Mechanism of fatty acid uptake and inhibition in human FATP2

Authors

Zhang, Z., Zhou, M., Huang, Y., Wu, W., Jiao, H., Dai, M., Liang, T., Wen, J., Cheng, Z., Ma, X., Yuan, J., Hu, H., Shang, J., Marmorstein, R., Wei, X.

Abstract

Fatty Acid Transport Protein 2 (FATP2) couples fatty acid uptake to intracellular activation and is associated with pathological lipid accumulation in cancer and nonalcoholic fatty liver disease. Here, we present cryo-electron microscopy structures of human FATP2 across its reaction cycle. Our structures suggest that FATP2 recruits fatty acids directly from the membrane interface through a hydrophobic tunnel. Catalysis involves a ~130{degrees} rotation of the C-terminal domain, a transition trapped by the antihypertensive drugs isradipine and benidipine. Both drugs lock the enzyme in a thioester-forming state, but benidipine exhibits superior efficacy by extending a bulky moiety into the primary catalytic tunnel to sterically block substrate entry. Furthermore, we identify a product inhibition mechanism where excess acyl-CoA traps the enzyme, potentially limiting metabolic overload. These findings provide a structural framework for understanding vectorial fatty acid channeling and a scaffold for developing modulators of metabolic flux.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 12 Jul 2026.

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