Mechanism of Orlistat Hydrolysis by the Thioesterase of Human Fatty Acid Synthase.

ABSTRACT: Fatty acid synthase (FASN), the sole protein capable of de novo synthesis of free fatty acids, is overexpressed in a wide variety of human cancers and is associated with poor prognosis and aggressiveness of these cancers. Orlistat, an FDA-approved drug for obesity treatment that inhibits pancreatic lipases in the GI tract, also inhibits the thioesterase (TE) of human FASN. The cocrystal structure of TE with orlistat shows a pseudo TE dimer containing two different forms of orlistat in the active site, an intermediate that is covalently bound to a serine residue (Ser²³⁰⁸) and a hydrolyzed and inactivated product. In this study, we attempted to understand the mechanism of TE-catalyzed orlistat hydrolysis by examining the role of the hexyl tail of the covalently bound orlistat in w

SUBMITTER: Fako VE 

PROVIDER: S-EPMC4188697 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature