C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A.
Cell chemical biology
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Hong, H., Samborskyy, M., Zhou, Y., & Leadlay, P. (2019). C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A.. Cell chemical biology, 26 (4), 493-501.e5. https://doi.org/10.1016/j.chembiol.2018.12.004
Malayamycin A is an unusual bicyclic C-nucleoside, with interesting antiviral, antifungal and anticancer bioactivity. We report here the discovery and characterization of the biosynthetic pathway to malayamycin by using genome mining of near-identical clusters from both the known producer Streptomyces malaysiensis and from Streptomyces chromofuscus. The key precursor 5'-pseudouridine monophosphate (5'-Ψ-MP) is supplied chiefly through the action of MalD, a TruD-like pseudouridine synthase. In vitro assays showed that MalO is an enoylpyruvyltransferase acting almost exclusively on 5'-Ψ-MP rather than 5'-UMP, while in contrast the counterpart enzyme NikO in the nikkomycin pathway readily accepts either substrate. As a result, deletion of malD in S. chromofuscus coupled with introduction of the gene for NikO led to production of non-natural N-malayamycin, as well as malayamycin A. Conversely, cloning malO into the nikkomycin producer Streptomyces tendae in place of nikO diverted biosynthesis towards C-nucleoside formation.
Streptomyces, Intramolecular Transferases, Aminoglycosides, Nucleosides, Bacterial Proteins, Antifungal Agents, Genome, Bacterial, Multigene Family, Biosynthetic Pathways, Bridged Bicyclo Compounds, Heterocyclic
BBSRC Syngenta plc UK
BBSRC (via University of Warwick) (RCHGC3013)
External DOI: https://doi.org/10.1016/j.chembiol.2018.12.004
This record's URL: https://www.repository.cam.ac.uk/handle/1810/288469