Statin inhibition of HMG-CoA reductase: a 3-dimensional view

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1 Atherosclerosis Supplements 4 (2003) 3/8 Statin inhibition of HMG-CoA reductase: a 3-dimensional view Eva Istvan * Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, Campus Box 8230, 660 South Euclid Avenue, St. Louis, MO 63110, USA Abstract Statins act by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and thereby reducing cholesterol synthesis. In X-ray crystallographic studies, we have determined the structures of the catalytic portions of the enzyme in complex with statin molecules. These studies show that the HMG-like moiety of statin molecules occupy the HMG binding site of the enzyme, with the hydrophobic groups of the statins occupying a binding site exposed by movement of flexible helices in the enzyme catalytic domain. In addition to bonds formed by the HMG-like moiety, statins exhibit different types and numbers of binding interactions in association with structural differences. Type 1 statins (e.g., simvastatin) exhibit binding via a decalin ring structure, and type 2 statins (e.g., rosuvastatin, atorvastatin, fluvastatin) exhibit additional binding via their fluorophenyl group. Rosuvastatin and atorvastatin exhibit hydrogen bonds absent from other type 2 statins; rosuvastatin exhibits a unique bond via its electronegative sulfone group. Differences in statin structure and binding characteristics may partially contribute to differences in potency of HMG- CoA reductase inhibition and other pharmacologic properties. # 2003 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Statins; HMG-CoA reductase; Binding interactions; Pharmacologic properties 1. Introduction 3-Hydroxy-3-methylglutaryl coenzyme A (HMG- CoA) reductase converts HMG-CoA to mevalonate, with this catalysis constituting a committed step in the biosynthesis of cholesterol (Fig. 1). Inhibition of this enzyme results in decreased synthesis of cholesterol and other products downstream of mevalonate. HMG-CoA reductase inhibitors, or statins, are used therapeutically to reduce risk of coronary heart disease by reducing cholesterol synthesis and upregulating low-density lipoprotein receptors in the liver, resulting in decreased levels of circulating cholesterol. All statins function similarly by binding to the active site of HMG-CoA reductase and thus inhibiting the enzyme. However, structural differences in statins may partially account for differences in potency of enzyme inhibition. 2. HMG-CoA reductase structure In order to study the mechanisms by which statins inhibit the activity of HMG-CoA reductase, we [1] first determined the 3-dimensional X-ray crystallographic * Tel.: / ; fax: / address: istvan@borcim.wustl.edu (E. Istvan). Fig. 1. The mevalonate pathway. Inhibition of HMG-CoA reductase (the enzyme which catalyzes the formation of mevalonate from HMG- CoA) results in decreased cholesterol synthesis /03/$ - see front matter # 2003 Elsevier Science Ireland Ltd. All rights reserved. doi: /s (03)

2 4 E. Istvan / Atherosclerosis Supplements 4 (2003) 3 /8 Fig. 2. (Top) Binding of substrates HMG-CoA and NADP to HMG- CoA reductase active site. See text for details. (Bottom) Close-up view of enzyme active site showing substrate binding. Binding interactions are indicated by dotted lines, with numerals indicating distance in angstroms. Reproduced with permission from Istvan and Deisenhofer [4]. structure of HMG-CoA reductase (Fig. 2, top). The enzyme normally forms a tightly associated tetramer, but it is only the dimer of the molecule that is crucial for catalysis. It is at the active site of the enzyme, at the center of the molecule, that the two substrate molecules are brought into proximity to allow catalysis to occur. The close-up view of the enzyme active site in the bottom portion of Fig. 2 shows why the enzyme can be considered to be ideally designed for binding and catalysis of its substrates. Fig. 3. (Top) Binding of statin (rosuvastatin), compared with binding of HMG-CoA and NADP. See text for details. (Bottom) Hydrophobic portion of statin molecule within binding groove exposed by movement of flexible alpha helices of HMG-CoA reductase active domain. Top and bottom reproduced with permission from Istvan and Deisenhofer [1]. With regard to binding of HMG-CoA, the enzyme contains an unusual structure motif, a cis-loop, that permits appropriate positioning of several amino acid residues (Ser 684, Asp 690, Lys 691, and Lys 692 ) to bind the HMG moiety. The right-hand portion of the figure shows a loop region containing Glu 559 and His 866,two residues important in binding the CoA moiety; this helical structure folds over the active site, shielding it

