Biosynthesis of Secondary Metabolites in Fungi

Fungal secondary metabolites comprise a vast array of bioactive compounds, including polyketides, non-ribosomal peptides and terpenoids, that are not required for primary growth but confer ecological advantages such as defence and competition. These compounds are typically encoded by discrete biosynthetic gene clusters, each harbouring genes for core enzymatic machinery—such as polyketide synthases and non-ribosomal peptide synthetases—alongside tailoring enzymes and pathway-specific regulators. Expression of these clusters is tightly regulated by environmental cues, developmental signals and global transcription factors, and many remain silent under standard laboratory conditions. Advances in genome sequencing have revealed hundreds of cryptic clusters across diverse fungal taxa, motivating genome-mining strategies and synthetic biology approaches to activate or reconstruct pathways. Subcellular compartmentalisation further influences flux through these biosynthetic routes, with pathway enzymes co-localising to specialised organelles to enhance efficiency and sequester intermediates. Collectively, understanding fungal secondary metabolism has profound implications for antibiotic discovery, agricultural pesticide development and industrial biotechnology.

Research from Nature Portfolio

Recent studies have identified and characterised the seven-gene cluster responsible for pleuromutilin biosynthesis in a basidiomycete, and successfully reconstituted it in Aspergillus oryzae, achieving over twenty-fold increases in antibiotic yield compared to the native host. Subsequent work employed rational heterologous expression in A. oryzae to delineate each enzymatic step by isolating and structurally elucidating pathway intermediates, and to generate semi-synthetic pleuromutilin derivatives with enhanced antibacterial potency. Together, these investigations demonstrate the power of transferring complex secondary metabolite pathways into genetically tractable fungal platforms to accelerate both mechanistic understanding and compound optimisation.

Biosynthesis of Secondary Metabolites in Fungi publication trend

The graph below shows the total number of articles in biosynthesis of secondary metabolites in fungi across all publications each year (not limited to Nature Index journals).

Technical terms

Secondary metabolite: A small bioactive molecule not essential for primary growth but conferring ecological or defensive functions.

Biosynthetic gene cluster: A contiguous set of genes encoding the enzymes and regulators required for synthesis of a specific secondary metabolite.

Polyketide synthase (PKS): A multifunctional enzyme complex that assembles polyketide backbones through sequential condensation of acyl-CoA substrates.

Non-ribosomal peptide synthetase (NRPS): A modular enzyme that catalyses the ribosome-independent assembly of peptide secondary metabolites from amino acid monomers.

Heterologous expression: The transfer and functional expression of a biosynthetic pathway in a non-native host organism to activate or enhance metabolite production.

Genome mining: The computational identification and analysis of biosynthetic gene clusters within genomic sequences to predict and exploit novel metabolites.

References

1. Comparative genomics reveals high biological diversity and specific adaptations in the industrially and medically important fungal genus Aspergillus. Genome Biology (2017).
2. Natural products from filamentous fungi and production by heterologous expression. Applied Microbiology and Biotechnology (2016).
3. Cellular compartmentalization of secondary metabolism. Frontiers in Microbiology (2015).
4. Fungal artificial chromosomes for mining of the fungal secondary metabolome. BMC Genomics (2015).
5. Heterologous expression reveals the biosynthesis of the antibiotic pleuromutilin and generates bioactive semi-synthetic derivatives. Nature Communications (2017).