Polyketide Biosynthesis and Natural Product Engineering

Polyketides comprise a diverse family of natural products with profound biomedical and agricultural importance, ranging from antibiotics and anticancer agents to cholesterol‐lowering compounds. These molecules are biosynthesised by polyketide synthases (PKSs), modular or iterative enzyme assemblies that catalyse the stepwise condensation of simple acyl‐CoA precursors into complex carbon scaffolds. Type I PKSs, found predominantly in bacteria, are large multienzyme complexes arranged into discrete modules, each responsible for specific chain‐elongation and modification steps; Type II PKSs produce aromatic polyketides via dissociated enzyme systems; and Type III PKSs, widespread in plants and microbes, act as homodimeric enzymes assembling small aromatic cores. Advances in structural biology, genome mining and synthetic biology have illuminated domain architecture, substrate selectivity and module crosstalk, enabling rational design of novel polyketide derivatives. Tailoring enzymes introduce modifications such as methylation, glycosylation and oxidation, further diversifying functionality. Natural product engineering now leverages domain swapping, active‐site mutagenesis and heterologous expression to reprogramme PKS assembly lines, driving sustainable production of high‐value compounds and expanding chemical diversity for drug discovery.

Research from Nature Portfolio

Recent studies have elucidated the mechanistic basis of β‐branching programming within trans‐AT PKSs, revealing how multi‐enzyme cassettes select specific intermediates for methyl incorporation. Integrative structural and biochemical analyses identified key residues dictating substrate recognition in modules of the virginiamycin M synthase, and demonstrated additional sites capable of β‐methylation when perturbed. These findings not only clarify fundamental control mechanisms underpinning β‐branch introduction but also suggest strategies for engineered diversification of polyketide backbones towards bespoke derivatives with enhanced bioactivities.

Polyketide Biosynthesis and Natural Product Engineering publication trend

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

Technical terms

Polyketide synthase (PKS): Large, multi‐domain enzyme assembly that catalyses the sequential condensation of acyl‐CoA units to form polyketide chains.

Trans-AT PKS: A PKS system in which acyltransferase activity is provided by separate, trans‐acting enzymes rather than embedded domains within each module.

Acyl carrier protein (ACP): Small protein domain that carries polyketide intermediates via a phosphopantetheine arm between catalytic sites.

β‐branching: Introduction of alkyl side chains at the β‐position of the polyketide backbone through specialised enzyme cassettes.

Iterative highly‐reducing PKS (hr-PKS): A type of PKS, often found in fungi, that repeatedly uses the same set of catalytic domains to generate fully or partially reduced polyketide products.

References

1. Decrypting the programming of β-methylation in virginiamycin M biosynthesis. Nature Communications (2023).
2. Structure and Function of the α‐Hydroxylation Bimodule of the Mupirocin Polyketide Synthase. Angewandte Chemie International Edition (2023).
3. Genome Mining from Agriculturally Relevant Fungi Led to a d‑Glucose Esterified Polyketide with a Terpene-like Core Structure. Journal of the American Chemical Society (2023).
4. Reprogramming of the Aurantinin Polyketide Assembly Line to Synthesize Auritriacids by Excising an Atypical Enoyl‐CoA Hydratase Domain. Advanced Science (2024).