期刊
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
卷 58, 期 33, 页码 11534-11540出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201906891
关键词
cyclodipeptides; biosynthesis; cytochrome P450; guaninyl transferase; natural products
资金
- DFG [INST 160/620-1, 201608310118]
- China Scholarship Council
Mining microbial genomes including those of Streptomyces reveals the presence of a large number of biosynthetic gene clusters. Unraveling this genetic potential has proved to be a useful approach for novel compound discovery. Here, we report the heterologous expression of two similar P450-associated cyclodipeptide synthase-containing gene clusters in Streptomyces coelicolor and identification of eight rare and novel natural products, the C3-guaninyl indole alkaloids guanitrypmycins. Expression of different gene combinations proved that the cyclodipeptide synthases assemble cyclo-l-Trp-l-Phe and cyclo-l-Trp-l-Tyr, which are consecutively and regiospecifically modified by cyclodipeptide oxidases, cytochrome P450 enzymes, and N-methyltransferases. In vivo and in vitro results proved that the P450 enzymes function as key biocatalysts and catalyze the regio- and stereospecific 3 alpha-guaninylation at the indole ring of the tryptophanyl moiety. Isotope-exchange experiments provided evidence for the non-enzymatic epimerization of the biosynthetic pathway products via keto-enol tautomerism. This post-pathway modification during cultivation further increases the structural diversity of guanitrypmycins.
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