Covering: up to July 2020 Fungal metabolites with diverse and novel scaffolds can be assembled from well-known biosynthetic precursors through various mechanisms. Recent examples of novel alkaloids (e.g., cytochalasans and diketopiperazine derivatives), terpenes (e.g., sesterterpenes and diterpenes) and polyketides produced by fungi are presented through case studies. We show that large-scale culture is a complementary and practical method for genome mining and OSMAC approaches to discover natural products of unprecedented skeletal classes from fungi. We also summarize the discovery strategies and challenges for characterizing these compounds.

Fungal bifunctional terpene synthase PstA catalyzes the formation of 5/15cis-fused ring system.

The cotylenin biosynthetic gene cluster was identified, and the total biosynthesis of several natural diterpene glycosides, including cotylenin C, F, I, and E, was achieved. Their stabilizing activity on 14-3-3 PPIs was demonstrated.

Irpex lacteus is an edible and medicinal macrofungus with significant biological activity and broad pharmaceutical prospects that has received increasing attention in recent years. Although it is an important resource for macrofungi, knowledge of it remains limited. In this study, we sequenced, de novo assembled, and annotated the whole genome of I. lacteus using a PacBio Sequel II sequencer. The assembled 41.83 Mb genome contains 13,135 predicted protein-coding genes, 83.44% of which have searchable sequence similarity to other genes available in public databases. Using genome-based bioinformatics analysis, we identified 556 enzymes involved in carbohydrate metabolism and 103 cytochrome P450 proteins. Genome annotation revealed genes for key enzymes responsible for the biosynthesis of secondary metabolites, such as terpenoids and polyketides. Among them, we identified 14 terpene synthases, 8 NRPS-like enzymes, and 4 polyketide synthases (PKS), as well as 2 clusters of biosynthetic genes presumably related to terpene synthesis in I. lacteus. Gene family analysis revealed that the MYB transcription factor gene family plays an important role in the growth and development of I. lacteus. This study further enriches the genomic content of I. lacteus, provides genomic information for further research on the molecular mechanism of I. lacteus, and promotes the development of I. lacteus in the fields of drug research and functional food production.

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. Graphical Abstract