Netter's Essential Biochemistry E-Book

Peter Ronner

BOOK

Netter's Essential Biochemistry E-Book

Peter Ronner

(2016)

Additional Information

Book Details

ISBN: 978-0-323-38873-3
Edition
Language: English
Pages: 560
Subjects: Bibliographic & subject control
Cytology
Medical study & revision guides & reference material
Biochemistry

Abstract

Concise writing, a focus on clinical applications, and superb illustrations make Netter’s Essential Biochemistry, by Peter Ronner, PhD, the perfect choice for a basic understanding of biochemistry.. A single expert voice, informed by the insights of a team of reviewers, provides continuity throughout the text, presenting essentials of biochemical principles step by step. Summary diagrams help you grasp key concepts quickly, and end-of-chapter questions reinforce key concepts.

Provides a highly visual, reader-friendly approach to the challenging area of biochemistry.

Integrates the clinical perspective throughout the text, giving context and meaning to biochemistry.

Frames every chapter with helpful synopses and summaries, and ends each chapter with review questions that reinforce major themes.

Illustrates key concepts with beautifully clear drawings and diagrams of biochemical processes which are supplemented with art from the renowned Netter collection, bridging basic sciences with clinical practice.

Section Title	Page	Action	Price
Front Cover	cover
Inside Front Cover	ifc1
Marketing page	i
Netter's Essential Biochemistry	iii
Copyright Page	iv
Dedication	v
About the Author	vi
Acknowledgments	vii
Coauthors and Chapter Reviewers	vii
About the Artist	x
Frank H. Netter, MD	x
Preface	xi
Table Of Contents	xii
1 Human Karyotype and the Structure of DNA	1
Learning Objectives	1
Synopsis	1
1. Chemical Structure of DNA	1
2. Hydrogen Bonding Between Complementary Bases	1
3. DNA Double Helix	2
4. Packing of DNA Double Helices Into Chromatids	3
5. Changes in DNA Topology	4
6. Human Karyotype	7
Summary	8
Further Reading	8
Review Questions	9
2 DNA Repair and Therapy of Cancer	10
Learning Objectives	10
Synopsis	10
1. Base-Excision Repair	10
2. Mismatch Repair	11
3. Nucleotide-Excision Repair	14
4. Repair of Double-Strand Breaks and Interstrand Crosslinks	15
4.1. Nonhomologous End Joining	15
4.2. Homologous Recombination Repair (Homology-Directed Repair)	17
5. DNA Damage Response Halts the Cell Cycle and Regulates Apoptosis	19
Summary	19
Further Reading	20
Review Questions	20
3 DNA Replication	22
Learning Objectives	22
Synopsis	22
1. DNA Replication	22
2. Translesion Dna Synthesis	25
3. Replication of the Ends of Chromosomes (Telomeres)	25
Summary	27
Further Reading	27
Review Questions	28
4 Clinical Tests Based on DNA or RNA	29
Learning Objectives	29
Synopsis	29
1. Conventional Cytogenetics and Fluorescence in Situ Hybridization	29
2. DNA Amplification by Polymerase Chain Reaction	30
3. Electrophoresis and Melting Curve Analysis of DNA	32
4. DNA Microarray–Based Technologies	32
5. DNA Sequencing	33
5.1. Sanger Sequencing	33
5.2. Massive Parallel Sequencing	33
6. Selected Clinical Applications of DNA-Based Testing	34
6.1. Prenatal Diagnosis	34
6.2. Other Common Nucleic Acid–Based Tests	35
Summary	36
Further Reading	36
Review Questions	36
5 Basic Genetics for Biochemistry	38
Learning Objectives	38
Synopsis	38
1. Chromosomes and Alleles	38
2. Imprinting and Patterns of Inheritance	39
3. Mutations and Markers	40
Summary	41
Review Question	41
6 Transcription and RNA Processing	42
Learning Objectives	42
Synopsis	42
1. DNA Methylation and Packing Impede Transcription	42
2. The Process of Transcription	44
3. Processing of RNA During and After Transcription	48
3.1. Capping of Pre-mRNA	48
3.2. Polyadenylation of Pre-mRNA	48
