Structure-guided inhibitor design for human acetyl-coenzyme A carboxylase by interspecies active site conversion.

ABSTRACT: Inhibition of acetyl-CoA carboxylases (ACCs), a crucial enzyme for fatty acid metabolism, has been shown to promote fatty acid oxidation and reduce body fat in animal models. Therefore, ACCs are attractive targets for structure-based inhibitor design, particularly the carboxyltransferase (CT) domain, which is the primary site for inhibitor interaction. We have cloned, expressed, and purified the CT domain of human ACC2 using baculovirus-mediated insect cell expression system. However, attempts to crystallize the human ACC2 CT domain have not been successful in our hands. Hence, we have been using the available crystal structure of yeast CT domain to design human ACC inhibitors. Unfortunately, as the selectivity of the lead series has increased against the full-length human enzyme, the pote

SUBMITTER: Rajamohan F 

PROVIDER: S-EPMC3308862 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature