Biosynthesis of Bioactive Natural Products

Biosynthesis of bioactive natural products encompasses the enzymatic assembly and modification of small molecules that exhibit pharmacological or ecological functions. Central to this field are cyclodipeptide synthases and non-ribosomal peptide synthetases that construct core scaffolds such as diketopiperazines, polyketide backbones and alkaloid frameworks. Subsequent tailoring by methyltransferases, prenyltransferases, cytochrome P450 monooxygenases and oxidoreductases introduces structural diversity, stereochemical complexity and enhanced biological activity. Advances in genome mining, heterologous pathway reconstitution and structural biology have revealed unprecedented enzymatic mechanisms—ranging from radical cascade reactions to unusual D/L isomerisations—illuminating Nature’s capacity to generate molecular complexity. These discoveries underpin efforts to engineer pathways in tractable hosts, enabling the scalable production of natural products and designer analogues with applications in antibiotic discovery, cancer therapy and agrochemicals. By integrating bioinformatics, structural enzymology and synthetic biology, the field now provides a roadmap for unlocking novel chemical scaffolds and tailoring enzymes from diverse microbial and plant sources, with significant implications for drug development and sustainable manufacturing.

Research from Nature Portfolio

Recent studies have elucidated the nocardioazine B pathway from a marine actinomycete, identifying a cyclodipeptide synthase that assembles a cyclo-L-Trp-L-Trp precursor and a discrete gene locus encoding an unusual aspartate/glutamate racemase-type stereoisomerase alongside a phytoene synthase-like prenyltransferase and a dual-function methyltransferase. These findings reveal novel paradigms for D/L isomerisation and N- and C-methylation in diketopiperazine maturation. In a foundational contribution, genome mining of cyclodipeptide synthase loci across Streptomyces strains uncovered CDPS-dependent pathways for the formation of terpenylated diketopiperazines (‘drimentines’). Characterisation of the associated prenyltransferase and membrane terpene cyclase clarified the enzymatic sequence of prenylation and macrocyclisation, setting the stage for biocatalytic diversification of complex DKP-terpene hybrids.

Research from all publishers

A recent study of fungal cytochrome P450 enzymes has advanced understanding of regio- and stereoselective dimerisation reactions in indole-containing diketopiperazines. By combining bioinformatics, heterologous expression and molecular docking, five new P450s responsible for selective C–C and C–N couplings were characterised, revealing sequence motifs that govern substrate orientation and enabling expansion of fungal di-DKP chemical space through pathway reconstitution. In the realm of antibiotic biosynthesis, the gene cluster for bicyclomycin was identified in diverse bacterial classes, demonstrating that a cyclodipeptide synthase generates the core DKP which is then extensively oxidised by a suite of dioxygenases and a P450. Horizontal transfer of this intact cluster across Actinobacteria and Proteobacteria was uncovered, providing insight into the natural dissemination of a clinically promising Rho-inhibiting antibiotic.

Biosynthesis of Bioactive Natural Products publication trend

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

Technical terms

Diketopiperazine (DKP): Cyclic dipeptide scaffold formed by cyclodipeptide synthases or non-ribosomal peptide synthetases, foundational to many bioactive natural products.

Cyclodipeptide synthase (CDPS): Enzyme that hijacks aminoacyl-tRNAs to form cyclodipeptides, initiating secondary metabolite pathways.

Prenyltransferase: Enzyme that installs prenyl groups onto small molecules, modulating solubility, membrane affinity and bioactivity.

Cytochrome P450: Heme-dependent monooxygenase family catalysing oxidative transformations such as hydroxylation, epoxidation and radical-mediated couplings.

Heterologous expression: Reconstruction of a biosynthetic pathway in a non-native microbial host to confirm enzyme function or increase metabolite yield.

Radical cascade reaction: Enzymatic sequence of radical-mediated bond formations that generates complex molecular architectures with precise regio- and stereocontrol.

References

1. Unveiling an indole alkaloid diketopiperazine biosynthetic pathway that features a unique stereoisomerase and multifunctional methyltransferase. Nature Communications (2023).
2. Genome mining of cyclodipeptide synthases unravels unusual tRNA-dependent diketopiperazine-terpene biosynthetic machinery. Nature Communications (2018).
3. Exploring the Diverse Landscape of Fungal Cytochrome P450‐Catalyzed Regio‐ and Stereoselective Dimerization of Diketopiperazines. Advanced Science (2024).
4. Discovery and Biosynthesis of the Antibiotic Bicyclomycin in Distantly Related Bacterial Classes. Applied and Environmental Microbiology (2018).
5. The tRNA-Dependent Biosynthesis of Modified Cyclic Dipeptides. International Journal of Molecular Sciences (2014).