Fatty Acid and Polyketide Biosynthesis Mechanisms

Fatty acid and polyketide biosynthesis share a modular enzymatic architecture that assembles acyl building blocks into complex molecules via successive chain‐elongation and modification reactions. In both pathways, acyl carrier proteins (ACPs) serve as dynamic shuttles, tethering growing intermediates through a phosphopantetheine linkage and delivering them to catalytic domains such as β‐ketoacyl synthase (KS), dehydratase, enoyl reductase, ketoreductase and thioesterase. Type I systems form megasynthases comprising multiple domains on a single polypeptide, facilitating processive catalysis; by contrast, type II systems employ discrete, monofunctional enzymes operating in a dissociated, iterative manner. Polyketide synthases (PKSs) adopt similar organisational principles but introduce greater chemical diversity through variant loading modules, tailoring domains and diverse starter units, yielding antibiotics, anticancer agents and other natural products. Advances in structural biology and mechanistic enzymology have revealed conformational gating, interdomain communication and substrate‐specificity determinants that underpin chain‐length control and regioselective modifications. This mechanistic insight underlies efforts to engineer FAS and PKS pathways for therapeutic inhibitor development, antibiotic discovery and biofuel production. Understanding the interplay between scaffold dynamics, domain cooperativity and substrate channeling remains crucial for unlocking the full potential of these biosynthetic machineries.

Research from Nature Portfolio

Recent studies have determined the near‐atomic structure of the core modifying region of human fatty acid synthase by cryo‐electron microscopy, revealing the arrangement of dehydratase, enoyl reductase and ketoreductase domains at 2.7 Å resolution and uncovering two major global conformational states. Examination of the dehydratase dimer showed a closed catalytic cavity accessible through a single opening, and the binding mode of an anti‐cancer inhibitor highlighted novel opportunities for structure‐guided drug design.

Separate structural and computational analyses of bacterial elongating β‐ketoacyl synthases have elucidated a dynamic gating mechanism that regulates acyl‐ACP substrate delivery. Crystal structures of KS–ACP complexes combined with molecular‐dynamics simulations uncovered two mobile active‐site loops that undergo large conformational shifts to coordinate substrate recognition, providing a molecular basis for the ping‐pong condensation cycle and suggesting an evolutionarily conserved feature across diverse KS enzymes.

Fatty Acid and Polyketide Biosynthesis Mechanisms publication trend

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

Technical terms

Acyl carrier protein (ACP): A small protein that carries acyl intermediates via a 4′-phosphopantetheine arm and shuttles them between catalytic domains during fatty acid and polyketide synthesis.

Fatty acid synthase (FAS): A multifunctional enzyme or complex that catalyses the de novo assembly of fatty acids through iterative condensation, reduction and dehydration steps.

Polyketide synthase (PKS): A modular enzyme system analogous to FAS that generates structurally diverse polyketide natural products by assembling ketide units with varied modifications.

β-Ketoacyl synthase (KS): The domain or enzyme that catalyses the decarboxylative Claisen-like condensation of malonyl-derived extender units with growing acyl chains.

Cryo-electron microscopy (cryo-EM): A structural biology technique that determines high-resolution macromolecular structures by imaging rapidly frozen specimens under an electron beam.

References

1. Atomic model for core modifying region of human fatty acid synthase in complex with Denifanstat. Nature Communications (2023).
2. Gating mechanism of elongating β-ketoacyl-ACP synthases. Nature Communications (2020).
3. How Acyl Carrier Proteins (ACPs) Direct Fatty Acid and Polyketide Biosynthesis. Angewandte Chemie International Edition (2023).
4. Structure of Acyl Carrier Protein Bound to FabI, the FASII Enoyl Reductase from Escherichia coli *. Journal of Biological Chemistry (2006).
5. Expanding our Understanding of Sequence-Function Relationships of Type II Polyketide Biosynthetic Gene Clusters: Bioinformatics-Guided Identification of Frankiamicin A from Frankia sp. EAN1pec. PLOS ONE (2015).