P86: Biosynthetic studies of NRPS-derived lipopeptides from marine bacteria

Many nonribosomal peptides and polyketides are derived from a strictly linear multi-enzymatic assembly line biosynthetic pathway. The “sequence” of the product molecule often directly correlates to each enzymatic module of the producing megasynthase and can enable the prediction of the chemical structure from gene sequence. However, this straightforward approach is not ubiquitous and departures from the rule provide an opportunity to expand our understanding of biosynthetic processes. This presentation will focus on the highly non-canonical hybrid NRPS/PKS biosynthesis of a family of lipopeptides of bacterial origin. The thalassospiramides are a group of potent calpain 1 protease inhibiting peptides produced by several different strains of marine bacteria (Thalassospira and Tistrella spp.). A single gene cluster is responsible for production of this large library of compounds where structural diversity within the family is generated by a fusion of several unusual mechanisms. Peptides of differing length and amino acid composition are generated by a combination of substrate channeling, in trans amino acid activation and iteration/skipping of multiple modules within the megasynthase. This system provides an excellent opportunity to explore several unusual facets of biosynthetic dogma and the presentation will describe our progress toward elucidating this and other fascinating pathways.