An interpreted atlas of biosynthetic gene clusters from 1,000 fungal genomes

Abstract

Fungi are prolific producers of natural products, compounds which have had a large societal impact as pharmaceuticals, mycotoxins, and agrochemicals. Despite the availability of over 1,000 fungal genomes and several decades of compound discovery efforts from fungi, the biosynthetic gene clusters (BGCs) encoded by these genomes and the associated chemical space have yet to be analyzed systematically. Here, we provide detailed annotation and analyses of fungal biosynthetic and chemical space to enable genome mining and discovery of fungal natural products. Using 1,037 genomes from species across the fungal kingdom (e.g., Ascomycota, Basidiomycota, and non-Dikarya taxa), 36,399 predicted BGCs were organized into a network of 12,067 gene cluster families (GCFs). Anchoring these GCFs with reference BGCs enabled automated annotation of 2,026 BGCs with predicted metabolite scaffolds. We performed parallel analyses of the chemical repertoire of fungi, organizing 15,213 fungal compounds into 2,945 molecular families (MFs). The taxonomic landscape of fungal GCFs is largely species specific, though select families such as the equisetin GCF are present across vast phylogenetic distances with parallel diversifications in the GCF and MF. We compare these fungal datasets with a set of 5,453 bacterial genomes and their BGCs and 9,382 bacterial compounds, revealing dramatic differences between bacterial and fungal biosynthetic logic and chemical space. These genomics and cheminformatics analyses reveal the large extent to which fungal and bacterial sources represent distinct compound reservoirs. With a >10-fold increase in the number of interpreted strains and annotated BGCs, this work better regularizes the biosynthetic potential of fungi for rational compound discovery.

Transcription Factor Repurposing Offers Insights into Evolution of Biosynthetic Gene Cluster Regulation

“…To gain insight into a possible PeXanC binding site and to gain perspective on the evolution of XanC in fungi, we identified homologous xan and cit BGCs using multigene BLASTN and BLASTP (see Materials and Methods for details). Because recent analysis of gene cluster families (GCFs) across all fungi ( 39 ) has suggested that the cit GCF is narrowly distributed within Eurotiales , we limited our search to the NCBI genome database within this group. In order to avoid possibly pseudogenized cluster variants that might confound our assessment of the relationship between xanC sequences and the presence of the xan and cit BGCs, we selected 16 species (11 Penicillium spp.…”

Presence, Mode of Action, and Application of Pathway Specific Transcription Factors in Aspergillus Biosynthetic Gene Clusters

“…SM = secondary metabolite, PSTF = pathway specific transcription factor, NRPS = nonribosomal peptide synthetase, HR-PKS = highly reducing polyketide synthase, NR-PKS = non-reducing polyketide synthase, TC = terpene cyclase. 1 No conserved domain means PSTF without conserved domain. 2 "x + x(+x)" means biosynthesis genes are not all located in a single cluster but in at least two chromosomal sites.…”

“…Secondary metabolites (SMs) in fungi, also known as natural products, are present and synthesized in ecologically diverse species [1]. In fungi, SMs can provide self-protection and act as mediators for communication with other organisms or as virulence factors during pathogenic interactions with plants and animals [2][3][4][5][6].…”

“…Over the last 90 years, medicinal properties of fungal SMs, such as penicillin, cyclosporin, and statins, were utilized for various health therapies [10][11][12]. However, thus far, only a small subset of fungal SMs is characterized, despite the realization that fungi contain 100,000 s to millions of SM biosynthetic gene clusters (BGCs) [1,4]. The growing interest in fungal SMs is to discover new drugs and to take control of their production.…”

Benefiting from big data in natural products: importance of preserving foundational skills and prioritizing data quality

“…For example, the COCONUT database has recently been leveraged to create a resource (called LOTUS) directly linking natural product chemical structures to freely available articles describing the characterization and biological evaluation of the compounds. 8 In another recent report, the Natural Products Atlas was queried by Robey et al 9 to collect data from 15 213 fungal metabolites. These compounds were organized into molecular families and used to annotate the fungal gene clusters from 1000 fungal genomes.…”