Snapshots of acyl carrier protein shuttling in human fatty acid synthase

Kollin Schultz (), Pedro Costa-Pinheiro, Lauren Gardner, Laura V. Pinheiro, Julio Ramirez-Solis, Sarah M. Gardner, Kathryn E. Wellen and Ronen Marmorstein ()
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Kollin Schultz: University of Pennsylvania
Pedro Costa-Pinheiro: University of Pennsylvania
Lauren Gardner: University of Pennsylvania
Laura V. Pinheiro: University of Pennsylvania
Julio Ramirez-Solis: University of Pennsylvania
Sarah M. Gardner: University of Pennsylvania
Kathryn E. Wellen: University of Pennsylvania
Ronen Marmorstein: University of Pennsylvania

Nature, 2025, vol. 641, issue 8062, 520-528

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08587-x

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