3.3. Splicing of Pre-mRNA	49
3.4. Alternative Splicing of Pre-mRNA	49
3.5. Export of mRNA Into the Cytosol	50
3.6. Degradation of mRNA	50
Summary	51
Further Reading	51
Review Questions	51
7 Translation and Posttranslational Protein Processing	53
Learning Objectives	53
Synopsis	53
1. Codons and the Genetic Code	53
2. Transfer RNAs	54
3. Ribosomes Translate mRNA Into Protein	55
4. Posttranslational Modification	58
4.1. General Comments	58
4.2. Glycosylation	59
4.3. Acylation With Fatty Acids and Prenylation	60
4.4. Phosphorylation, Sulfation, and Nitrosylation	61
4.5. Ubiquitylation and SUMOylation	61
5. Protein Sorting and Quality Control	61
Summary	62
Further Reading	63
Review Questions	63
8 Cell Cycle and Cancer	64
Learning Objectives	64
Synopsis	64
1. Cell Cycle and Its Regulation	64
1.1. Cell Cycle and the Retinoblastoma Pathway	64
1.2. The p53 Tumor Suppressor Pathway	66
1.3. The WNT/β-Catenin Pathway	67
1.4. Role of MYCs	67
1.5. Apoptosis	68
1.6. Control of S, G2, and M Phases of the Cell Cycle	69
2. Genetic Alterations in Cancer Cells	69
2.1. Genetic Alterations That Favor Neoplasia	69
2.2. Effect of Age on Tumorigenesis	70
2.3. Smoking and Cancer	71
2.4. Obesity, Alcohol, and Cancer	71
2.5. Circulating Tumor Cells	72
3. Examples of Common Neoplasms	72
3.1. Breast Cancer	72
3.2. Lung Cancer	74
3.3. Prostate Cancer	74
3.4. Colorectal Cancer	75
3.5. Melanoma	77
4. Glucose Use by Tumors	78
Summary	78
Further Reading	80
Review Questions	80
9 Structure of Proteins and Protein Aggregates in Degenerative Diseases	81
Learning Objectives	81
Synopsis	81
1. Amino Acids as Building Blocks of Peptides and Proteins	81
1.1. General Comments About Amino Acids	81
1.2. Classification of Amino Acids	82
2. Peptide Bonds, Disulfide Bridges, and Crosslinks	84
2.1. Peptide Bonds	84
2.2. Disulfide Bridges and Other Crosslinks	84
3. Forces That Determine the Conformation of Proteins and Peptides	84
3.1. Hydrophobic Effects	84
3.2. Hydrogen Bonds	85
3.3. Electrostatic Interactions	85
3.4. Van der Waals Interactions	85
3.5. Coordination of Metal Ions	86
3.6. Entropy	86
4. Elements of the Three-Dimensional Protein Structure	86
4.1. α-Helix	86
4.2. β-Sheets	88
4.3. Loops	90
4.4. Motifs and Domains	90
4.5. Primary, Secondary, Tertiary, and Quaternary Protein Structure	90
5. Unstructured Proteins	91
6. Protein Folding	91
7. Denaturation of Proteins	91
8. Diseases That Are Accompanied by Excessive Protein Aggregation	92
8.1. Formation of Extracellular Amyloid Fibrils	92
8.2. Formation of Intracellular Aggregates	93
8.3. Alzheimer Disease	93
8.4. Type 2 Diabetes	93
8.5. Parkinson Disease	94
Summary	94
Further Reading	95
Review Questions	95
10 Enzymes and Consequences of Enzyme Deficiencies	96
Learning Objectives	96
Synopsis	96
1. Nomenclature of Enzymes	96
2. Enzyme Catalysis of Chemical Reactions	98
3. Enzyme Activity as A Function of the Concentration of Substrates	100
4. Activators and Inhibitors of Enzymes	102
5. Enzyme Activity and Flux in Metabolic Pathways	102
6. Enzymes in the Blood That Have Diagnostic Significance	104
7. Enzyme-Linked Immunosorbent Assay	104
Summary	105
Further Reading	106
Review Questions	106
11 Biological Membranes	108
Learning Objectives	108
Synopsis	108
1. Structure and Composition of Membranes	108
1.1. Physiological Roles of Membranes	108
1.2. Structure of Lipids	108
1.3. Composition and Structure of Bilayer Membranes	110
1.4. Transport of Lipids Inside Membranes	111
1.5. Membrane Proteins	112
2. Movement of Molecules Across Membranes	113
2.1. Simple Diffusion of Molecules Through the Hydrophobic Core of the Lipid Bilayer	113
2.2. Transport of Molecules Through Transport Proteins in Membranes	114
Summary	114
Further Reading	114
Review Questions	115