3 E. Istvan / Atherosclerosis Supplements 4 (2003) 3 /8 5 Fig. 4. (Top) Structure of HMG-CoA (left), the type 1 statins compactin and simvastatin, and the type 2 statins cerivastatin, atorvastatin, rosuvastatin, and fluvastatin. Median inhibitory concentrations (IC 50 ) of statins for inhibition of HMG-CoA reductase in studies using purified human enzyme catalytic domain are shown. See text for description of differences in statin structure. (Bottom) Comparison of basic type 1 statin structure and type 2 statin structure (type 2 statin shown is rosuvastatin). Top is reproduced with permission from Istvan and Deisenhofer [1]. from water and creating a narrow binding site for the CoA portion of the substrate. 3. Site of statin binding to HMG-CoA reductase All statins share a structural component that is very similar to the HMG portion of HMG-CoA, and all differ from HMG-CoA in being more bulky and more hydrophobic. As discussed below, statins differ in structure apart from this HMG-like moiety, with these structural differences resulting in different binding characteristics apart from the binding of the HMGlike portion. In all of the statins, the HMG-like portion is covalently linked to a rigid hydrophobic group, which ranges from very hydrophobic (e.g., in the case of cerivastatin) to partly hydrophobic (e.g., in the case of rosuvastatin). Consistent with the presence of the HMG-like moiety, all statins are competitive inhibitors of HMG-CoA reductase with respect to binding of

4 6 E. Istvan / Atherosclerosis Supplements 4 (2003) 3 /8 Fig. 5. HMG-CoA reductase complexes with compactin, simvastatin, fluvastatin, cerivastatin, atorvastatin, and rosuvastatin. Binding interactions are indicated by dotted lines, and numerals indicate distance in angstroms. Additional binding interactions of atorvastatin and rosuvastatin, compared with other type 2 statins, are indicated. Adapted with permission from Istvan and Deisenhofer [1]. HMG-CoA, but not with respect to binding of NADPH; K i values for NADPH range from 0.1 to 2.3 nm, compared with the K m for HMG-CoA of 4 mm. Fig. 3 compares the binding of the statins with that of the HMG-CoA and NADP substrates. The statin is positioned approximately in the HMG-CoA binding site; it is noteworthy that this positioning is consistent with enzymatic data available before the inhibitor / HMG-CoA reductase complex structure was solved. The statin molecule does not occupy the NADP(H) binding pocket, a finding that is also consistent with prior enzyme kinetic studies. The binding of the HMGlike portion of the statin molecule is associated with a conformational change in the enzyme whereby movement of flexible C-terminal alpha helices exposes a shallow hydrophobic binding site for the bulky hydrophobic groups of the statin molecules (Fig. 3, bottom). The flexibility of these residues is a key feature of statin binding to the enzyme. Thus, these studies have demonstrated that statins sterically hinder substrate binding by binding to the active site of HMG-CoA reductase. 4. Differences in statin structure The top part of Fig. 4 shows the median inhibitory concentrations of the statins for HMG-CoA inhibition; as can be seen, rosuvastatin is the most potent of the inhibitors, followed by atorvastatin [1/3]. Statins can be divided into two classes based on their structure (Fig. 4, bottom). In addition to the HMG-like moiety, type 1 inhibitors (compactin, pravastatin, and simvastatin) feature a decalin ring. Type 2 inhibitors (rosuvastatin, atorvastatin, cerivastatin, fluvastatin) contain a fluorophenyl group and a methylethyl group not present in the type 1 inhibitors in addition to the HMG-like moiety. Type 2 inhibitors differ with regard to central ring structure; as magnified in the bottom part of Fig. 4, the

