Biosynthesis of Natural Products from Fungi

Fungi synthesise a diverse array of secondary metabolites—polyketides, non-ribosomal peptides, terpenoids and alkaloids—through highly orchestrated enzymatic pathways. Enzymes such as polyketide synthases and non-ribosomal peptide synthetases assemble simple building blocks like acetyl-CoA and amino acids into complex architectures. These pathways are typically encoded in biosynthetic gene clusters that encompass core enzymes, tailoring enzymes (oxidases, methyltransferases, cyclases) and regulatory proteins. Oxidative transformations, cycloadditions and dimerisations further diversify the structures, yielding compounds with antibiotic, antifungal, anticancer or agrochemical properties. Recent advances in genome sequencing and bioinformatics have revealed cryptic gene clusters and novel enzymatic activities, enabling the discovery, heterologous expression and even chemo-enzymatic total synthesis of these natural products. Understanding these biosynthetic routes not only informs fundamental enzymology and evolutionary biology but also accelerates the development of new drugs and sustainable bioactive compounds.

Research from Nature Portfolio

Recent studies have combined chemical and enzymatic methods to achieve the first total synthesis of spirosorbicillinols, a subclass of fungal sorbicillinoids. A convergent chemo-enzymatic route transforms a readily available polyketide precursor into a reactive intermediate, which then undergoes a Diels-Alder cycloaddition to form the characteristic bicyclo[2.2.2]octane core. This unified approach grants access to both natural and novel stereoisomers, demonstrating the power of integrating biocatalysis with classical synthesis. In parallel, genomic and biochemical dissection of Basidiomycete fungi has elucidated the complete gene cluster responsible for strobilurin biosynthesis. Expression of a highly reducing polyketide synthase with unusual C-terminal domains in a heterologous host reveals steps leading to the β-methoxyacrylate toxophore, while an FAD-dependent oxygenase catalyses a key oxidative rearrangement. Reconstruction of the entire pathway in a model organism confirms the sequential roles of methyltransferases and oxygenases in assembly of this agriculturally important fungicide scaffold.

Biosynthesis of Natural Products from Fungi publication trend

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

Technical terms

Polyketide synthase (PKS): multi-domain enzyme that sequentially condenses acyl-CoA units to form polyketide backbones.

Non-ribosomal peptide synthetase (NRPS): enzyme complex that assembles peptides from amino acid substrates, bypassing ribosomal machinery.

Biosynthetic gene cluster: contiguous genomic region encoding all enzymes and regulators necessary for the production of a specific secondary metabolite.

Diels-Alder cycloaddition: pericyclic reaction creating six-membered rings via [4+2] cyclisation between a diene and a dienophile.

Flavin-dependent monooxygenase: enzyme that uses a flavin cofactor to introduce oxygen atoms, often facilitating ring formation or oxidation in biosynthetic pathways.

References

1. Chemo-enzymatic total synthesis of the spirosorbicillinols. Communications Chemistry (2023).
2. Strobilurin biosynthesis in Basidiomycete fungi. Nature Communications (2018).
3. Arcopilins: A New Family of Staphylococcus aureus Biofilm Disruptors from the Soil Fungus Arcopilus navicularis. Journal of Medicinal Chemistry (2024).
4. New Sorbicillinoids from the Mangrove Endophytic Fungus Trichoderma reesei SCNU-F0042. Marine Drugs (2023).