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DOI: 10.1055/s-0035-1556108
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.
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(3) Liu, X. et al. (2013) J Nat Prod 76, 685 – 693.
(4) Eustáquio, A. S. et al. (2014) Proc Natl Acad Sci U S A 111, E3376-E3385.
(5) Dirico, K. J. et al. (2014) Patent application WO 2014068443.