5 E. Istvan / Atherosclerosis Supplements 4 (2003) 3 /8 7 Fig. 6. Close-up view of binding of type 1 statin simvastatin, showing decalin ring binding interactions in addition to binding interactions of HMG-like moiety. Adapted with permission from Istvan and Deisenhofer [1]. central ring structure in the type 2 inhibitor rosuvastatin is a pyrimidinyl group. 5. Differences in statin binding Fig. 5 shows complexes of compactin, simvastatin, fluvastatin, cerivastatin, atorvastatin, and rosuvastatin bound with HMG-CoA reductase. Figs. 6 and 7 show close-up views of complexes of the enzyme with the type 1 statin simvastatin and the type 2 statin rosuvastatin, which exhibits the greatest number of interactions with the enzyme. The interactions between the HMG-like moieties of the statins and the enzyme, as indicated by the dotted lines, are predominantly ionic or polar and are similar for all the statins. The rigid hydrophobic groups of all the statin molecules are in the shallow binding site between helices La1 and La10 at the bottom of each depicted complex. As shown more clearly in Fig. 6 for simvastatin, the binding of the type 1 statins involves the numerous hydrogen binding interactions similar to those formed with the HMG-CoA substrate, as well as interaction of the decalin ring structure with a helix of the enzyme. In contrast, the methylethyl groups of the type 2 inhibitors functionally replace the decalin structure of the type 1 statins, and the type 2 inhibitors exhibit additional binding interactions between their fluorophenyl groups and the HMG-CoA reductase Arg 590 residue (see closeup view for rosuvastatin in Fig. 7). Fig. 7. Close-up view of binding of type 2 statin rosuvastatin, showing methylethyl group, fluorophenyl group, sulfone oxygen, and sulfone group interactions in addition to HMG-like moiety interactions. ZD4522 is rosuvastatin. Adapted with permission from Istvan and Deisenhofer [1]. In addition to these interactions, rosuvastatin and atorvastatin exhibit hydrogen bonds with the HMG- CoA Ser 565 residue, involving a sulfone oxygen atom in the case of rosuvastatin and a carbonyl oxygen atom in the case of atorvastatin. Rosuvastatin is unique (exhibits a further binding interaction) among the statins in that it forms a polar interaction between its electronegative sulfone group and the enzyme Arg 568 side chain. 6. Conclusions The structure of HMG-CoA reductase and complexes with six statins have been determined with X-ray crystallography. These studies show that the HMGlike moiety common to the statin molecules occupies the HMG binding site of the enzyme, with the hydrophobic groups of the statins being positioned in a shallow groove formed by rearrangement of the C-terminal residues of the enzyme. Thus, statins act by binding to the active site of HMG-CoA reductase and sterically preventing the substrate from binding. These studies further show that type 2 statins exhibit additional binding interactions via their fluorophenyl groups, that atorvastatin and rosuvastatin exhibit hydrogen bonds absent in other type 2 statins, and that rosuvastatin exhibits a unique binding interaction and the greatest number of interactions overall among the statins.

6 8 E. Istvan / Atherosclerosis Supplements 4 (2003) 3 /8 References [1] Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001;292:1160/4. [2] Holdgate GA, Ward WHJ, Davidson M, Thornton M, March R, McTaggart F. Kinetics of inhibition of HMG-CoA reductase by a new statin, rosuvastatin. Atherosclerosis 2001;2(Suppl.):90 (Abstract 174). [3] McTaggart F, Buckett L, Davidson R, Holdgate G, McCormick A, Schneck D, et al. Preclinical and clinical pharmacology of rosuvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor. Am J Cardiol 2001;87(Suppl.):28B/ 32B. [4] Istvan ES, Deisenhofer J. The structure of the catalytic portion of human HMG-CoA reductase. Biochim Biophys Acta 2000;1529:9/ 18.

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