Article | Published:

Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat

Nature Structural & Molecular Biology volume 14, pages 704709 (2007) | Download Citation

Abstract

Human fatty acid synthase (FAS) is uniquely expressed at high levels in many tumor types. Pharmacological inhibition of FAS therefore represents an important therapeutic opportunity. The drug Orlistat, which has been approved by the US Food and Drug Administration, inhibits FAS, induces tumor cell–specific apoptosis and inhibits the growth of prostate tumor xenografts. We determined the 2.3-Å-resolution crystal structure of the thioesterase domain of FAS inhibited by Orlistat. Orlistat was captured in the active sites of two thioesterase molecules as a stable acyl-enzyme intermediate and as the hydrolyzed product. The details of these interactions reveal the molecular basis for inhibition and suggest a mechanism for acyl-chain length discrimination during the FAS catalytic cycle. Our findings provide a foundation for the development of new cancer drugs that target FAS.

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Acknowledgements

This work was supported by developmental funds from Wake Forest University School of Medicine, the Kulynych Interdisciplinary Cancer Research Fund, the US Department of Defense Prostrate Cancer Research Program (W81XWH-05-1-0065) and the US National Institutes of Health, National Cancer Institute (R01 CA114104) to S.J.K and W.T.L. The authors' views and opinions do not reflect those of the US Army or the Department of Defense. The authors thank T. Hollis and D.A. Lehtinen for assistance in collecting diffraction data on beamline x12c at the National Synchrotron Light Source, Brookhaven National Laboratory. The National Synchrotron Light Source is supported by funds from the US Department of Energy, Office of Science, Office of Basic Energy Sciences under contract no. DE-AC02-98CH10886. We also thank J.D. Schmitt for insightful discussions and comments on the manuscript.

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Affiliations

  1. Center for Structural Biology and Department of Biochemistry, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.

    • Charles W Pemble IV
    • , Lynnette C Johnson
    •  & W Todd Lowther
  2. Department of Cancer Biology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.

    • Steven J Kridel
  3. Comprehensive Cancer Center of Wake Forest University, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, North Carolina 27157, USA.

    • Steven J Kridel
    •  & W Todd Lowther

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Contributions

C.W.P., S.J.K. and W.T.L. designed the experiments and interpreted the structure; S.J.K. generated the expression clone; C.W.P. and L.C.J. performed all protein expression, purification and crystallization; C.W.P. and W.T.L. contributed to structure solution and refinement; all authors contributed to manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to W Todd Lowther.

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https://doi.org/10.1038/nsmb1265

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