Polyketide Biosynthesis Mechanisms and Stereochemical Control
Summary
Polyketides represent a broad class of natural products renowned for their structural diversity and potent biological activities, including antibiotic, anticancer and immunosuppressive properties. Their assembly is orchestrated by polyketide synthases (PKSs), large multifunctional enzyme complexes that adopt modular or iterative architectures. Each module selects and condenses specific acyl‐CoA extender units, with subsequent ketoreductase (KR), dehydratase (DH) and enoylreductase (ER) domains tailoring the oxidation state and stereochemistry at each centre. The intrinsic programming of these domains ensures precise control over chain length, functional group placement and three‐dimensional configuration, which underpins the rigidity and bioactivity of the final molecule. Advances in structural biology, mutagenesis and bioinformatic prediction have revealed how subtle variations in active‐site helices or interdomain interfaces steer substrate orientation and catalytic outcome. Together, these insights inform strategies for rational reengineering of native PKSs to generate novel compounds with bespoke stereochemical patterns and improved pharmacological profiles.
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Polyketide Biosynthesis Mechanisms and Stereochemical Control publication trend
The graph below shows the total number of articles in polyketide biosynthesis mechanisms and stereochemical control across all publications each year (not limited to Nature Index journals).
Technical terms
Polyketide synthase (PKS): A multi‐domain enzyme complex that assembles polyketide chains through successive condensations of acyl‐CoA substrates.
Acyl carrier protein (ACP): A small protein domain that tethers growing polyketide intermediates via a phosphopantetheine arm, delivering them to catalytic sites.
Ketoreductase (KR) domain: The PKS domain responsible for stereospecific reduction of β-keto groups to β-hydroxy intermediates, influencing stereochemistry at that centre.
Dehydratase (DH) domain: The PKS domain that catalyses the removal of water from β-hydroxyacyl intermediates to generate α,β-unsaturated bonds with defined geometry.
Stereochemistry: The three-dimensional arrangement of atoms in a molecule, critical for the biological activity and specificity of polyketide natural products.
References
- Expanding the Utility of Bioinformatic Data for the Full Stereostructural Assignments of Marinolides A and B, 24- and 26-Membered Macrolactones Produced by a Chemically Exceptional Marine-Derived Bacterium. Marine Drugs (2023).
- Investigation of chain-length selection by the tenellin iterative highly-reducing polyketide synthase. RSC Advances (2024).
- Polyketide stereocontrol: a study in chemical biology. Beilstein Journal of Organic Chemistry (2017).
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