Spliceostatin biosynthesis in Burkholderia spp.

Spliceostatins are a suite of bacterial natural products that have been shown to target the spliceosome, an emerging mode of action in cancer therapy1. Spliceostatin biosynthesis in Burkholderia species is catalyzed by a hybrid nonribosomal peptide synthetase-polyketide synthase system of the trans-acyl transferase type2, 3. In this presentation, genetic and biochemical evidence for hemiketal biosynthesis via oxidative decarboxylation – rather than the previously hypothesized Baeyer-Villiger oxidation – will be described4. In addition, roles for a cytochrome P450 and a flavin-dependent monooxygenase are proposed based on genetic studies. Understanding late steps in spliceostatin biosynthesis was instrumental to achieve gram-scale production and nearly single-component fermentation of a stable analog (thailanstatin A), which has enabled pre-clinical development of this class of natural products as chemotherapy5.