NMR-Metabolomic Profiling and Genome Mining Drive the Discovery of Cyclic Decapeptides from a Marine <i>Streptomyces</i>
Huiming Huang, Liangguang Yue, Fayu Deng, Xiaoyu Wang, Ning Wang, Chen Hu, Huayue Li
Abstract
The integration of NMR-metabolomic and genomic analyses can provide enhanced identification of structural properties as well as key biosynthetic information, thus achieving the targeted discovery of new natural products. For this purpose, NMR-based metabolomic profiling of the marine-derived Streptomyces sp. S063 (CGMCC 14582) was performed, by which N -methylated peptides possessing unusual negative 1 H NMR chemical shift values were tracked. Meanwhile, genome mining of this strain revealed the presence of an unknown NRPS gene cluster ( len ) with piperazic-acid-encoding genes ( lenE and lenF ). Under the guidance of the combined information, two cyclic decapeptides, lenziamides D1 ( 1 ) and B1 ( 2 ), were isolated from Streptomyces sp. S063, which contains piperazic acids with negative 1 H NMR values. The structures of 1 and 2 were determined by extensive spectroscopic analysis combined with Marfey’s method and ECD calculations. Furthermore, we provided a detailed model of lenziamide ( 1 and 2 ) biosynthesis in Streptomyces sp. S063. In the cytotoxicity evaluation, 1 and 2 showed moderate growth inhibition against the human cancer cells HEL, H1975, H1299, and drug-resistant A549–taxol with IC 50 values of 8–24 μM.