1 Introduction 1 Introduction THE VALUE OF BIOCHEMISTRY HOW THIS BOOK TELLS THE STORY OF BIOCHEMISTRY 2 Amino Acids and Proteins 2 Amino Acids and Proteins INTRODUCTION AMINO ACIDS AMINO ACIDS Stereochemistry: configuration at the α-carbon, d- and l-isomers Classification of amino acids based on chemical structure Aliphatic amino acids Aromatic amino acids Neutral polar amino acids Acidic amino acids Basic amino acids Sulfur-containing amino acids Proline, a cyclic amino acid Classification of amino acids based on the polarity of the amino acid side chains Ionization state of an amino acid Henderson-Hasselbalch equation and pKa BUFFERS PEPTIDES AND PROTEINS PEPTIDES AND PROTEINS Primary structure of proteins The charge and polarity characteristics of a peptide chain Secondary structure is determined by hydrogen bonding interactions of carbonyl and amide residues in the peptide backbone Tertiary structure results from folding of the peptide chain Quaternary structure is formed by interactions between peptide chains PURIFICATION AND CHARACTERIZATION OF PROTEINS PURIFICATION AND CHARACTERIZATION OF PROTEINS Salting-out Separation on the basis of size Separation on the basis of charge: ion-exchange chromatography Affinity chromatography Determination of purity and molecular weight of proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis Isoelectric focusing ANALYSIS OF PROTEIN STRUCTURE PROTEIN FOLDING AND FOLDING DISEASE PROTEIN FOLDING AND FOLDING DISEASE Summary 3 Blood: Cells and Plasma Proteins 3 Blood: Cells and Plasma Proteins INTRODUCTION PLASMA AND SERUM FORMED ELEMENTS OF BLOOD FORMED ELEMENTS OF BLOOD Erythrocytes Leukocytes PLASMA PROTEINS PLASMA PROTEINS Albumin Proteins that transport metal ions Immunoglobulins THE ACUTE PHASE RESPONSE AND C-REACTIVE PROTEIN THE ACUTE PHASE RESPONSE AND C-REACTIVE PROTEIN Summary 4 Oxygen Transport 4 Oxygen Transport INTRODUCTION INTRODUCTION Properties of O2 STRUCTURE OF THE HEME PROSTHETIC GROUP CHARACTERISTICS OF MAMMALIAN GLOBIN PROTEINS CHARACTERISTICS OF MAMMALIAN GLOBIN PROTEINS Myoglobin: an O2-storage protein Hemoglobin: an O2-transport protein Transition between deoxygenated and oxygenated hemoglobin Interactions with allosteric effectors RECENTLY IDENTIFIED VERTEBRATE GLOBINS INSIGHTS FROM MYOGLOBIN KNOCKOUT MICE INTERACTIONS OF HEMOGLOBIN WITH NITRIC OXIDE NORMAL HB VARIANTS SICKLE CELL DISEASE OTHER HEMOGLOBINOPATHIES OTHER HEMOGLOBINOPATHIES Summary 5 Catalytic Proteins-Enzymes 5 Catalytic Proteins-Enzymes INTRODUCTION ENZYMATIC REACTIONS ENZYMATIC REACTIONS Factors affecting enzymatic reactions Definition of enzyme activity Roles of coenzymes ENZYME KINETICS ENZYME KINETICS The Michaelis-Menten equation: a simple model of an enzymatic reaction ENZYME INHIBITION ENZYME INHIBITION Enzymes are inhibited in different ways REGULATION OF ENZYME ACTIVITY REGULATION OF ENZYME ACTIVITY Proteolytic activation of digestive enzymes Allosteric regulation of rate-limiting enzymes in metabolic pathways Summary 6 Hemostasis and Thrombosis 6 Hemostasis and Thrombosis INTRODUCTION HEMOSTASIS THE VESSEL WALL PLATELETS PLATELETS Platelet-related bleeding disorders Antiplatelet drugs COAGULATION COAGULATION The intrinsic