Targeted Discovery of Unknown Eremophilane Sesquiterpenes Guided by the Characteristic Post-Modification Colocalization Strategy
Qinglin Zhang, Zian Wang, Huixue Ma, Chuanteng Ma, Fuhao Liu, Xingtao Ren, Qian Che, Tianjiao Zhu, Guojian Zhang, Wenxue Wang, Dehai LiAbstract
PR-toxin and Sporogen-AO1 have garnered widespread interest, and their structural divergence is attributed to two distinctive sets of tailoring enzymes. Despite recent elucidation of their respective biosynthetic pathways, these two distinctive tailoring cassettes can only operate independently within natural hosts. Based on the Characteristic Post-Modification Colocalization genome mining strategy, this study reports the first discovery of a new class of biosynthetic gene clusters with merged characteristic post-modifications. Furthermore, heterologous expression of pbe gene cluster, led to the production of seven new eremophilane-type sesquiterpenoids (1−7). Notably, compound 1 represents the first occurring eremophilane-type sesquiterpene bearing both 1,2-epoxy and 6,7-epoxy moieties. In bioassays, compounds 3 and 8 exhibited significant cytotoxicity against the K562 cell line, with IC50 values of 10.93 μM and 1.03 μM, respectively. Taken together, this research offers an innovative method for the directed discovery of natural products.