Title : Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat - Pemble_2007_Nat.Struct.Mol.Biol_14_704 |
Author(s) : Pemble CWt , Johnson LC , Kridel SJ , Lowther WT |
Ref : Nat Struct Mol Biol , 14 :704 , 2007 |
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-A-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. |
PubMedSearch : Pemble_2007_Nat.Struct.Mol.Biol_14_704 |
PubMedID: 17618296 |
Gene_locus related to this paper: human-FASN |
Inhibitor | Orlistat |
Substrate | Orlistat |
Gene_locus | human-FASN |
Family | Thioesterase |
Structure | 2PX6 |
Pemble CWt, Johnson LC, Kridel SJ, Lowther WT (2007)
Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat
Nat Struct Mol Biol
14 :704
Pemble CWt, Johnson LC, Kridel SJ, Lowther WT (2007)
Nat Struct Mol Biol
14 :704