pathway The extrinsic pathway The final common pathway Thrombin FIBRINOLYSIS FIBRINOLYSIS Summary 7 Membranes and Transport 7 Membranes and Transport INTRODUCTION MEMBRANE LIPIDS MEMBRANE LIPIDS Structure and properties of membrane lipids COMPOSITION OF BIOMEMBRANES COMPOSITION OF BIOMEMBRANES Current structural model of the membrane Structural and metabolic role of membranes TYPES OF TRANSPORT PROCESSES TYPES OF TRANSPORT PROCESSES Simple diffusion through the phospholipid bilayer Transport mediated by membrane proteins Characteristics of glucose transporters Transport by channels and pores Active transport Examples of transport systems and their coupling Summary 8 Bioenergetics and Oxidative Metabolism 8 Bioenergetics and Oxidative Metabolism INTRODUCTION OXIDATION AS A SOURCE OF ENERGY OXIDATION AS A SOURCE OF ENERGY Energy content of foods The basal metabolic rate Stages of fuel oxidation FREE ENERGY CONSERVATION OF ENERGY BY COUPLING WITH ATP MITOCHONDRIAL SYNTHESIS OF ATP FROM REDUCED COENZYMES MITOCHONDRIAL SYNTHESIS OF ATP FROM REDUCED COENZYMES Transduction of energy from reduced coenzymes to high-energy phosphate THE MITOCHONDRIAL ELECTRON TRANSPORT SYSTEM THE MITOCHONDRIAL ELECTRON TRANSPORT SYSTEM Flavoproteins contain FAD or FMN prosthetic groups Ubiquinone transfers electrons to complex III Complex III - Cytochrome c reductase Cytochrome c Complex IV THE ATP-SYNTHETIC PROTON GRADIENT P:O RATIOS AND RESPIRATORY CONTROL P:O RATIOS AND RESPIRATORY CONTROL Uncouplers Uncoupling proteins INHIBITORS OF OXIDATIVE METABOLISM INHIBITORS OF OXIDATIVE METABOLISM Electron transport system inhibitors Inhibitors of ATP synthase Inhibitors of the ADP-ATP translocase REGULATION OF OXIDATIVE PHOSPHORYLATION REGULATION OF OXIDATIVE PHOSPHORYLATION Respiratory control and feedback regulation Regulation by covalent modification and allosteric effectors Regulation by thyroid hormones Summary 9 Function of the gastrointestinal tract 9 Function of the gastrointestinal tract INTRODUCTION DIGESTION DIGESTION The mechanical and anatomical basis of digestion Volume and pH of intestinal secretions General principles of digestion Digestive enzymes and zymogens Digestion and absorption of carbohydrates Digestion and absorption of lipids Digestion and absorption of proteins Summary 10 Micronutrients: Vitamins and Minerals 10 Micronutrients: Vitamins and Minerals INTRODUCTION FAT-SOLUBLE VITAMINS FAT-SOLUBLE VITAMINS Vitamin A Vitamin D Vitamin E Vitamin K WATER-SOLUBLE VITAMINS WATER-SOLUBLE VITAMINS B-complex vitamins Biotin Panthotenic acid Folic acid Vitamin B12 Vitamin C Dietary supplementation of vitamins TRACE ELEMENTS TRACE ELEMENTS Iron Zinc Copper Selenium Summary 11 Anaerobic Metabolism of Glucose in the Red Blood Cell 11 Anaerobic Metabolism of Glucose in the Red Blood Cell INTRODUCTION THE ERYTHROCYTE GLYCOLYSIS GLYCOLYSIS Overview The investment stage of glycolysis The splitting stage of glycolysis The yield stage of glycolysis - synthesis of ATP by substrate-level phosphorylation Fermentation Regulation of glycolysis in erythrocytes SYNTHESIS OF 2,3-BISPHOSPHOGLYCERATE THE PENTOSE PHOSPHATE PATHWAY THE PENTOSE PHOSPHATE PATHWAY Overview The redox stage of the