Discovery of C-Glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 by a Combined NMR-Based Metabolomics and Bioinformatics Workflow.
Discovery of C-Glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 by a Combined NMR-Based Metabolomics and Bioinformatics Workflow.
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DOI：
10.1021/acs.jnatprod.6b00478
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发表时间：
2017-02-24
影响因子：
5.1
通讯作者：
van Wezel GP
中科院分区：
文献类型：
--
作者：
Wu C;Du C;Ichinose K;Choi YH;van Wezel GP
对微生物基因组的挖掘揭示了放线菌对生物活性天然产物的生物合成潜力比预期的要大得多。生物合成基因簇的激活和相应代谢产物的鉴定已成为药物发现的焦点。本文应用核磁共振代谢组学和生物信息学相结合的方法，对链霉菌MBT 76中的新型C-糖基吡喃萘醌类化合物进行了鉴定，并阐明了其生物合成途径。在通过组成型表达其途径特异性激活剂激活II型聚酮合酶（PKS）的隐藏qin基因簇之后，生物信息学结合NMR分析促进了qinimycins A-C的色谱分离和结构解析（1-3）。qinimycins的有趣的结构特征，包括8-C-糖基化，5，14-环氧化，和13-羟基化，区分这些分子从模型pyranonaphthoquinones放线菌紫素，medermycin，和granaticin。另一个新奇在于在抗生素BE-54238 A和B的生物合成过程中脱氧氨基糖与吡喃萘醌骨架的不寻常融合（4，5）。秦尼霉素对革兰氏阳性菌的抗菌活性较弱。我们的工作显示了结合生物信息学，靶向激活隐藏基因簇和基于NMR的代谢谱作为发现具有独特骨架的微生物天然产物的有效管道的实用性。
Mining of microbial genomes has revealed that actinomycetes harbor far more biosynthetic potential for bioactive natural products than anticipated. Activation of (cryptic) biosynthetic gene clusters and identification of the corresponding metabolites has become a focal point for drug discovery. Here, we applied NMR-based metabolomics combined with bioinformatics to identify novel C-glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 and to elucidate the biosynthetic pathway. Following activation of the cryptic qin gene cluster for a type II polyketide synthase (PKS) by constitutive expression of its pathway-specific activator, bioinformatics coupled to NMR profiling facilitated the chromatographic isolation and structural elucidation of qinimycins A–C (1–3). The intriguing structural features of the qinimycins, including 8-C-glycosylation, 5,14-epoxidation, and 13-hydroxylation, distinguished these molecules from the model pyranonaphthoquinones actinorhodin, medermycin, and granaticin. Another novelty lies in the unusual fusion of a deoxyaminosugar to the pyranonaphthoquinone backbone during biosynthesis of the antibiotics BE-54238 A and B (4, 5). Qinimycins showed weak antimicrobial activity against Gram-positive bacteria. Our work shows the utility of combining bioinformatics, targeted activation of cryptic gene clusters, and NMR-based metabolic profiling as an effective pipeline for the discovery of microbial natural products with distinctive skeletons.