---
OA_place: publisher
OA_type: hybrid
_id: '21912'
abstract:
- lang: eng
  text: 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.
article_processing_charge: Yes (in subscription journal)
article_type: original
author:
- first_name: Kollin
  full_name: Schultz, Kollin
  last_name: Schultz
- first_name: Pedro
  full_name: Costa-Pinheiro, Pedro
  last_name: Costa-Pinheiro
- first_name: Lauren
  full_name: Gardner, Lauren
  id: f9dedd98-6d15-11f0-88a5-a7b4143fdec5
  last_name: Gardner
  orcid: 0009-0000-5733-1546
- first_name: Laura V.
  full_name: Pinheiro, Laura V.
  last_name: Pinheiro
- first_name: Julio
  full_name: Ramirez-Solis, Julio
  last_name: Ramirez-Solis
- first_name: Sarah M.
  full_name: Gardner, Sarah M.
  last_name: Gardner
- first_name: Kathryn E.
  full_name: Wellen, Kathryn E.
  last_name: Wellen
- first_name: Ronen
  full_name: Marmorstein, Ronen
  last_name: Marmorstein
citation:
  ama: 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>
  apa: 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>
  chicago: 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>.
  ieee: 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.
  ista: 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.
  mla: 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>.
  short: 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.
date_created: 2026-05-24T08:25:19Z
date_published: 2025-05-08T00:00:00Z
date_updated: 2026-06-02T14:57:52Z
day: '08'
ddc:
- '572'
doi: 10.1038/s41586-025-08587-x
extern: '1'
external_id:
  pmid:
  - '39979457 '
has_accepted_license: '1'
intvolume: '       641'
issue: '8062'
language:
- iso: eng
main_file_link:
- open_access: '1'
  url: https://doi.org/10.1038/s41586-025-08587-x
month: '05'
oa: 1
oa_version: Published Version
page: 520-528
pmid: 1
publication: Nature
publication_identifier:
  eissn:
  - 1476-4687
  issn:
  - 0028-0836
publication_status: published
publisher: Springer Nature
quality_controlled: '1'
status: public
title: Snapshots of acyl carrier protein shuttling in human fatty acid synthase
tmp:
  image: /images/cc_by_nc_nd.png
  legal_code_url: https://creativecommons.org/licenses/by-nc-nd/4.0/legalcode
  name: Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
    (CC BY-NC-ND 4.0)
  short: CC BY-NC-ND (4.0)
type: journal_article
user_id: 2DF688A6-F248-11E8-B48F-1D18A9856A87
volume: 641
year: '2025'
...