Biosynthesis and Biological Activity of Fungal Secondary Metabolites

Fungal secondary metabolites encompass a chemically diverse array of small molecules, including polyketides, non-ribosomal peptides and terpenoids, which are often assembled by dedicated biosynthetic gene clusters (BGCs). These clusters encode large multimodular enzymes such as polyketide synthases (PKSs) and non-ribosomal peptide synthetases (NRPSs), along with tailoring enzymes—oxidases, methyltransferases and transporters—that sculpt core scaffolds into bioactive compounds. Epipolythiodioxopiperazines (ETPs), exemplified by gliotoxin, feature a characteristic disulfide bridge that mediates redox cycling and metal chelation. Biosynthesis is tightly regulated at both transcriptional and post-translational levels to prevent self-toxicity; self-protection mechanisms include reductases and sequestration into vacuoles. Secondary metabolites serve ecological roles in competition, defence and symbiosis, while their potent antibacterial, antifungal, anticancer and immunomodulatory activities have inspired drug discovery endeavours. Advances in genome mining, heterologous expression and synthetic biology have greatly expanded access to cryptic and marine-derived fungal BGCs, illuminating novel pathways and enzyme functions. A deeper understanding of regulatory networks, enzymology and cellular compartmentalisation is now informing strain engineering for efficient production and the rational design of analogue compounds with improved therapeutic properties.

Research from Nature Portfolio

Recent studies have elucidated critical regulatory and self-protection mechanisms in gliotoxin biosynthesis. One investigation revealed that a mitogen-activated protein kinase orchestrates gliotoxin production in Aspergillus fumigatus by physically interacting with and directing the subcellular localisation of oxidoreductase and methyltransferase enzymes, thereby coupling biosynthesis to a self-defence programme. This work underscores how kinase-mediated signalling integrates environmental cues with cluster activation and vacuolar sequestration to balance toxin yield and cellular safety. In parallel, research into bacterial inhibition by dithiol gliotoxin has demonstrated that its potent antibacterial activity arises from zinc and copper chelation. The addition of divalent metal ions reverses growth inhibition in both Gram-positive and Gram-negative species, implicating metal depletion as the primary mode of action. Proteomic profiling of treated bacteria further revealed induction of metal-uptake systems and ribosomal remodelling, highlighting the profound impact of fungal ETPs on microbial metal homeostasis and suggesting novel avenues for adjuvant therapies against resistant pathogens.

Biosynthesis and Biological Activity of Fungal Secondary Metabolites publication trend

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

Technical terms

Biosynthetic gene cluster (BGC): A contiguous set of genes encoding enzymes and regulators responsible for the assembly and modification of a secondary metabolite.

Non-ribosomal peptide synthetase (NRPS): A multimodular enzyme complex that assembles peptide natural products independently of the ribosome, often incorporating unusual amino acids.

Epipolythiodioxopiperazine (ETP): A class of fungal secondary metabolites characterised by a diketopiperazine core bearing a disulfide bridge, conferring redox activity and metal chelation.

Dithiol gliotoxin (DTG): The reduced form of gliotoxin possessing two free thiol groups that chelate metal ions and mediate toxicity.

Heterologous expression: The production of a metabolic pathway or enzyme in a non-native host organism to investigate function or enhance compound yield.

References

1. Aspergillus fumigatus mitogen-activated protein kinase MpkA is involved in gliotoxin production and self-protection. Nature Communications (2024).
2. Gliotoxin-mediated bacterial growth inhibition is caused by specific metal ion depletion. Scientific Reports (2023).
3. Gliotoxin and related metabolites as zinc chelators: implications and exploitation to overcome antimicrobial resistance. Essays in Biochemistry (2023).
4. Genome mining and biosynthetic pathways of marine-derived fungal bioactive natural products. Frontiers in Microbiology (2024).