Issue 18, 2019

Genome mining and biosynthesis of kitacinnamycins as a STING activator


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.

Graphical abstract: Genome mining and biosynthesis of kitacinnamycins as a STING activator

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Article information

Article type
Edge Article
17 Feb 2019
01 Apr 2019
First published
02 Apr 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 4839-4846

Genome mining and biosynthesis of kitacinnamycins as a STING activator

J. Shi, C. L. Liu, B. Zhang, W. J. Guo, J. Zhu, C. Chang, E. J. Zhao, R. H. Jiao, R. X. Tan and H. M. Ge, Chem. Sci., 2019, 10, 4839 DOI: 10.1039/C9SC00815B

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