pentose phosphate pathway - synthesis of NADPH CONCENTRATIONS OF REDOX COENZYMES IN THE CELL CONCENTRATIONS OF REDOX COENZYMES IN THE CELL The interconversion stage of the pentose phosphate pathway Function of the pentose phosphate pathway in the red cell Summary 12 Carbohydrate Storage and Synthesis in Liver and Muscle 12 Carbohydrate Storage and Synthesis in Liver and Muscle INTRODUCTION STRUCTURE OF GLYCOGEN PATHWAY OF GLYCOGENESIS FROM BLOOD GLUCOSE IN LIVER PATHWAY OF GLYCOGENOLYSIS IN LIVER HORMONAL REGULATION OF HEPATIC GLYCOGENOLYSIS MECHANISM OF ACTION OF GLUCAGON MOBILIZATION OF HEPATIC GLYCOGEN BY EPINEPHRINE GLYCOGENOLYSIS IN MUSCLE REGULATION OF GLYCOGENESIS GLUCONEOGENESIS GLUCONEOGENESIS Gluconeogenesis from lactate Gluconeogenesis from amino acids and glycerol Regulation of gluconeogenesis Conversion of fructose and galactose to glucose Summary 13 The Tricarboxylic Acid Cycle 13 The Tricarboxylic Acid Cycle INTRODUCTION ENERGY PRODUCTION IN THE TCA CYCLE BIOSYNTHESES LINKED TO TCA CYCLE PYRUVATE CARBOXYLASE THE PYRUVATE DEHYDROGENASE COMPLEX ENZYMES AND REACTIONS OF THE TCA CYCLE ENZYMES AND REACTIONS OF THE TCA CYCLE Citrate synthase Aconitase Isocitrate dehydrogenase and α-ketoglutarate dehydrogenase Succinyl-CoA synthetase Succinate dehydrogenase Fumarase Malate dehydrogenase ENERGY YIELD FROM THE TCA CYCLE REGULATION OF THE TCA CYCLE ANAPLEROTIC REACTIONS ANAPLEROTIC REACTIONS Summary 14 Oxidative Metabolism of Lipids in Liver and Muscle 14 Oxidative Metabolism of Lipids in Liver and Muscle INTRODUCTION ACTIVATION OF FATTY ACIDS AND THEIR TRANSPORT TO THE MITOCHONDRION ACTIVATION OF FATTY ACIDS AND THEIR TRANSPORT TO THE MITOCHONDRION The carnitine shuttle OXIDATION OF FATTY ACIDS OXIDATION OF FATTY ACIDS Mitochondrial β-oxidation Alternative pathways of oxidation of fatty acids KETOGENESIS IN LIVER KETOGENESIS IN LIVER Gluconeogenesis in fasting and starvation Mobilization of lipids during gluconeogenesis and work Summary 15 Biosynthesis and Storage of Fatty Acids in Liver and Adipose Tissue 15 Biosynthesis and Storage of Fatty Acids in Liver and Adipose Tissue INTRODUCTION FATTY ACID SYNTHESIS FATTY ACID SYNTHESIS Acetyl-CoA carboxylase Fatty acid synthase The malate shuttle FATTY ACID ELONGATION DESATURATION OF FATTY ACIDS ESSENTIAL FATTY ACIDS STORAGE AND TRANSPORT OF FATTY ACIDS: THE SYNTHESIS OF TRIACYLGLYCEROLS REGULATION OF TOTAL BODY FAT STORES REGULATION OF TOTAL BODY FAT STORES Summary 16 Biosynthesis of Cholesterol and Steroids 16 Biosynthesis of Cholesterol and Steroids INTRODUCTION CHOLESTEROL STRUCTURE THE FREE AND ESTERIFIED CHOLESTEROL CHOLESTEROL BIOSYNTHESIS CHOLESTEROL BIOSYNTHESIS Regulation of cholesterol biosynthesis BILE ACIDS CHOLESTEROL EXCRETION STEROID HORMONES STEROID HORMONES Biosynthesis of the steroid hormones The corticosteroids The androgens The estrogens Mechanism of action and elimination of the steroid hormones VITAMIN D3 VITAMIN D3 Summary 17 Lipids and Lipoproteins 17 Lipids and Lipoproteins INTRODUCTION STRUCTURE AND FUNCTION OF LIPOPROTEINS STRUCTURE AND FUNCTION OF LIPOPROTEINS Apoproteins Functions of lipoproteins Enzymes and transfer proteins LIPOPROTEIN RECEPTORS LIPOPROTEIN RECEPTORS Scavenger receptors