LydiaTabernero, Victor W. Rodwell, and Cynthia V. Stauffacher

Departments of Biological Sciences and Biochemistry, Purdue University, West Lafayette, Indiana 47907, USA.

HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase catalyzes the interconversion of HMG-CoA and mevalonate. This reaction is considered to be the major rate-limiting step in the biosynthetic pathway of sterols and isoprenoids, including cholesterol and its derivatives. In mammals this reaction is the first committed step in cholesterol biosynthesis, therefore HMG-CoA reductase is a primary target enzyme for chemotherapy of hypercholesterolemias.

Lovastatin® is a potent inhibitor of HMG-CoA reductase that has led to the development of several drugs of current medical use. These drugs are highly efficient in lowering cholesterol levels in human subjects over a short period of time. Nevertheless, the side effects caused by these drugs is still a major drawback for long term treatment. Knowledge of the binding mode of these inhibitors to the target is crucial for rational drug design and development of new inhibitors. We will present the X-ray crystallographic structure of the HMG-CoA reductase complex with lovastatin® and discuss the mechanism of catalysis and inhibition for this enzyme.