期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 60, 期 40, 页码 21679-21684出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.202106275
关键词
cardiovascular activities; isoxazole-benzimidazole hybrids; molecular networking analysis; myxadazoles; precursor-directed biosynthesis
资金
- National Key Research and Development Programs of China [2019YFA0905700, 2021YFC2101000, 2018YFA0900400, 2018YFA0901704]
- National Natural Science Foundation of China (NSFC) [81973215, 31900042, 31670076, 31471183]
- Excellent Youth Program of Shandong Natural Science Foundation [ZR2020YQ62]
- Qingdao Postdoctoral Application Research Project [62450070311089]
Myxadazoles are novel chimeric small molecules isolated from Myxococcus sp. SDU36, featuring a unique biosynthetic pathway and chemical structure. They exhibit potential effects on vasculogenesis promotion and antithrombotic activity.
There is a continuous need for novel microbial natural products to fill the drying-up drug development pipeline. Herein, we report myxadazoles from Myxococcus sp. SDU36, a family of novel chimeric small molecules that consist of N-ribityl 5,6-dimethylbenzimidazole and a linear fatty acid chain endowed with an isoxazole ring. The experiments of genome sequencing, gene insertion mutation, isotope labelling, and precursor feeding demonstrated that the fatty acid chain was encoded by a non-canonical PKS/NRPS gene cluster, whereas the origin of N-ribityl 5,6-dimethylbenzimidazole was related to the vitamin B-12 metabolism. The convergence of these two distinct biosynthetic pathways through a C-N coupling led to the unique chemical framework of myxadazoles, which is an unprecedented hybridization mode in the paradigm of natural products. Myxadazoles exhibited potent vasculogenesis promotion effect and moderate antithrombotic activity, underscoring their potential usage for the treatment of cardiovascular diseases.
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