MEASUREMENT OF LIPOPROTEINS METABOLISM OF LIPOPROTEINS METABOLISM OF LIPOPROTEINS The integrated view of lipoprotein metabolism: the two pathways DYSLIPIDEMIAS ATHEROGENESIS CARDIOVASCULAR RISK AND ITS ASSESSMENT CARDIOVASCULAR RISK AND ITS ASSESSMENT Summary 18 Biosynthesis and Degradation of Amino Acids 18 Biosynthesis and Degradation of Amino Acids INTRODUCTION INTRODUCTION Amino acids from body proteins and the diet Amino acid degradation The urea cycle and its relationship to central metabolism The concept of nitrogen balance METABOLISM OF THE CARBON SKELETONS OF AMINO ACIDS METABOLISM OF THE CARBON SKELETONS OF AMINO ACIDS Metabolism of the carbon skeletons of selected amino acids AMINO ACID BIOSYNTHESIS INHERITED DISEASES OF AMINO ACID METABOLISM INHERITED DISEASES OF AMINO ACID METABOLISM Phenylketonuria Alkaptonuria Maple syrup urine disease AMINO ACIDS AS PRECURSORS OF SIGNALING MOLECULES AMINO ACIDS AS PRECURSORS OF SIGNALING MOLECULES Summary 19 Muscle: Energy Metabolism and Contraction 19 Muscle: Energy Metabolism and Contraction INTRODUCTION STRUCTURE OF MUSCLE STRUCTURE OF MUSCLE Development of Muscle Sarcomere; the functional contractile unit Muscle contraction: The thick and thin filaments MUSCLE PROTEINS MUSCLE PROTEINS Myosin Actin Tropomyosin and troponins MUSCLE ENERGY METABOLISM METABOLISM AND MUSCLE CONTRACTION METABOLISM AND MUSCLE CONTRACTION Summary 20 Glucose Homeostasis, Fuel Metabolism, and Insulin 20 Glucose Homeostasis, Fuel Metabolism, and Insulin THE ORGAN-FUEL INTERACTIONS GLUCOSE HOMEOSTASIS INSULIN INSULIN Metabolic effects of insulin Metabolic effects of glucagon and anti-insulin hormones HYPOGLYCEMIA METABOLISM AFTER A MEAL AND IN THE FASTING STATE METABOLISM AFTER A MEAL AND IN THE FASTING STATE Postprandial state Postabsorptive state Prolonged fasting and starvation METABOLISM DURING STRESS, AND THE METABOLIC RESPONSE TO INJURY METABOLISM DURING STRESS, AND THE METABOLIC RESPONSE TO INJURY Stress response and laboratory tests DIABETES MELLITUS: THE PRINCIPAL DISORDER OF FUEL METABOLISM DIABETES MELLITUS: THE PRINCIPAL DISORDER OF FUEL METABOLISM Type 1 diabetes Type 2 diabetes Metabolism in diabetes In diabetes, glucose present in excess is a toxic substrate Toxicity of glucose is associated with long-term complications of diabetes Insulin resistance The metabolic syndrome TREATMENT OF DIABETES ASSESSMENT OF FUEL METABOLISM ASSESSMENT OF FUEL METABOLISM Summary 21 Nutrition 21 Nutrition INTRODUCTION KEY DEFINITIONS AND RECOMMENDATIONS USED IN NUTRITION SCIENCE KEY DEFINITIONS AND RECOMMENDATIONS USED IN NUTRITION SCIENCE Recommendations on nutrient intake are based on Dietary Reference Intakes NUTRITION AND GENETICS NUTRITION AND GENETICS Nutritional genomics and metabolomics Genotype influences plasma concentrations of nutrients Nutrition, life cycle and metabolic adaptation Nutrition and disease THE MAIN CLASSES OF NUTRIENTS THE MAIN CLASSES OF NUTRIENTS Carbohydrates Proteins Fats THE ESSENTIAL NUTRIENTS THE ESSENTIAL NUTRIENTS Essential amino acids Essential lipids WATER AND MINERALS WATER AND MINERALS Trace metals and vitamins ENERGY HOMEOSTASIS ENERGY HOMEOSTASIS Energy expenditure The caloric value of nutrients