Genome mining and biosynthesis of kitacinnamycins as a STING activator.

摘要: 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 CCNPs include peptide synthases (NRPSs) for assembly depsipeptide backbone and type II polyketide (PKSs) N-terminal cinnamoyl moiety construction. Here, we present genome mining approach targeting both NRPS PKS discovery new CCNPs, which led to identification 51 putative CCNP gene clusters from public bacterial databases. After strain prioritization, novel class CCNP-type glycopeptides named kitacinnamycins, one showing activation ability towards stimulator interferon genes (STING) protein, was identified. Bioinformatic, genetic biochemical analysis revealed use line form macrocyclic backbone, followed P450 monooxygenase generate terminal oxidized groups. A glycosyltransferase relatively broad substrate specificity transfers sugars newly generated OH/COOH group. The protein crystallographic study further provided structural insights into this glycosylation. Our results not only demonstrated feasibility prioritization bioactive natural products but also disclosed biosynthetic pathway kitacinnamycins.