Genome mining and biosynthesis of kitacinnamycins as a STING activator

Jing Shi, Cheng Li Liu, Bo Zhang, Wen Jie Guo, Jiapeng Zhu, Chin-Yuan Chang, Er Juan Zhao, Rui Hua Jiao, Ren Xiang Tan*, Hui Ming Ge

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageAmerican English
Pages (from-to)4839-4846
Number of pages8
JournalChemical Science
Volume10
Issue number18
DOIs
StatePublished - 1 Jan 2019

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