REGULATION OF FOOD INTAKE ASSESSMENT OF NUTRITIONAL STATUS ASSESSMENT OF NUTRITIONAL STATUS Body weight and the body mass index Biochemical markers of nutrition MALNUTRITION OBESITY DIET IN HEALTH AND DISEASE DIET IN HEALTH AND DISEASE Diets in health Weight reduction Low-carbohydrate, high-fat diet and associated controversies NUTRITION AND CHRONIC DISEASE NUTRITION AND CHRONIC DISEASE Diabetes mellitus Cancer Renal disease Nutritional support Summary 22 Water and Electrolyte Balance: Kidney Function 22 Water and Electrolyte Balance: Kidney Function INTRODUCTION WATER, SODIUM, AND POTASSIUM METABOLISM WATER, SODIUM, AND POTASSIUM METABOLISM Body water compartments OSMOLALITY AND VOLUME OF ECF AND ICF OSMOLALITY AND VOLUME OF ECF AND ICF Regulation of cell osmolality and volume THE WATER BALANCE THE KIDNEY THE KIDNEY Energy metabolism and transport function of the kidney The glomerulus The glomerular filtrate The urine Assessment of renal function Serum creatinine concentration and creatinine clearance THE IMPORTANCE OF PLASMA POTASSIUM CONCENTRATION THE RENIN-ANGIOTENSIN SYSTEM WATER REABSORPTION IN THE DISTAL TUBULE AND THE COLLECTING DUCT WATER METABOLISM AND SODIUM METABOLISM ARE INTERRELATED WATER METABOLISM AND SODIUM METABOLISM ARE INTERRELATED Vasopressin and the renin-angiotensin system in water and electrolyte disorders Summary 23 Lung and Kidney: The Control of Acid-Base Balance 23 Lung and Kidney: The Control of Acid-Base Balance THE BODY BUFFER SYSTEMS THE BODY BUFFER SYSTEMS The bicarbonate buffer Intracellular buffering Classification of the acid-base disorders The measurement of blood gases THE LUNGS AND THE GAS EXCHANGE THE LUNGS AND THE GAS EXCHANGE The handling of carbon dioxide KIDNEYS AND THE HANDLING OF BICARBONATE THE CLINICAL DISORDERS OF THE ACID-BASE BALANCE THE CLINICAL DISORDERS OF THE ACID-BASE BALANCE Acidosis Alkalosis Summary 24 Calcium and Bone Metabolism 24 Calcium and Bone Metabolism CALCIUM METABOLISM CALCIUM METABOLISM Factors influencIng calcium homeostasis DISORDERS OF CALCIUM METABOLISM AND BONE DISORDERS OF CALCIUM METABOLISM AND BONE Hypercalcemia Hypocalcemia Genetics of calcium disorders METABOLIC BONE DISEASE METABOLIC BONE DISEASE Summary 25 Complex Carbohydrates: Glycoproteins 25 Complex Carbohydrates: Glycoproteins GLYCOPROTEINS: STRUCTURES AND LINKAGES GLYCOPROTEINS: STRUCTURES AND LINKAGES Structures of the oligosaccharides attached to proteins General structures of glycoproteins INTERCONVERSIONS AND ACTIVATION OF DIETARY SUGARS INTERCONVERSIONS AND ACTIVATION OF DIETARY SUGARS Glucose is a precursor of all sugars in the body Galactose Fructose OTHER PATHWAYS OF SUGAR NUCLEOTIDE METABOLISM OTHER PATHWAYS OF SUGAR NUCLEOTIDE METABOLISM UDP-glucose Guanosine diphosphate-mannose Fructose-6-phosphate N-Acetyl-neuraminic acid BIOSYNTHESIS OF OLIGOSACCHARIDES BIOSYNTHESIS OF OLIGOSACCHARIDES N-linked oligosaccharides O-linked oligosaccharides FUNCTIONS OF THE OLIGOSACCHARIDE CHAINS OF GLYCOPROTEINS FUNCTIONS OF THE OLIGOSACCHARIDE CHAINS OF GLYCOPROTEINS N-linked oligosaccharides Lectins - plant and animal carbohydrate-binding proteins Summary 26 Complex Lipids 26 Complex Lipids INTRODUCTION GLYCEROPHOSPHOLIPIDS