Genome mining and biosynthesis of kitacinnamycins as a STING activator
| Autor: | Chin-Yuan Chang, Ren-Xiang Tan, Bo Zhang, Jing Shi, Jiapeng Zhu, Cheng Li Liu, Wen Jie Guo, Rui Hua Jiao, Er Juan Zhao, Hui Ming Ge |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
chemistry.chemical_classification
Depsipeptide Glycosylation biology 010405 organic chemistry General Chemistry Bacterial genome size Computational biology 010402 general chemistry 01 natural sciences 0104 chemical sciences chemistry.chemical_compound Polyketide chemistry Biosynthesis Nonribosomal peptide Glycosyltransferase biology.protein Gene |
| Zdroj: | Chemical Science. 10:4839-4846 |
| ISSN: | 2041-6539 2041-6520 |
| Popis: | Cinnamoyl-containing nonribosomal peptides (CCNPs) are a small group of secondary metabolites with potent biological activities produced by actinobacteria. Two remarkable features in the biosynthesis of CCNPs include the nonribosomal peptide synthases (NRPSs) for assembly of the depsipeptide backbone and the type II polyketide synthases (PKSs) for N-terminal cinnamoyl moiety construction. Here, we present a genome mining approach targeting both NRPS and type II PKS for discovery of new CCNPs, which led to the identification of 51 putative CCNP gene clusters from public bacterial genome databases. After strain prioritization, a novel class of CCNP-type glycopeptides named kitacinnamycins, one of which showing potent activation ability towards the stimulator of interferon genes (STING) protein, was identified. Bioinformatic, genetic and biochemical analysis revealed the use of the NRPS assembly line to form the macrocyclic peptide backbone, followed by a P450 monooxygenase to generate terminal oxidized groups. A glycosyltransferase with relatively broad substrate specificity transfers sugars to the newly generated OH/COOH group. The protein crystallographic study further provided structural insights into this glycosylation. Our results not only demonstrated the feasibility of genome mining and strain prioritization for the discovery of new bioactive natural products but also disclosed the biosynthetic pathway for kitacinnamycins. |
| Databáze: | OpenAIRE |
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