Biosynthesis of Fungal Meroterpenoids

Meroterpenoids are hybrid natural products that arise from the fusion of terpenoid units with non-terpenoid precursors, most commonly polyketides or aromatic compounds. Fungi produce a vast and structurally diverse array of these metabolites, many of which exhibit potent biological activities such as antimicrobial, anticancer and enzyme-inhibitory effects. Biosynthetic pathways typically begin with assembly of a core scaffold via polyketide synthases or aromatic precursors, followed by prenylation, cyclisation and a cascade of oxidative tailoring steps. Recent advances in genome mining, synthetic biology and enzyme characterisation have revealed unprecedented enzymatic strategies, broadening access to new molecular scaffolds and guiding efforts to engineer pathways for novel compound generation.

Research from Nature Portfolio

Recent studies have harnessed domainless enzyme-targeted genome mining across thousands of fungal genomes to identify novel biosynthetic gene clusters encoding previously unrecognised terpene cyclases. Characterisation of selected clusters led to the discovery of onoceroid triterpenoids and unique sesquiterpene hydroquinones, underpinned by new onoceroid synthases. In parallel, CRISPR–Cas9-mediated deletions and in vitro reconstitutions elucidated the pathway to a heavily oxygenated meroterpenoid featuring an orthoester moiety. A non-haem iron endoperoxide isomerase was shown to catalyse a rare orthoester formation, revealing an unexpected enzymatic logic within fungal metabolism.

Biosynthesis of Fungal Meroterpenoids publication trend

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

Technical terms

Meroterpenoid: A natural product partly derived from terpenoid biosynthesis and partially from non‐terpenoid pathways.

Biosynthetic gene cluster (BGC): A contiguous set of genes encoding enzymes that cooperatively synthesise a specialised metabolite.

Prenyltransferase: An enzyme that attaches isoprenoid (prenyl) groups to aromatic or aliphatic acceptors.

Terpene cyclase: An enzyme that converts linear prenyl pyrophosphates into cyclic terpenoid scaffolds.

Endoperoxide isomerase: An enzyme that rearranges peroxy bonds to form cyclic ether or orthoester moieties.

Genome mining: A bioinformatics-driven approach to identify potential natural product pathways in sequenced genomes.

Heterologous biosynthesis: Reconstruction of metabolic pathways in a genetically tractable host to access or diversify natural products.

References

1. Discovery of fungal onoceroid triterpenoids through domainless enzyme-targeted global genome mining. Nature Communications (2024).
2. Global genome mining-driven discovery of an unusual biosynthetic logic for fungal polyketide–terpenoid hybrids. Chemical Science (2024).
3. Biosynthesis of fungal meroterpenoids. Natural Product Reports (2016).
4. Novofumigatonin biosynthesis involves a non-heme iron-dependent endoperoxide isomerase for orthoester formation. Nature Communications (2018).