GLYCEROPHOSPHOLIPIDS Structure of phospholipids Biosynthesis of precursors: phosphatidic acid and diacylglycerol Biosynthesis of phospholipids Plasmalogens Turnover of phospholipids SPHINGOLIPIDS SPHINGOLIPIDS Structure and biosynthesis of sphingosine Sphingomyelin Glycolipids Structure and nomenclature of gangliosides Summary 27 The Extracellular Matrix 27 The Extracellular Matrix INTRODUCTION COLLAGENS COLLAGENS Triple-helical structure of collagens Types of collagen Synthesis and post-translational modification of collagens NONCOLLAGENOUS PROTEINS IN THE EXTRACELLULAR MATRIX NONCOLLAGENOUS PROTEINS IN THE EXTRACELLULAR MATRIX Elastin Fibronectin Laminins PROTEOGLYCANS PROTEOGLYCANS Structure of proteoglycans Synthesis and degradation of proteoglycans Functions of the proteoglycans Summary 28 Special Liver Function 28 Special Liver Function INTRODUCTION STRUCTURE OF THE LIVER PARTICIPATION OF THE LIVER IN CARBOHYDRATE METABOLISM LIVER AND PROTEIN METABOLISM LIVER AND PROTEIN METABOLISM Acute phase proteins Clinical conditions associated with abnormal plasma concentrations of specific liver proteins Proteolysis The urea cycle and ammonia HEME SYNTHESIS BILIRUBIN METABOLISM BILIRUBIN METABOLISM Bile acid metabolism DRUG METABOLISM DRUG METABOLISM Drug hepatotoxicity Alcohol PHARMACOGENOMICS GENOMICS OF LIVER DISEASE BIOCHEMICAL TESTS OF LIVER FUNCTION BIOCHEMICAL TESTS OF LIVER FUNCTION Transaminases Alkaline phosphatase CLASSIFICATION OF LIVER DISORDERS CLASSIFICATION OF LIVER DISORDERS Hepatocellular disease Cholestatic disease Jaundice Genetic causes of jaundice Summary 29 Biosynthesis and Degradation of Nucleotides 29 Biosynthesis and Degradation of Nucleotides INTRODUCTION PURINE METABOLISM PURINE METABOLISM De novo synthesis of purine ring: inosine monophosphate Synthesis of purine nucleotides, ATP, and guanosine triphosphate from IMP Preformed nucleotides can be recycled by salvage pathways Degradation of purines in humans to uric acid PYRIMIDINE METABOLISM PYRIMIDINE METABOLISM De novo pathway CTP is synthesized from UTP Pyrimidine-salvage pathways Degradation of pyrimidines is essentially the reverse of synthesis FORMATION OF DEOXYNUCLEOTIDES FORMATION OF DEOXYNUCLEOTIDES Feedback control of ribonucleotide reductase maintains similar amounts of all four deoxynucleotides De novo nucleotide metabolism is highly regulated Summary 30 Deoxyribonucleic acid 30 Deoxyribonucleic acid INTRODUCTION STRUCTURE OF DNA STRUCTURE OF DNA Alternate forms of DNA may help to regulate gene expression Separated DNA strands can reassociate to form duplex DNA DNA is compacted into chromosomes THE CELL CYCLE THE CELL CYCLE DNA is replicated by separating and copying the strands Cells can repair damaged DNA Summary 31 Ribonucleic Acid 31 Ribonucleic Acid MOLECULAR ANATOMY OF RNA MOLECULES RNA POLYMERASES THE PROCESS OF TRANSCRIPTION THE PROCESS OF TRANSCRIPTION Initiation of transcription Elongation Termination Post-transcriptional processing Summary 32 Protein Synthesis and Turnover 32 Protein Synthesis and Turnover INTRODUCTION THE GENETIC CODE THE MACHINERY OF PROTEIN SYNTHESIS THE PROCESS OF PROTEIN SYNTHESIS THE PROCESS OF PROTEIN SYNTHESIS Initiation Elongation Termination