The structure of the catalytic portion of human HMG-CoA reductase

In higher plants, fungi, and animals isoprenoids are derived from the meval onate pathway. The carboxylic acid mevalonate is formed from acetyl-CoA and acetoacetyl-CoA via the intermediate 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). The four-electron reduction of HMG-CoA to mevalonate, which uti lizes two molecules of NADPH, is the committed step in the biosynthesis of isoprenoids. This reaction is catalyzed by HMG-CoA reductase (HMGR). The ac tivity of HMGR is controlled through synthesis, degradation and phosphoryla tion. The human enzyme has also been targeted successfully by drugs, known as statins, in the clinical treatment of high serum cholesterol levels. The crystal structure of the catalytic portion of HMGR has been determined rec ently with bound reaction substrates and products. The structure illustrate s how HMG-CoA and NADPH are recognized and suggests a catalytic mechanism. Catalytic portions of human HMGR form tight tetramers, explaining the influ ence of the enzyme's oligomeric state on the activity and suggesting a mech anism for cholesterol sensing. (C) 2000 Elsevier Science B.V. All rights re served.