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Human fatty acid synthase complexed with the anti-tumor compound Orlistat: mechanism of inhibition and chain-length selectivity

¹ Biochemistry, Wake Forest University School of Medicine, Medical Center Blvd., BGTC Center for Structural Biology, Winston Salem, NC, 27157,
² Biochemistry,
³ Cancer Biology, Wake Forest University School of Medicine, Medical Center Blvd., Winston Salem, NC, 27157

ABSTRACT

Human fatty acid synthase (hFAS) is highly expressed in many tumors, making it an attractive target for therapeutic intervention. Orlistat inhibits the thioesterase (hTE) activity of hFAS and induces tumor cell-specific death. To understand the molecular details of Orlistat inhibition, we solved the crystal structure of hTE complexed with Orlistat. This represents the first ligand complex available for any of the seven functional domains of hFAS. The structure reveals the mechanistic details of ß-lactone inhibition and the molecular basis behind Orlistat potency. Moreover, the substrate mimicry displayed by the core, C₁₆ lipid chain of Orlistat resolves many questions about the critical role hTE plays in the selection of chain length during the hFAS catalytic cycle. Interestingly, two modes of binding were captured: the acyl-enzyme intermediate and hydrolyzed product. This fortuitous event mimics hTE interactions with natural C₁₆ and C₁₈ substrates. Contrary to a previous modeling study, hTE-Orlistat reveals that natural substrates most likely bind to a novel hydrophobic "specificity channel" carved by the unique domain insertion within the /ß hydrolase fold. Additional Orlistat substituents mimic shorter fatty acids. The data provide a rationale for the discrimination of chain length by the coordination among three surface features: short chain pocket, interface cavity, and specificity channel.

This work is supported by the Department of Defense PCRP program (W81XWH-05-1-0065) and NIH/NCI (R01 CA411401).

This Article Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Pemble, C. W. Articles by Lowther, W. T. PubMed Articles by Pemble, C. W., IV Articles by Lowther, W. T.