FASs and PKSs: Our Molecular Machines of Interest

FASs and PKSs as research objects

FASs: Fatty acid biosynthesis is a fundamental and broadly relevant biological process. It is essential for life, supplying the molecular building blocks for membranes, storage lipids, and signaling molecules, while also intersecting with core metabolic pathways through the consumption of acetyl-CoA and NADPH. Beyond its central role in metabolism, fatty acid biosynthesis has attracted attention as a target for medical intervention: its upregulation is a hallmark of many cancer types, and the bacterial pathway is a well-established target for antibiotic development. Furthermore, fatty acid biosynthesis offers a powerful platform for biotechnology, with promising applications in the sustainable production of fuels, platform chemicals, and food-related products. Structural and dynamic aspects of fatty acid synthases (FASs) have been the subject of extensive investigation. Over the past two decades, studies have identified the conformational variability as a hallmark feature of the multidomain FAS. For example, recent studies have provided insights into how the interplay between structure and conformational dynamics governs enzymatic function (11,12).   
 
PKSs: Polyketide biosynthesis is a specialized adaptation of fatty acid biosynthesis. It employs related enzymatic principles to produce a wide range of chemically diverse and biologically active natural products. While fatty acid biosynthesis is a streamlined, highly conserved process, polyketide biosynthesis introduces modular variation to enable the generation of structurally complex compounds. New structural information obtained during the past few years provides substantial direct insight into the orchestration of catalytic events within a PKS module (13,14). The mechanistic principles of assembly-line-synthesis of modular PKSs remain largely unresolved to this day.

FASs and PKSs are evolutionarily related: A central question in this field concerns the relationship between FASs and PKSs. Although they are evolutionarily related and share core chemical features and structural motifs, they differ fundamentally in their operational logic. In FASs, synthesis is iterative and one set of catalytic domains is reused multiple times to extend the growing fatty acid chain. In contrast, modular PKSs perform synthesis in a non-iterative, assembly-line manner, where each module is responsible for a single chain elongation step.

PKZILLA as the extreme example of polyketide biosynthesis: The number of modules can vary widely—from a few, as in the synthesis of the erythromycin precursor 6-deoxyerythronolide B, to dozens, as recently demonstrated in the biosynthesis of prymnesin-1. Prymnesin-1 is a highly toxic polyketide produced by the microalga Prymnesium parvum, known for causing massive fish deaths during harmful algal blooms, such as the large-scale die-off in river Oder in 2022. The recent discovery of its gene cluster revealed an exceptionally large modular PKS system, termed PKSzilla, in reference to its massive size and complexity (15).

Why studying FASs and PKSs?

The modular PKSs function as molecular assembly lines, executing a defined sequence of chemical transformations with extraordinary fidelity (16). Each module performs its catalytic task with precision, ensuring the correct incorporation of building blocks with accurate regio- and stereochemistry. This gives rise to several fundamental scientific questions: How do such enormous and flexible systems achieve strict control over sequential catalysis? What mechanisms govern the communication and coordination between distant modules? And how is fidelity preserved across the entire biosynthetic sequence?
 
Modular PKSs have evolved from iterative systems, such as the mammalian FAS or related iteratively operating PKSs. This evolutionary link raises a fundamental question of how modular PKSs acquired the ability to transfer intermediates between distinct modules? In particular, this development involved the coordinated translocation of the growing polyketide to the downstream module after each elongation step. Such a process must be tightly regulated to prevent repeated processing by the same module, as seen in the iterative systems.
 
Beyond the scientific curiosity surrounding these most intricate of biosynthetic machines, there is also a strong practical rationale for studying them. A deep mechanistic understanding of FASs and PKSs lays the groundwork for the rational engineering of new biosynthetic pathways—enabling the design and production of novel molecules with potential applications in medicine, materials, and sustainable chemistry (17,18).

11.  Choi, W., Li, C., Chen, Y., Wang, Y. & Cheng, Y. Structural dynamics of human fatty acid synthase in the condensing cycle. Nature 641, 529–536 (2025).
12.  Schultz, K. et al. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. Nature 641, 520–528 (2025).
13.  Cogan, D. P. et al. Mapping the catalytic conformations of an assembly-line polyketide synthase module. Science 374, 729–734 (2021).
14.  Bagde, S. R., Mathews, I. I., Fromme, J. C. & Kim, C.-Y. Modular polyketide synthase contains two reaction chambers that operate asynchronously. Science 374, 723–729 (2021).
15.  Fallon, T. R. et al. Giant polyketide synthase enzymes in the biosynthesis of giant marine polyether toxins. Science 385, 671–678 (2024).
16.  Grininger, M. Enzymology of assembly line synthesis by modular polyketide synthases. Nat. Chem. Biol. 19, 401–415 (2023).
17.  Klaus, M. & Grininger, M. Engineering strategies for rational polyketide synthase design. Nat Prod Rep 35, 1070–1081 (2018).
18.  Grininger, M. Design principles imprinted by evolution. Nat. Chem. Biol. (2025) doi:10.1038/s41589-025-01880-w.