PROTEIN TARGETING AND POST-TRANSLATIONAL MODIFICATIONS PROTEIN TARGETING AND POST-TRANSLATIONAL MODIFICATIONS Protein targeting Post-translational modification Proteasomes: Cellular machinery for protein turnover Summary 33 Control of Gene Expression 33 Control of Gene Expression INTRODUCTION BASIC MECHANISMS OF GENE EXPRESSION BASIC MECHANISMS OF GENE EXPRESSION Promoters Enhancers Response elements Transcription factors STEROID RECEPTORS STEROID RECEPTORS The zinc finger region Organization of the steroid receptor molecule ALTERNATIVE APPROACHES TO GENE REGULATION IN HUMANS ALTERNATIVE APPROACHES TO GENE REGULATION IN HUMANS Promoter access Methylation of DNA regulates gene expression GENE EXPRESSION GENE EXPRESSION Summary 34 Recombinant DNA Technology 34 Recombinant DNA Technology INTRODUCTION HYBRIDIZATION HYBRIDIZATION The principles of molecular hybridization Methods used in labeling nucleotide probes DNA storage DNA AMPLIFICATION AND CLONING DNA AMPLIFICATION AND CLONING Cell-based cloning DNA cloning by the polymerase chain reaction SPECIFIC METHODS USED IN THE ANALYSIS OF DNA SPECIFIC METHODS USED IN THE ANALYSIS OF DNA Hybridization-based methods Restriction fragment length polymorphisms Allele-specific oligonucleotides and dot-blot hybridization PCR-based methods Other methods for the detection of variation in DNA Denaturant-gradient gel electrophoresis DNA SEQUENCING DNA SEQUENCING Chain termination DNA sequencing Summary 35 Oxygen and Life 35 Oxygen and Life INTRODUCTION THE INERTNESS OF OXYGEN REACTIVE OXYGEN SPECIES REACTIVE NITROGEN SPECIES THE NATURE OF OXYGEN RADICAL DAMAGE ANTIOXIDANT DEFENSES ANTIOXIDANT DEFENSES Summary 36 The Immune Response 36 The Immune Response INTRODUCTION THE NONSPECIFIC IMMUNE RESPONSE THE NONSPECIFIC IMMUNE RESPONSE Inflammatory mediators contribute to the immune response THE SPECIFIC IMMUNE RESPONSE LYMPHOID TISSUES AND TRAFFIC BETWEEN THEM LYMPHOID TISSUES AND TRAFFIC BETWEEN THEM Primary lymphoid tissues Secondary lymphoid tissues LYMPHOCYTES LYMPHOCYTES Lymphocyte circulation Adhesion molecules T and B lymphocytes MOLECULES INVOLVED IN ANTIGEN RECOGNITION MOLECULES INVOLVED IN ANTIGEN RECOGNITION T-cell antigen receptors The B-cell antigen receptor THE REACTION WITH, THE RESPONSE TO, AND THE ELIMINATION OF, ANTIGENS MAJOR HISTOCOMPATIBILITY COMPLEX MHC EXPRESSION PATTERNS AND MHC RESTRICTED STIMULATION HUMORAL SPECIFIC IMMUNE RESPONSE THE CELLULAR AND MOLECULAR ELEMENTS OF THE INTEGRATED IMMUNE RESPONSE IMMUNOLOGIC DYSFUNCTION IMMUNOLOGIC DYSFUNCTION Summary 37 Biochemical Endocrinology 37 Biochemical Endocrinology INTRODUCTION HORMONES HORMONES Types of hormones Circulation, action, and inactivation of hormones THE HYPOTHALAMO-PITUITARY REGULATORY SYSTEM THE HYPOTHALAMO-PITUITARY REGULATORY SYSTEM Hormones of the posterior pituitary gland Hormones of the hypothalamo-anterior pituitary regulatory system THE HYPOTHALAMO-PITUITARY-THYROID AXIS THE HYPOTHALAMO-PITUITARY-THYROID AXIS Thyrotropin-releasing hormone Thyroid-stimulating hormone Thyroxine and tri-iodothyronine Biochemical actions of thyroid hormones Clinical disorders of thyroid function THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS THE