Regulation of HMG-CoA Reductase

Regulation of HMG-CoA Reductase is a nine-chapter text that focuses on the research developments in the regulation of HMG-CoA reductase enzyme and cholesterol biosynthesis. This book deals first with the role of cholesterol in the regulation of its own biosynthesis and the work involving compactin and related competitive inhibitors of HMG-CoA reductase. The subsequent chapters examine the reversible phosphorylation of HMG-CoA reductase in hormonal and other short-term physiological changes and the structure and properties of the enzyme, including evidence for modulation of enzyme activity and structure unrelated to phosphorylation. These topics are followed by discussions on the regulation of reductase in the biosynthesis of ubiquinone, dolichols, and isopentenyl-tRNA and the regulation of reductase activity in extrahepatic tissues. This text further explores the contributions made through the use of cultured cells and their genetic manipulation, with emphasis on the great potential of this approach. The concluding chapters address the status of the low-density lipoprotein pathway and related mechanisms. These chapters also consider the regulation of human hepatic HMG-CoA reductase and the special problems inherent in work with human tissues. Enzyme scientists and researchers and graduate students will find this book invaluable.

Contributors Preface 1 Membrane-Mediated Control of Reductase Activity I. Introduction II. Regulation of HMG-CoA Reductase Activity III. The Concept of Feedback Inhibition in Cholesterogenesis IV. Relationship between Cellular Cholesterol Concentration and HMG-CoA Reductase Activity V. Architectural Organization of Biological Membranes VI. Modulation of HMG-CoA Reductase by Nonesterified Cholesterol VII. Conclusions and Prospectives References 2 Specific Nonsterol Inhibitors of HMG-CoA Reductase I. Introduction II. Isolation and Chemistry of Compactin (ML-236B)-Related Compounds III. Inhibition of HMG-CoA Reductase IV. Inhibition of Sterol and Other Isoprenoid Syntheses V. Induction of HMG-CoA Reductase VI. Growth Inhibition VII. Compactin-Resistant Cells VIII. Relationship between the Effects of Compactin and Oxygenated Sterols on HMG-CoA Reductase IX. Hypocholesterolemic Activity X. Summary and Conclusion References3 Reversible Phosphorylation of Hepatic HMG-CoA Reductase in Endocrine and Feedback Control of Cholesterol Biosynthesis I. Introduction II. Short-Term Control of HMG-CoA Reductase III. Biological Significance of Reversible Phosphorylation of HMG-CoA Reductase References 4 Studies on Purified Mammalian HMG-CoA Reductase and Regulation of Enzyme Activity I. Introduction II. Purification of HMG-CoA Reductase III. Different Forms of HMG-CoA Reductase IV. Structure of the Microsomal-Bound Enzyme V. Enzyme Regulation References 5 Regulation of HMG-CoA Reductase and the Biosynthesis of Nonsteroid Prenyl Derivatives I. Introduction II. Biosynthesis of Ubiquinone III. Biosynthesis of Dolichols IV. Isopentenyl Transfer RNA and Its Metabolites V. Other Isoprenoid Derivatives of Mevalonate VI. Overview of the Regulation of Isoprenoid Biosynthesis References 6 Regulation of HMG-CoA Reductase in Extrahepatic Tissues I. Introduction II. Intestinal HMG-CoA Reductase III. HMG-CoA Reductase in Steroid-Hormone-Producing Tissues IV. Conclusions References 7 Somatic Cell Genetic Analysis of Cholesterol Biosynthesis I. Introduction II. Cholesterol Auxotrophs III. 25-Hydroxycholesterol-Resistant Mutants IV. Compactin-Resistant Variants V. Somatic Cell Mutants Defective in Internalization of Low Density Lipoprotein VI. Analysis of the Effect of Membrane Cholesterol Levels on Membrane Structure and Function References 8 Plasma Lipoproteins and 3-Hydroxy-3-methylglutaryl-coenzyme A Reductase: A Status Report I. Introduction II. Plasma Lipoproteins III. Lipoprotein Synthesis and Secretion IV. Lipoprotein Dynamics V. Intravascular Lipoprotein Metabolism VI. Receptor-Mediated Uptake of Plasma Lipoproteins VII. Nonreceptor-Mediated Cellular Uptake of Cholesterol and Lipoproteins VIII. Regulation of Gene Expression IX. Summary and Future Directions References 9 Regulation of HMG-CoA Reductase in Human Liver I. Introduction II. Overall Aspects of Cholesterol Metabolism in Humans III. Assay and Properties of Hepatic Microsomal HMG-CoA Reductase in Humans IV. Studies on Clinical Conditions V. Studies Using Experimental Perturbations VI. Conclusions and Implications for Future Work References Reductase: Future Directions Index