Principles of Metabolic Control in Mammalian Systems

1 The Principles of Metabolic Control.- I. The First Fundamental Theorem of Theoretical Biology.- A. The Nature of the Life Process.- B. The Products of Protein Biosynthesis.- C. Cellular Replacement and Replication.- II. The Second Fundamental Theorem of Theoretical Biology.- A. The Order of Acquisition of Function.- B. The Functional Specialization of DNA, RNA, and Protein.- C. Biochemical Implications of Evolution.- >III. Other Fundamental Theorems of Theoretical Biology.- A. Theorem 3.- B. Theorem 4.- C. Theorem 5.- IV. Summary.- References.- 2 Nonequilibrium Thermodynamics, Noncovalent Forces, and Water.- I. Introduction.- II. Stability, Thermodynamics, and Biological Organization.- A. The Development of a General Theory of Thermodynamics.- B. Order through Fluctuations.- C. Stability Criteria, Instability, and Thermodynamic Theory.- D. Model Dissipative Structures.- E. Evolutionary Feedback.- III. Noncovalent Forces.- A. Electrostatic Interactions.- B. Van der Waals Forces.- C. Hydrogen Bonding.- D. Hydrophobic Interactions.- IV. Water.- V. Conclusions and Implications.- Appendix I.- Appendix II: Glossary.- References.- 3 Enzymes and Coenzymes: A Mechanistic View.- I. Introduction.- II. Chemical Bonding.- A. Bond Energy.- B. Noncovalent Interactions.- III. Chemical Reactions.- A. Reaction Intermediates.- IV. The Protein Nature of Enzymes.- A. The Amino Acid Side Chains.- B. The Active Site.- V. Enzyme Mechanisms.- A. Approximation and Orientation.- B. The Transition State.- C. Other Factors in Catalysis.- VI. Coenzymes.- A. Adenosine Triphosphate.- B. Nicotinamide Nucleotides.- C. Coenzyme A.- D. Pyridoxal Phosphate.- E. Lipoic Acid.- F. Thiamine Pyrophosphate.- G. Flavins.- H. Biotin.- I. Folate Coenzymes.- J. Metal Ions in Catalysis.- K. Coenzyme B12.- VII. Evolution of Enzyme Function.- References.- 4 Modulation of Enzyme Activity.- I. Introduction.- II. Noncovalent Regulatory Mechanisms.- A. Modulation by Substrate and Product Concentration in Enzymes Following Classical Michaelis-Menten Kinetics.- B. Cooperativity.- C. Modulation of Enzyme Activity by Binding of Small Molecules to Regulatory Sites.- D. Kinetics of Interacting Enzyme Sites.- E. Modulation by Metabolite Ratios.- F. Modulation by Protein-Protein Interaction.- G. Other Regulatory Phenomena.- H. Summary of Noncovalent Regulation of Enzyme Activity.- III. Covalent Regulatory Mechanisms.- A. Covalent Modification by Irreversible Interconversions.- B. Modification by Reversible Covalent Action.- C. Substrate Cycles.- IV. Enzyme Synthesis and Degradation.- V. Evaluation of the Physiologic Importance of Regulatory Mechanisms.- A. Identification of Potentially Rate-Controlling Steps.- VI. Conclusion: An Overview of Regulation.- References.- 5 Regulation of Protein Biosynthesis.- I. Introduction.- A. The Reason for Protein Biosynthesis.- B. The Complexity of Protein Biosynthesis.- C. The Third Fundamental Theorem of Theoretical Biology.- II. The Mechanism of Protein Biosynthesis.- A. A General Description of Protein Biosynthesis.- B. Gene Structure and Protein-Nucleic Acid Interactions.- C. Genetic Code.- D. DNA-Dependent RNA Polymerase.- E. Posttranscriptional Modification of Ribonucleic Acids.- F. Protein Biosynthesis.- III. The Regulation of Protein Biosynthesis.- A. Regulation at the Gene Level.- B. Translational Control of Protein Synthesis.