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

Charles W Pemble1, Lynnette C Johnson, Steven J Kridel

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

Nature Structural & Molecular Biology
|July 10, 2007
PubMed

Insights

Human fatty acid synthase (FAS) is a key target for cancer drugs. Orlistat inhibits FAS, showing promise in preclinical cancer models by inducing apoptosis and slowing tumor growth.

Area of Science:

  • Biochemistry
  • Structural Biology
  • Oncology

Background:

  • Human fatty acid synthase (FAS) is overexpressed in many cancer types, making it a potential therapeutic target.
  • Pharmacological inhibition of FAS offers a promising strategy for cancer treatment.
  • Orlistat, an FDA-approved drug, demonstrates FAS inhibitory activity and anti-tumor effects in preclinical models.

Purpose of the Study:

  • To elucidate the molecular mechanism of Orlistat inhibition of human fatty acid synthase (FAS).
  • To determine the crystal structure of the FAS thioesterase domain in complex with Orlistat.

Main Methods:

  • X-ray crystallography was used to determine the 2.3-Å resolution crystal structure of the FAS thioesterase domain.
  • The structure captured Orlistat as both a stable acyl-enzyme intermediate and a hydrolyzed product within the enzyme's active site.

Main Results:

  • The crystal structure revealed the precise interactions of Orlistat within the FAS active site.
  • Orlistat was observed in two distinct states: an acyl-enzyme intermediate and a hydrolyzed product.
  • These interactions provide insights into the molecular basis of FAS inhibition and substrate specificity.

Conclusions:

  • The structural data elucidates the mechanism by which Orlistat inhibits human FAS.
  • Findings support the development of novel FAS-targeting cancer therapeutics.
  • Understanding FAS inhibition is crucial for designing more effective anti-cancer drugs.

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