Genome mining and biosynthesis of kitacinnamycins as a STING activator

Abstract

Genome mining targeting unique type II PKS and NRPS led to the identification of a novel class of glycopeptides named kitacinnamycins.

An Unusual Type II Polyketide Synthase System Involved in Cinnamoyl Lipid Biosynthesis

“…Cinnamoyl lipid (CL) containing compounds, featuring with an ortho ‐substituted cinnamoyl group, constitute a small family of natural products. Up to now, only a handful of CL containing compounds have been reported, such as youssoufenes ( 1 – 5 ), [1] serpentene ( 6 ), [2] diacidene, [3] lahorenoic acids, [4] and cinnamoyl‐containing nonribosomal peptides (CCNPs) (kitacinnamycins, [5] skyllamycins, [6] et al.) (Figures 1 A, S1).…”

“…(Figures 1 A, S1). Notably, CL containing compounds display a broad range of physiological activities, including but not limited to antiangiogenic, [7] antitumor, [5] antibacterial, [1] antifungal, [8] antituberculosis, [9, 10] and enzyme inhibitor [11, 12] . For example, atratumycin displays potent antituberculosis activity, [10] skyllamycin A is a potent inhibitor of the platelet‐derived growth factor (PDGF) signaling pathway, [6] and serpentemycin A possesses a strong inhibitory activity against glycosyltransferase [11]…”

“…The CL moiety was proposed to be assembled by a repeating cycle of condensation, reduction, dehydration, isomerization and then cyclization, to give the required product (Figure 1 B). Identification of the biosynthetic gene clusters (BGCs) of CLs and CCNPs indicated that the CL moiety is possibly derived from a type II polyketide synthase (PKS) system [1, 5, 6, 9, 10, 13, 14] . However, unlike the type II aromatic, [15] highly reducing (HR), [16] and acyl polyene (APE) [17] PKSs, CL PKSs not only harbor acyl carrier protein (ACP), ketosynthase (KS), ketoreductase (KR), and dehydratase (DH) (absent in some cases [9] ) domains, but also an isomerase (ISO).…”

An Unusual Type II Polyketide Synthase System Involved in Cinnamoyl Lipid Biosynthesis

“…Cinnamoyl lipid (CL) containing compounds, featuring with an ortho-substituted cinnamoyl group, constitute a small family of natural products. Up to now, only a handful of CL containing compounds have been reported, such as youssoufenes (1-5), [1] serpentene (6), [2] diacidene, [3] lahorenoic acids, [4] and cinnamoyl-containing nonribosomal peptides (CCNPs) (kitacinnamycins, [5] skyllamycins, [6] et al) (Figures 1 A, S1). Notably, CL containing compounds display a broad range of physiological activities, including but not limited to antiangiogenic, [7] antitumor, [5] antibacterial, [1] antifungal, [8] antituberculosis, [9,10] and enzyme inhibitor.…”

Discovery of a Cryptic Depsipeptide from Streptomyces ghanaensis via MALDI‐MS‐Guided High‐Throughput Elicitor Screening

“…Cinnapeptin is a novel cyclic depsipeptide. It is similar to the depsipeptides skyllamycin, kitacinnamycin, and atratumycin; [23–25] the sequence in the macrocycle of 5 is unique as is the appearance of several non‐canonical amino acids. Among all NRPs reported, the 2‐MeCin group has only been observed in atratumycin thus far [24] …”