期刊
NATURE CHEMISTRY
卷 14, 期 10, 页码 1193-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41557-022-01020-0
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资金
- European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme [742739]
- Gordon and Betty Moore Foundation [9204]
- Swiss National Science Foundation [407240_167051, NRP72]
- Japan Society for the Promotion of Science (JSPS) [17H06411, 19H05640]
- Swiss National Science Foundation (SNF) [407240_167051] Funding Source: Swiss National Science Foundation (SNF)
Host-associated bacteria are valuable sources of bioactive natural products. A new bacterium called Gynuella sunshinyii has been discovered, which contains multiple biosynthetic gene clusters and has the potential for specialized metabolism. It also produces a unique polyketide alkaloid called janustatins, which exhibit potent cytotoxicity.
Host-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 C-13 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.
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