2px6
Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by OrlistatCrystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat
Structural highlights
FunctionFAS_HUMAN Fatty acid synthetase catalyzes the formation of long-chain fatty acids from acetyl-CoA, malonyl-CoA and NADPH. This multifunctional protein has 7 catalytic activities and an acyl carrier protein. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedHuman 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. Crystal structure of the thioesterase domain of human fatty acid synthase inhibited by Orlistat.,Pemble CW 4th, Johnson LC, Kridel SJ, Lowther WT Nat Struct Mol Biol. 2007 Aug;14(8):704-9. Epub 2007 Jul 8. PMID:17618296[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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