Biosynthetic Pathways of Natural Antitumor Antibiotics

Biosynthetic pathways of natural antitumor antibiotics encompass diverse enzymatic assembly lines that generate structurally complex molecules with potent cytotoxic activity. Central to these pathways are modular type I polyketide synthases (PKSs), in which successive catalytic domains—such as ketosynthase, acyltransferase and acyl carrier protein modules—condense acyl precursors to form a carbon backbone. Tailoring enzymes, including ketoreductases, dehydratases and methyltransferases, further refine stereochemistry and functionality, while glycosyltransferases append sugar residues essential for cell-target recognition and solubility. Nonribosomal peptide synthetases (NRPSs) similarly orchestrate the assembly of peptide scaffolds incorporating non-proteinogenic amino acids, and hybrid PKS–NRPS systems expand the repertoire of antitumor scaffolds to include anthracyclines, glycopeptides and enediynes. Recent advances in genome mining and structural biology have uncovered novel starter units, atypical extender substrates and domain–domain interactions that govern chain initiation, elongation and release. Integration of synthetic biology with high-throughput screening has accelerated the discovery of cryptic gene clusters from underexplored microbial taxa, yielding new leads against resistant cancer cell lines. Emerging CRISPR-Cas editing of biosynthetic gene clusters enables precise modulation of pathway flux and generation of designer analogues with enhanced efficacy or reduced toxicity. Insights into membrane transporters and self-resistance mechanisms further inform engineering strategies for efficient export and high-yield production. Collectively, these developments underscore the global significance of natural antitumor antibiotics in drug discovery and the promise of pathway engineering for sustainable biomanufacturing of next-generation chemotherapeutics.

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Biosynthetic Pathways of Natural Antitumor Antibiotics publication trend

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

Technical terms

Polyketide synthase (PKS): A multi-enzyme complex that assembles polyketide chains by sequential condensation of acyl-CoA precursors.

Nonribosomal peptide synthetase (NRPS): A modular enzyme that builds peptide scaffolds using amino acids, often including non-proteinogenic residues, without ribosomal machinery.

Acyltransferase (AT): A catalytic domain within PKSs that selects and transfers extender or starter acyl units onto the acyl carrier protein.

Aglycone: The non-sugar core structure of a glycosylated natural product, often the bioactive component following sugar removal.

Glycosyltransferase: An enzyme that attaches sugar moieties to aglycones, influencing solubility, stability and target binding.

Atypical primer unit: A non-standard acyl building block used to initiate polyketide chain assembly, leading to structural diversity.

Acyl carrier protein (ACP): A small protein domain that shuttles growing polyketide or peptide intermediates between catalytic sites.

Efflux pump: A membrane transporter that exports secondary metabolites from producing cells, providing self-resistance and enabling high yields.

References

1. A unique dual acyltransferase system shared in the polyketide chain initiation of kidamycinone and rubiflavinone biosynthesis. Frontiers in Microbiology (2023).
2. Antibiotic export: transporters involved in the final step of natural product production. Microbiology (2019).