Planta Med 2015; 81 - IL11
DOI: 10.1055/s-0035-1556108

Spliceostatin biosynthesis in Burkholderia spp.

AS Eustáquio 1, 2, JE Janso 1, AS Ratnayake 1, LP Chang 1, CJ O'Donnell 1, FE Koehn 1
  • 1Natural Products Laboratory, Worldwide Medicinal Chemistry, Pfizer Worldwide Research and Development, Groton, CT 06340, USA
  • 2Currently at: Department of Biology, University of Bergen, Norway

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.

References

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(2) Zhang, F. et al. (2011) J Am Chem Soc 133, 2452 – 2462.

(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.