced under iron-starvation conditions. Initial DNA sequencin g suggested that this system is highly conserved among the pathogenic Yersinia. Yersiniabactin contains a phenolic group and three five-memb ered thiazole heterocycles that serve as iron ligands. Results: The en tire Y. pestis yersiniabactin region has been sequenced. Sequence anal ysis of yersiniabactin biosynthetic regions (irp2-ybtE and ybtS) revea ls a strategy for siderophore production using a mixed polyketide synt hase/ nonribosomal peptide synthetase complex formed between HMWP1 and HMWP2 (encoded by irp1 and irp2). The complex contains 16 domains, fi ve of them variants of phosphopantetheine-modified peptidyl carrier pr otein or acyl carrier protein domains. HMWP1 and HMWP2 also contain me thyltransferase and heterocyclization domains. Mutating ybtS revealed that this gene encodes a protein essential for yersiniabactin synthesi s. Conclusions: The HMWP1 and HMWP2 domain organization suggests that the yersiniabactin siderophore is assembled in a modular fashion; in w hich a series of covalent intermediates are passed from the amino term inus of HMWP2 to the carboxyl terminus of HMWP1. Biosynthetic labeling studies indicate that the three yersiniabactin methyl moieties are do nated by S-adenosylmethionine and that the linker between the thiazoli ne and thiazolidine rings is derived from malonyl-CoA. The salicylate moiety is probably synthesized using the aromatic amino-acid biosynthe tic pathway, the final step of which converts chorismate to salicylate . YbtS might be necessary for converting chorismate to salicylate.