Principles of Metabolic Control in Mammalian Systems

In this work we present the basic principles of metabolic control which we hope will serve as a foundation for the vast array of factual matter which the biochemist and the physician engaged in metabolic research must accumulate. Accordingly, we attempt to set forth these principles, along with sufficient explanation, so that the reader may apply them to the ever-expanding literature of biochemistry. If we are successful, this will provide a theoretical approach which can be applied to any given set of metabolic reactions. It is impossible to enumerate each and every biochemical reaction and pathway since such a work would be too unwieldy for efficient use. Rather, we hope our presentation of the principles of metabolic control will be sufficiently basic to be of lasting usefulness no matter how detailed biochemistry may become. We would like to be able to con- dense biochemistry into a theoretical biology that will not only allow for the general treatment of any given reaction but will enable predic- tions to be made as to the existence of necessary pathways and the con- sequences of altered control. Such is not possible today, but this may be accomplished in the future. We believe it is now possible to institute the beginnings of such a theoretical biology.

Table of Contents:
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.