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C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A.

Accepted version
Peer-reviewed

Type

Article

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Authors

Hong, Hui 
Samborskyy, Markiyan 
Zhou, Yongjun 
Leadlay, Peter F 

Abstract

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 both from 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 toward C-nucleoside formation.

Description

Keywords

Streptomyces, TruD, biosynthetic engineering, enoylpyruvyltransferase, genome mining, nucleoside antibiotic, pseudouridine synthase, Aminoglycosides, Antifungal Agents, Bacterial Proteins, Biosynthetic Pathways, Bridged Bicyclo Compounds, Heterocyclic, Genome, Bacterial, Intramolecular Transferases, Multigene Family, Nucleosides, Streptomyces

Journal Title

Cell Chem Biol

Conference Name

Journal ISSN

2451-9456
2451-9448

Volume Title

26

Publisher

Elsevier BV
Sponsorship
BBSRC (via University of Warwick) (RCHGC3013)
BBSRC Syngenta plc UK