Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium
2022; Nature Portfolio; Volume: 14; Issue: 10 Linguagem: Inglês
10.1038/s41557-022-01020-0
ISSN1755-4349
AutoresReiko Ueoka, Philipp Sondermann, Stefan Leopold‐Messer, Yizhou Liu, Rei Suo, Agneya Bhushan, Lida Vadakumchery, Ute Greczmiel, Yoko Yashiroda, Hiromi Kimura, Shinichi Nishimura, Yojiro Hoshikawa, Minoru Yoshida, Annette Oxenius, Shigeki Matsunaga, R. Thomas Williamson, Erick M. Carreira, Jörn Piel,
Tópico(s)Phytochemical compounds biological activities
ResumoHost-associated bacteria are increasingly being recognized as underexplored sources of bioactive natural products with unprecedented chemical scaffolds. A recently identified example is the plant-root-associated marine bacterium Gynuella sunshinyii of the chemically underexplored order Oceanospirillales. Its genome contains at least 22 biosynthetic gene clusters, suggesting a rich and mostly uncharacterized specialized metabolism. Here, in silico chemical prediction of a non-canonical polyketide synthase cluster has led to the discovery of janustatins, structurally unprecedented polyketide alkaloids with potent cytotoxicity that are produced in minute quantities. A combination of MS and two-dimensional NMR experiments, density functional theory calculations of 13C chemical shifts and semiquantitative interpretation of transverse rotating-frame Overhauser effect spectroscopy data were conducted to determine the relative configuration, which enabled the total synthesis of both enantiomers and assignment of the absolute configuration. Janustatins feature a previously unknown pyridodihydropyranone heterocycle and an unusual biological activity consisting of delayed, synchronized cell death at subnanomolar concentrations. In silico chemical prediction of a polyketide synthase gene cluster in the bacterium Gynuella sunshinyii has led to the discovery of a class of natural products called janustatins. The absolute configuration of the stereocentres in these compounds was determined by a combination of techniques including DFT calculations and 2D NMR experiments—and finally confirmed by total synthesis. Janustatins were found to cause delayed, synchronized cell death at subnanomolar concentrations.
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