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.

真菌是天然产物的多产生产者，这些化合物对药物、霉菌毒素和农用化学品产生了巨大的社会影响。尽管已有 1,000 多个真菌基因组和几十年的真菌化合物发现努力，但这些基因组编码的生物合成基因簇 (BGC) 和相关的化学空间尚未得到系统分析。在这里，我们提供真菌生物合成和化学空间的详细注释和分析，以实现基因组挖掘和真菌天然产物的发现。使用来自整个真菌界物种（例如，子囊菌门、担子菌门和非 Dikarya 分类群）的 1,037 个基因组，将 36,399 个预测的 BGC 组织成一个由 12,067 个基因簇家族 (GCF) 组成的网络。使用参考 BGC 锚定这些 GCF 启用了 2 的自动注释，026 个具有预测代谢物支架的 BGC。我们对真菌的化学成分进行了平行分析，将 15,213 种真​​菌化合物组织成 2,945 个分子家族 (MF)。真菌 GCF 的分类学景观在很大程度上是物种特异性的，尽管像木皮素 GCF 这样的精选家族存在于广阔的系统发育距离上，在 GCF 和 MF 中具有平行的多样化。我们将这些真菌数据集与一组 5,453 个细菌基因组及其 BGC 和 9,382 种细菌化合物进行比较，揭示了细菌和真菌生物合成逻辑和化学空间之间的巨大差异。这些基因组学和化学信息学分析揭示了真菌和细菌来源在很大程度上代表了不同的复合储库。随着解释菌株和带注释的 BGC 数量增加 > 10 倍，