Acetyl-coenzyme A carboxylase
Saccharomyces cerevisiae (Baker's yeast)
With obesity becoming a major health problem across the world, research for drugs that might counter it has gained prominence. Obese individuals are more prone to be affected by other serious diseases like type 2 diabetes and cardiovascular diseases. Obesity results from the storage of excess fat. Fatty acids are long hydrocarbon chains with terminal carboxylate groups. One of the functions of fatty acids is to act as fuel molecules in the form of triacylglycerols. When energy is required, fatty acids are created from triacylglycerols and oxidized to acetyl-CoA, which in turn is oxidized to produce ATP. Acetyl-CoA carboxylases (ACC) play an important role in controlling fatty acid metabolism or degradation. ACCs catalyze the carboxylation of acetyl-CoA to produce malonyl-CoA. Large amounts of malonyl-CoA are present in times of plenty. It inhibits carnitine palmitoyltransferase I, thus preventing the entry of fatty acyl-CoA into the mitochondrial matrix for oxidation. It has been shown that mice lacking ACC have high levels of fatty acid oxidation with low body fat and low body weight. Thus inhibitors of ACC are promising candidates for anti-obesity drugs.
The structure shown here is that of the ACC in yeast. It is a large enzyme with three main domains - a biotin carboxylase (BC) domain, a biotin carboxyl carrier protein (BCCP) domain and a carboxyl transferase (CT) domain. Dimerization of ACC at the BC domain is required for its activity. Soraphen A is an inhibitor of the activity of ACC by binding to the BC domain and preventing dimerization of ACC (the structure of ACC with bound Soraphen A can be seen under the xPSSS:1W96). Thus Soraphen A is a potential anti-obesity drug.
Protein Data Bank (PDB)
author: Ashwini Patil.