- References.- 6 Degradation of Enzymes.- I. Introduction.- A. Why Enzyme Degradation?.- B. Partial or Complete Degradation?.- II. Kinetics of Enzyme Degradation.- A. Kinetic Order.- B. First-Order Kinetics.- III. Techniques for the Measurement of Enzyme Degradation.- A. Steady-State Methods for the Determination of Degradation Rate Constants.- B. Non-Steady-State Methods.- IV. Variability of Enzyme Half-Lives.- A. Enzymes with Short Half-Lives.- B. Stable Enzymes.- C. Abnormal Enzymes.- D. Lysosomal Enzymes.- E. Mitochondrial Enzymes.- F. Protein Properties Correlating with Half-Lives.- G. Half-Lives of the Same Enzymes in Different Tissues.- V. Changes to Degradation Rate Constants.- A. Effects of Ligands.- B. Effects of Hormones and Nutrients.- C. Effects of Growth and Development.- D. Relative Contribution of Changes in kd to Alterations in Enzyme Content.- VI. Intracellular Localization of Degradative Pathways.- A. Lysosomes and Autophagy.- B. Degradation of Proteins within Organelles.- C. Possible Experimental Approaches for Defining the Intracellular Localization of Protein Breakdown.- VII. Initial Reactions in Enzyme Degradation.- A. Inactivation of Enzymes in Vitro.- B. Sulfhydryl Reactions and Protein Catabolism.- C. Coenzyme Dissociation.- D. Specific Proteolytic Enzymes.- VIII. Conclusions.- References.- 7 DNA Replication and the Cell Cycle.- I. Introduction.- II. Chromatin Structure.- III. The Cell Cycle.- IV. DNA Synthesis.- V. Mitosis.- VI. Gene Activation and Inactivation.- VII. Summary.- References.- 8 Servomechanisms and Oscillatory Phenomena.- I. Introduction.- II. Feedback and Feedforward Phenomena.- A. Glycolysis: The Pasteur Effect.- B. Fatty Acid Synthesis.- C. Cholesterol Synthesis.- D. Other Examples of Feedback Control.- III. Oscillatory Phenomena.- A. Oscillations in Open Systems.- B. Biological Examples.- C. Involvement of Oscillatory Behavior in Collective Phenomena.- IV. Proposed Physiological Significance of Oscillatory Phenomena.- References.- 9 Membrane-Bound Enzymes.- I. Introduction.- II. Membrane Composition and Structure.- A. Isolation and Solubilization of Membrane-Bound Enzymes.- III. Endoplasmic Reticulum.- A. Microsomal Acyl-CoA Desaturation System.- B. Microsomal Hydroxylation System.- C. Sarcoplasmic Reticulum.- IV. Golgi Apparatus.- V. Mitochondria.- A. Respiratory Chain and Electron Transport.- B. H+-ATPase.- VI. Plasma Membrane.- VII. Temperature Effects.- A. Lipid Liquid Crystals.- B. Lipid-Protein Interactions.- VIII. Conclusion: Effects of Lipids on Enzymatic Activity.- References.- 10 The Importance of Phospholipid-Protein Interactions for Regulation of the Activities of Membrane-Bound Enzymes.- I. Introduction.- II. Effect of Lipid Composition on the Properties of Membranes and Membrane-Bound Proteins.- A. Influence of Chain Length and Unsaturation of Phospholipid Fatty Acids on Membrane Structure and Function.- B. Influence of Phospholipid Headgroups on Membrane Structure and Function.- C. Influence of Cholesterol on the Properties of Phospholipid Membranes.- D. Inhomogeneous Nature of the Lipid Phase of Biological Membranes.- E. Sensitivity of Membrane-Bound Proteins to Temperature-Induced Changes in Membrane Lipids.- III. The Effect of Proteins on the Properties of Membrane Lipids.- IV. The Effect of Phospholipids on the Activities of Soluble Enzymes and Proteins.- V. Reconstituted Systems.