Structural studies of the human ATP:citrate-Lyase (hACL)

In eukaryotes, de novo fatty acid and cholesterol synthesis occurs in the cytosol. The production of these lipids depends on the cytosolic abundance of acetyl-CoA and on the availability of reducing NADPH equivalents. Acetyl-CoA is produced in the mitochondria through oxidative decarboxylation of pyruvate and through oxidation of fatty acids. The mitochondrial inner membrane is impermeable to acetyl-CoA and therefore it is transported indirectly, under the form of citrate. Human ATP:citrate-lyase (hACL) plays a vital role in this process by catalyzing the ATP-dependent cleavage of citrate into acetyl-CoA and oxaloacetate; Citrate + ATP + CoA acetyl-CoA + oxaloacetate + ADP + Pi Because of its metabolic function, ACL is a target for the development of hypolipidemic drugs. Studies in rats with the competitive inhibitor hydroxycitrate have shown that in liver, fat and other tissues, the fatty acid production diminishes, along with plasma cholesterol, triglyceride and VLDL levels. hACL is a homotetramer of 4 subunits and has a molecular mass of 0.5 MDa. The kinetics, mechanism and transcriptional and posttranslational regulation of the enzyme have bee