Discovery, Structure Correction, and Biosynthesis of Actinopyrones, Cytotoxic Polyketides from the Deep-Sea Hydrothermal-Vent-Derived Streptomyces sp. SCSIO ZS0520

Abstract

Three new actinopyrone derivatives, actinopyrones E−G (1, 3, and 4), together with three known analogues, PM050463 (2), actinopyrone D (5), and PM050511 (6), were isolated from Streptomyces sp. SCSIO ZS0520 derived from a deepsea hydrothermal vent. Their structures, complete with absolute configurations, were elucidated using extensive spectroscopic analyses combined with Mosher's method, ECD calculations, and bioinformatics analyses. These findings corrected the absolute configurations of previously reported actinopyrone analogues 2, 5, and 6 at C-3, C-9, and C-10. Notably, compound 6 displayed notable cytotoxicity against six human cell lines with IC 50 values of 0.26−2.22 μM. A likely biosynthetic pathway and annotations of protein function are proposed on the basis of bioinformatics analyses. Genes coding for methyltransferase and glycosyltransferase tailoring chemistries needed to generate final structures were notably absent from the biosynthetic gene cluster. Taken together, these results enable further bioengineering of the actinopyrones and related congeners as potential antitumor agents.

Secondary Metabolites and Biosynthetic Gene Clusters Analysis of Deep-Sea Hydrothermal Vent-Derived Streptomyces sp. SCSIO ZS0520

“…This finding suggests that ZS0520 possesses the potential to produce at least 34 different types of NPs with distinct skeletons. Cluster 10 (atpn), responsible for actinopyrone biosynthesis, was proposed in our previous study [2]. Clusters 3, 32, and 34, related to salinomycin, N-acetyl-aminobacteriohopanetriol, and elaiophylin, were identified by comparisons with the literature [19,22,23].…”

“…ZS0520 mainly produces cytotoxic actinopyrones, as previously described [2]. By fermentation in a modified-RA medium, some other compounds were enriched.…”

“…The genome assembly and annotation methods were reported previously [2]. In brief, the genome DNA of ZS0520 was extracted using a Bacteria DNA Kit (OMEGA, Norcross, GA, USA).…”

“…SCSIO ZS0520, the deep-sea hydrothermal vent-derived Streptomyces, was isolated from sediment in the Okinawa trough at a depth of −1039 m. In our previous metabolite exploration, a cytotoxic polyketide PM050511 and several new analogs were isolated from Streptomyces sp. SCSIO ZS0520, indicating its actinopyrone production ability [2]. Nevertheless, Streptomyces usually contains 20-40 biosynthetic gene clusters (BGCs), suggesting that the metabolic capacity of ZS0520 could be further explored.…”

MGCEP 1.0: A Genetic-Engineered Marine-Derived Chassis Cell for a Scaled Heterologous Expression Platform of Microbial Bioactive Metabolites

“…Actinopyrone E (16) was detected in the culture broth of MGCEP 1.0/atpn by HPLC and mass spectrometry with low-level production compared to its wild type and other chassis strains such as S. albus J1047 and S. lividans SBT5 (Figures 3A, trace vi and S28). 51 The reason for the low success rate in the expression of the type I polyketide BGCs in the chassis cell MGCEP 1.0 is worth further investigating.…”