Uncovering a novel biosynthetic gene cluster for sordarin through genome mining in the fungus Talaromyces adpressus

To explore the chemical and biological diversities of diterpenoids from the fungus Talaromyces adpressus, a previously unknown biosynthetic gene cluster (BGC, tdn) for sordarin (a well-known fungal antibiotics) was discovered by leveraging the genome mining method. Heterologous expressions of key genes of tdn in Aspergillus oryzae, led to the determination of one new diterpenoid, cycloaraneosene-9-ol-8-one (4), and three known diterpenoids, cycloaraneosene (1), cycloaraneosene-9-ol (2), cycloaraneosene-8,9-diol (3). The structures of 1-4 was elucidated well via detailed analysis of 1D and 2D NMR, GCMS, HRESIMS, IR data, and comparison with reported data. Structurally, compounds 1-4 were belonging to fusicoccane diterpenoids with a classical tricyclic 5/8/5 ring system, which are participated in the biosynthesis of sordarin. Compound 4 maybe a key precursor for a Baeyer-Villiger like reaction with C8-C9 bond cleavage in the biosynthetic pathway of sordarin. Moreover, all isolates were evaluated for their bioactivities, compounds 3, and 4 exhibited inhibitory activities against the human cancer cell lines with IC₅₀ values ranging from 7.8 to 32.4 µM. 3 and 4 promote cell apoptosis of HCT-116 and HepG2 cells, and suppress cell migration of HepG2 cells. As well, 3 and 4 also decrease gene expression of cell proliferation related molecules BCL-2 and cyclin D1, while increase expression of cell apoptosis related gene BAX. Targets predication and molecular docking indicate that compound 4 exhibits stronger affinity for DBL, suggesting its excellent binding potential. This finding will be enriched the structures and bioactivities of diterpenoids with a tricyclic 5/8/5 ring system, most importantly, will provide new strategies for the synthetic biological research of sordarins.