Reference - Detail
| RRC ID | 74394 |
|---|---|
| Author | Ueoka R, Sondermann P, Leopold-Messer S, Liu Y, Suo R, Bhushan A, Vadakumchery L, Greczmiel U, Yashiroda Y, Kimura H, Nishimura S, Hoshikawa Y, Yoshida M, Oxenius A, Matsunaga S, Williamson RT, Carreira EM, Piel J. |
| Title | Genome-based discovery and total synthesis of janustatins, potent cytotoxins from a plant-associated bacterium. |
| Journal | Nat Chem |
| Abstract |
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 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. |
| Volume | 14(10) |
| Pages | 1193-1201 |
| Published | 2022-10-1 |
| DOI | 10.1038/s41557-022-01020-0 |
| PII | 10.1038/s41557-022-01020-0 |
| PMID | 36064972 |
| PMC | PMC7613652 |
| MeSH | Bacteria / metabolism Biological Products* / chemistry Cytotoxins / metabolism Cytotoxins / pharmacology Polyketide Synthases / metabolism Polyketides* / metabolism |
| Altmetric score |
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 58 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | 3Y1 HeLa P388(RCB2776) |