HYPOTHALAMO-PITUITARY-ADRENAL AXIS Adrenocorticotropic hormone Biosynthesis of cortisol Clinical disorders of cortisol secretion THE HYPOTHALAMO-PITUITARY-GONADAL AXIS THE HYPOTHALAMO-PITUITARY-GONADAL AXIS Gonadotropin-releasing hormone Follicle-stimulating hormone and luteinizing hormone Actions of FSH and LH on the testes Biochemical actions of testosterone in the male Clinical disorders of testosterone secretion in males Actions of FSH and LH on the ovary Actions of steroid hormones in the female Disorders of steroid secretion in the female THE GROWTH HORMONE AXIS THE GROWTH HORMONE AXIS Growth hormone-releasing hormone and somatostatin Growth hormone Control of GH secretion Biochemical actions of GH Insulin-like growth factor I Clinical disorders of GH secretion THE PROLACTIN AXIS THE PROLACTIN AXIS Dopamine Prolactin Clinical disorders of prolactin secretion Summary 38 Membrane Receptors and Signal Transduction 38 Membrane Receptors and Signal Transduction INTRODUCTION HORMONE RECEPTORS HORMONE RECEPTORS Intracellular receptors: steroid hormone receptors Cell-surface receptors: polypeptide hormone receptors Receptor-independent signaling mechanisms RECEPTOR COUPLING TO INTRACELLULAR SIGNAL TRANSDUCTION RECEPTOR COUPLING TO INTRACELLULAR SIGNAL TRANSDUCTION G-protein-coupled receptors SECOND MESSENGERS SECOND MESSENGERS Cyclic AMP Protein kinase A Phosphodiesterases Calcium Ion Calmodulin Phosphatidylinositol 4,5-bisphosphate Inositol 1,4,5-trisphosphate Diacylglycerol Phospholipases Arachidonic acid Eicosanoids Leukotrienes Summary 39 Neurochemistry 39 Neurochemistry INTRODUCTION BRAIN AND PERIPHERAL NERVE BRAIN AND PERIPHERAL NERVE The blood-brain barrier CELLS OF THE NERVOUS SYSTEM CELLS OF THE NERVOUS SYSTEM Neurons Neuroglial structures SYNAPTIC TRANSMISSION SYNAPTIC TRANSMISSION Types of synapse Cholinergic transmission Adrenergic transmission Ion channels THE MECHANISM OF VISION THE MECHANISM OF VISION Summary 40 Neurotransmitters 40 Neurotransmitters INTRODUCTION DEFINITION OF A NEUROTRANSMITTER CLASSIFICATION OF NEUROTRANSMITTERS NEUROTRANSMISSION NEUROTRANSMISSION Receptors Regulation of neurotransmitters VARIOUS CLASSES OF NEUROTRANSMITTERS VARIOUS CLASSES OF NEUROTRANSMITTERS Amino acids Catecholamines Acetylcholine Nitric oxide gas Other small molecules Peptides Summary 41 Cell Growth, Differentiation, and Cancer 41 Cell Growth, Differentiation, and Cancer INTRODUCTION THE CELL CYCLE GROWTH FACTORS GROWTH FACTORS PDGF-receptor signaling Cytokine receptor signaling REGULATION OF THE CELL CYCLE APOPTOSIS APOPTOSIS Caspases The Bcl-2 gene family CANCER CANCER Oncogenes: mutant signal transducers Tumor suppressor genes The retinoblastoma gene p53 Summary 42 Aging 42 Aging INTRODUCTION INTRODUCTION Aging of complex systems Mathematical models of aging THEORIES OF AGING THEORIES OF AGING The free radical theory of aging Mitochondrial theories of aging AGING OF MUSCLE - DAMAGE TO MITOCHONDRIAL DNA INTERVENTIONS TO DELAY AGING -WHAT WORKS AND WHAT DOESN'T INTERVENTIONS TO DELAY AGING -WHAT WORKS AND WHAT DOESN'T Antioxidant supplements Calorie restriction GENETIC MODELS OF AGING GENETIC MODELS OF AGING Summary open all | close all | decrease font | increase font