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

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Pemble CW 4th, Johnson LC, Kridel SJ, Lowther WT

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

Nat Struct Mol Biol. 2007 Aug;14(8):704-9. Epub 2007 Jul 8.

PubMed ID

17618296 [View in PubMed

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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.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Ph值armacological Action	Actions
Orlistat	Fatty acid synthase	Protein	Humans	Unknown	Inhibitor	Details

Drug Enzymes

Drug	Enzyme	Kind	Organism	Ph值armacological Action	Actions
Orlistat	Fatty acid synthase	Protein	Humans	Unknown	Inhibitor	Details

Polypeptides

Name	UniProt ID
Fatty acid synthase	P49327	Details