article published yes Kollin Schultz author Pedro Costa-Pinheiro author Lauren Gardner author f9dedd98-6d15-11f0-88a5-a7b4143fdec50009-0000-5733-1546 Laura V. Pinheiro author Julio Ramirez-Solis author Sarah M. Gardner author Kathryn E. Wellen author Ronen Marmorstein author The mammalian fatty acid synthase (FASN) enzyme is a dynamic multienzyme that belongs to the megasynthase family. In mammals, a single gene encodes six catalytically active domains and a flexibly tethered acyl carrier protein (ACP) domain that shuttles intermediates between active sites for fatty acid biosynthesis1. FASN is an essential enzyme in mammalian development through the role that fatty acids have in membrane formation, energy storage, cell signalling and protein modifications. Thus, FASN is a promising target for treatment of a large variety of diseases including cancer, metabolic dysfunction-associated fatty liver disease, and viral and parasite infections2,3. The multi-faceted mechanism of FASN and the dynamic nature of the protein, in particular of the ACP, have made it challenging to understand at the molecular level. Here we report cryo-electron microscopy structures of human FASN in a multitude of conformational states with NADPH and NADP+ plus acetoacetyl-CoA present, including structures with the ACP stalled at the dehydratase (DH) and enoyl-reductase (ER) domains. We show that FASN activity in vitro and de novo lipogenesis in cells is inhibited by mutations at the ACP–DH and ACP–ER interfaces. Together, these studies provide new molecular insights into the dynamic nature of FASN and the ACP shuttling mechanism, with implications for developing improved FASN-targeted therapeutics. Springer Nature2025 eng 0028-0836 1476-4687 39979457 10.1038/s41586-025-08587-x 6418062520-528 yes K. Schultz <i>et al.</i>, “Snapshots of acyl carrier protein shuttling in human fatty acid synthase,” <i>Nature</i>, vol. 641, no. 8062. Springer Nature, pp. 520–528, 2025. Schultz, Kollin, Pedro Costa-Pinheiro, Lauren Gardner, Laura V. Pinheiro, Julio Ramirez-Solis, Sarah M. Gardner, Kathryn E. Wellen, and Ronen Marmorstein. “Snapshots of Acyl Carrier Protein Shuttling in Human Fatty Acid Synthase.” <i>Nature</i>. Springer Nature, 2025. <a href="https://doi.org/10.1038/s41586-025-08587-x">https://doi.org/10.1038/s41586-025-08587-x</a>. Schultz K, Costa-Pinheiro P, Gardner L, Pinheiro LV, Ramirez-Solis J, Gardner SM, Wellen KE, Marmorstein R. 2025. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. Nature. 641(8062), 520–528. Schultz, K., Costa-Pinheiro, P., Gardner, L., Pinheiro, L. V., Ramirez-Solis, J., Gardner, S. M., … Marmorstein, R. (2025). Snapshots of acyl carrier protein shuttling in human fatty acid synthase. <i>Nature</i>. Springer Nature. <a href="https://doi.org/10.1038/s41586-025-08587-x">https://doi.org/10.1038/s41586-025-08587-x</a> K. Schultz, P. Costa-Pinheiro, L. Gardner, L.V. Pinheiro, J. Ramirez-Solis, S.M. Gardner, K.E. Wellen, R. Marmorstein, Nature 641 (2025) 520–528. Schultz K, Costa-Pinheiro P, Gardner L, et al. Snapshots of acyl carrier protein shuttling in human fatty acid synthase. <i>Nature</i>. 2025;641(8062):520-528. doi:<a href="https://doi.org/10.1038/s41586-025-08587-x">10.1038/s41586-025-08587-x</a> Schultz, Kollin, et al. “Snapshots of Acyl Carrier Protein Shuttling in Human Fatty Acid Synthase.” <i>Nature</i>, vol. 641, no. 8062, Springer Nature, 2025, pp. 520–28, doi:<a href="https://doi.org/10.1038/s41586-025-08587-x">10.1038/s41586-025-08587-x</a>. 219122026-05-24T08:25:19Z2026-06-02T14:57:52Z