Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat.
Nat Struct Mol Biol
; 14(8): 704-9, 2007 Aug.
Article
en En
| MEDLINE
| ID: mdl-17618296
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.
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Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Inhibidores Enzimáticos
/
Ácido Graso Sintasas
/
Lactonas
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Nat Struct Mol Biol
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2007
Tipo del documento:
Article
País de afiliación:
Estados Unidos