title: Discovery of C-Glycosylpyranonaphthoquinones in Streptomyces sp. MBT76 by a Combined NMR-Based Metabolomics and Bioinformatics Workflow.
abstract: 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.
authors.affiliation: Molecular Biotechnology, Institute of Biology, Leiden University , Sylviusweg 72, 2333 BE Leiden, The Netherlands.|Natural Products Laboratory, Institute of Biology, Leiden University , Sylviusweg 72 2333 BE Leiden, The Netherlands.
authors.forename: Changsheng
authors.initials: C
authors.lastname: Wu
authors.affiliation: Molecular Biotechnology, Institute of Biology, Leiden University , Sylviusweg 72, 2333 BE Leiden, The Netherlands.
authors.forename: Chao
authors.initials: C
authors.lastname: Du
authors.affiliation: Research Institute of Pharmaceutical Sciences, Musashino University , Shinmachi, Nishitokyo-shi, Tokyo 202-8585, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ichinose
authors.affiliation: Natural Products Laboratory, Institute of Biology, Leiden University , Sylviusweg 72 2333 BE Leiden, The Netherlands.
authors.forename: Young Hae
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Molecular Biotechnology, Institute of Biology, Leiden University , Sylviusweg 72, 2333 BE Leiden, The Netherlands.
authors.forename: Gilles P
authors.identifier: 0000-0003-0341-1561
authors.initials: GP
authors.lastname: van Wezel
mesh_terms: D039903:Actinobacteria / Q000737:chemistry*; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D001412:Bacillus subtilis / Q000187:drug effects; D019295:Computational Biology; D004926:Escherichia coli / Q000187:drug effects; D006027:Glycosides / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D055432:Metabolomics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry* / Q000302:isolation & purification*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D011763:Pyrrolizidine Alkaloids / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects; D013302:Streptomyces / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; C406045:BE 54238B; D006027:Glycosides; D009285:Naphthoquinones; D011763:Pyrrolizidine Alkaloids; C406044:BE 54238A