C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A
C-Nucleoside Formation in the Biosynthesis of the Antifungal Malayamycin A
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DOI：
10.1016/j.chembiol.2018.12.004
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发表时间：
2019-04-18
影响因子：
8.6
通讯作者：
Leadlay, Peter F.
中科院分区：
文献类型：
--
作者：
Hong, Hui;Samborskyy, Markiyan;Leadlay, Peter F.
马来霉素A是一种不常见的双环C-核苷，具有抗病毒、抗真菌和抗癌的生物活性。我们在这里报告的发现和表征的生物合成途径，马来霉素通过使用基因组挖掘几乎相同的集群都从已知的生产商链霉菌马来西亚和从链霉菌chromofuscus。关键前体5 '-假尿苷一磷酸（5'-Psi-MP）主要通过MaID（一种TruD样假尿苷合酶）的作用提供。体外试验表明，MalO是一种烯酰基乙酰基转移酶，几乎只作用于5 '-Psi-MP而不是5'-UMP，而相反，尼可霉素途径中的对应酶NikO容易接受任一底物。因此，在S. chromofuscus与NikO基因的引入相结合导致非天然N-马来霉素以及马来霉素A的产生。相反，将malO克隆到尼可霉素生产菌Streptomyces tendae中代替nikO使生物合成转向C-核苷形成。
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'-Psi-MP) is supplied chiefly through the action of MaID, a TruD-like pseudouridine synthase. In vitro assays showed that MalO is an enoylpyruvyltransferase acting almost exclusively on 5'-Psi-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 maID 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.