- VI. Alteration of the Properties of Tightly-Bound Membrane Enzymes by Perturbation of Their Membrane Lipid Environment.- A. Glucose-6-Phosphatase.- B. UDP-Glucuronyltransferase.- VII. Model for Lipid-Protein Interactions.- VIII. Consideration of Factors Regulating the Activities of Membrane-Bound Enzymes in Vivo.- IX. Conclusions.- References.- 11 Membrane Structure and Transport Systems.- I. Introduction.- II. Contact Inhibition and Intercellular Communication.- III. Antigenic and Receptor Sites.- IV. Membrane Structure.- V. Membrane Composition.- A. Carbohydrates.- B. Proteins.- C. Lipids.- VI. Transport Systems.- A. Free Diffusion.- B. Diffusion through Pores.- C. Pinocytosis.- D. Carrier-Mediated Transport and Ion Pumps.- E. Transport of Amino Acids and Sugars.- F. Water Transport.- VII. Summary.- References.- 12 Cellular Mechanisms of Secretion.- I. Introduction.- II. Representative Secretory Cells.- A. The Pancreatic Exocrine Cell.- B. The Intestinal Goblet Cell.- C. The Intestinal Absorptive Cell.- III. Membrane Flow and Differentiation.- A. The Hypothesis.- B. Supportive Experimental Data.- IV. Membrane Reutilization.- A. Supportive Experimental Data.- B. Reutilization versus Flow and Differentiation of Membranes.- C. Unidirectional Secretory Product Transport.- V. The Clinical Importance of Intracellular Membranes for Secretion.- VI. Microtubules.- A. Structure.- B. Function.- C. Microtubules and Secretion.- VII. Mechanisms of Secretory Activation.- A. Calcium and cAMP.- B. A Hypothesis of Secretory Activation.- VIII. Types of Secretory Discharge.- IX. Summary.- References.- 13 Compartmentation and Its Role in Metabolic Regulation.- I. Introduction.- II. Nature of Intracellular Compartments.- III. Zymogen Activation and Compartmentation.- A. Enzymes as Zymogens in Their Own Degradation.- B. Compartmentation of Secretory Proteins-The Signal Peptide Theory.- IV. Membrane Permeability and the Movement of Molecules in the Cell.- A. Compartmentation and Oxidative Phosphorylation.- B. ATP Translocation across the Inner Mitochondrial Membrane.- C. Compartmentation of Citric-Acid-Cycle Intermediates and Other Anions.- D. Species Differences in Compartmentation.- E. Measurement of the Compartmentation of Intermediates-Limitations of Available Methods.- V. Examples of the Role of Compartmentation in the Regulation of Energy Metabolism.- A. Gluconeogenesis.- B. Lipid Biosynthesis.- C. Fatty Acid Oxidation.- VI. Conclusions.- References.- 14 The Mechanism of Action of Hormones.- I. Introduction.- A. Definitions.- B. Classification of Hormones.- C. The Criteria for Establishing a Substance as a Hormone.- D. The Need for Hormones and Other Signal Molecules.- II. Hormones.- A. The Basic Principles of Hormone Function.- B. The Membrane Receptor-Adenylate Cyclase-cAMP-Cyclic Nucleotide Systems.- C. The Membrane Receptor-Non-Adenylate-Cyclase System.- D. Intracellular Hormone-Binding Proteins.- References.- 15 The Biochemical Basis of Disease.- I. Introduction.- A. The Biochemical Nature of Disease.- B. The Definition of Intermediary Metabolism.- II. The Biochemical Basis of Disease.- A. Implications of the Basic Thesis.- B. The Adaptive Response.- C. The Biochemical Abnormality.- D. Enzyme Deficiency States.- III. Therapeutic Approaches to Disease.- A. Treatment of Inborn Errors of Metabolism.- B. The Classical Modes of Therapy in Medicine.- References.