Biosynthetic Engineering of Anticancer Natural Products

Despite the longstanding success of plant- and microbe-derived natural products in oncology, their complex structures, low native yields and genetic intractability of producing organisms have posed significant challenges to large-scale supply. Biosynthetic engineering addresses these issues by deciphering and redesigning the underlying gene clusters that encode polyketide synthases, nonribosomal peptide synthetases and tailoring enzymes such as cytochrome P450 monooxygenases. Strategies include promoter replacement, pathway refactoring and heterologous expression in fast-growing chassis to boost titres and diversify analogue portfolios. Genome-editing tools and systems-level analyses have enabled activation of silent pathways, combinatorial biosynthesis of new derivatives and optimisation of precursor supply. These advances not only enhance production of established anticancer agents—exemplified by epothilones and taxanes—but also accelerate discovery of novel molecules with superior pharmacological properties. By integrating synthetic biology, fermentation engineering and metabolic modelling, the field is moving towards predictable, sustainable and scalable manufacture of complex anticancer natural products.

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Biosynthetic Engineering of Anticancer Natural Products publication trend

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

Technical terms

Biosynthetic engineering: The application of molecular and synthetic biology to modify or reconstruct natural product pathways for enhanced or novel compound production.

Polyketide synthase (PKS): A multi-enzyme complex that assembles polyketide chains through iterative condensation of small acyl-CoA building blocks.

Nonribosomal peptide synthetase (NRPS): A modular enzyme system that generates bioactive peptides independently of the ribosome, often incorporating unusual amino acids.

Heterologous expression: The introduction and functional expression of biosynthetic genes in a non-native host organism to improve yield or enable pathway engineering.

Ferredoxin: An iron–sulfur protein that transfers electrons to redox enzymes such as cytochrome P450 monooxygenases during biosynthesis.

Cytochrome P450 monooxygenase (e.g. EpoK): A heme-containing enzyme that catalyses regio- and stereospecific oxidations, critical for tailoring natural product scaffolds.

Epothilone B: A 16-membered macrolide stabilising microtubules similarly to paclitaxel, used in clinical oncology and a prime target for biosynthetic yield improvement.

References

1. Production and bioprocessing of epothilone B from Aspergillus niger, an endophyte of Latania loddegesii, with a conceivable biosynthetic stability: anticancer, anti-wound healing activities and cell cycle analysis. Microbial Cell Factories (2024).
2. Bioprocessing of Epothilone B from Aspergillus fumigatus under solid state fermentation: Antiproliferative activity, tubulin polymerization and cell cycle analysis. BMC Microbiology (2024).
3. Heterologous redox partners supporting the efficient catalysis of epothilone B biosynthesis by EpoK in Schlegelella brevitalea. Microbial Cell Factories (2020).