12 Collagen, Collagenopathies, and Diseases of Mineralization	116
Learning Objectives	116
Synopsis	116
1. Biosynthesis and Degradation of Fibrillar Collagens	116
1.1. Overview of Types of Collagen	116
1.2. Biosynthesis and Posttranslational Modification of Fibrillar Collagens	117
1.3. Mineralization of Fibrillar Collagens in Bone	118
1.4. Degradation of Fibrillar Collagens	119
2. Diseases of Bone That Are Associated With Fibrillar Collagens	119
2.1. Overview and General Comments	120
2.2. Hypochondroplasia and Achondroplasia	120
2.3. Vitamin C (Ascorbate) Deficiency	121
2.4. Osteogenesis Imperfecta	122
2.5. Ehlers-Danlos Syndrome	122
2.6. Rickets and Osteomalacia	123
2.7. Paget Disease of Bone (Osteitis Deformans)	123
2.8. Osteoporosis	124
3. Type IV Collagen: a Network-Forming Collagen	125
4. Type VII Collagen: the Collagen of Anchoring Fibrils	127
Summary	127
Further Reading	128
Review Questions	129
13 Pathologic Alterations of the Extracellular Matrix That Involve Fibrillin, Elastin, or Proteoglycans	130
Learning Objectives	130
Synopsis	130
1. Elastin and Fibrillins	130
1.1. Synthesis of Elastic Fibers	130
1.2. Marfan Syndrome	131
1.3. Supravalvular Aortic Stenosis	131
1.4. Degradation of Elastic Fibers, Emphysema, and α-1-Antitrypsin Deficiency	132
2. Proteoglycans and Glycosaminoglycans	133
2.1. Synthesis and Degradation of Proteoglycans Containing Heparan, Keratan, Chondroitin, or Dermatan Sulfate	133
2.2. Hyaluronate, a Glycosaminoglycan That Binds to Link Proteins	135
2.3. Osteoarthritis	135
2.4. Mucopolysaccharidoses	136
3. Remodeling of the Extracellular Matrix	137
3.1. Wound Healing	137
3.2. Remodeling of the Cervix	138
3.3. Fibrosis	138
Summary	139
Further Reading	139
Review Questions	139
14 Heme Metabolism, Porphyrias, and Hyperbilirubinemia	140
Learning Objectives	140
Synopsis	140
1. Heme Synthesis	140
1.1. Use of Heme in Proteins	140
1.2. Pathway and Regulation of Heme Synthesis	140
2. Diseases Associated With Heme Synthesis	141
2.1. General Considerations	141
2.2. Use of Porphyrins for Photodiagnostic Purposes and Photodynamic Therapy	141
2.3. Diseases of Heme Synthesis That Primarily Affect the Nervous System	143
2.3.1. Acute Intermittent Porphyria	143
2.3.2. Lead Poisoning and ALA Dehydratase-Deficient Porphyria	143
2.4. Diseases of Heme Synthesis That Affect Only the Skin	144
2.4.1. Porphyria Cutanea Tarda	144
2.4.2. Other Porphyrias That Affect the Skin but Not the Nervous System	144
2.5. Porphyrias That Affects Both the Nervous System and the Skin	145
2.6. Diseases of Heme Synthesis That Cause Anemia but Not Neurotoxicity or Skin Damage	146
3. Degradation of Heme to Bilirubin	146
4. Lab Assays: Direct, Total, and Indirect Bilirubin	147
5. Problems With the Degradation of Heme	147
5.1. General Considerations	147
5.2. Hyperbilirubinemia Due to Impaired Excretion of Conjugated Bilirubin	148
5.2.1. Acquired Cholestasis	148
5.2.2. Congenital Impairment of Hepatic Bilirubin Diglucuronide Secretion: Dubin-Johnson Syndrome	149
5.3. Hyperbilirubinemia Due to Increased Degradation of Heme	149
5.4. Hyperbilirubinemia Due to Inadequate Conjugation of Bilirubin	149
5.4.1. Neonatal Jaundice	149
5.4.2. Crigler-Najjar Syndrome	150
5.4.3. Gilbert Syndrome	151
5.4.4. Acquired Deficiency of Bilirubin Conjugation	151
Summary	151
Further Reading	152
Review Questions	152
15 Iron Metabolism	153
Learning Objectives	153
Synopsis	153
1. The Body’s Principal Iron Stores	153
2. Absorption of Dietary Iron	154
3. Regulation of Iron Release Into the Bloodstream	155
4. Transport of Iron in the Blood	156
5. Iron in Mitochondria	157
6. Daily Flow of Iron	157
7. Interpretation of Laboratory Data Related to Iron	158
8. Iron Deficiency	158
8.1. Iron-Deficiency Anemia	158
8.2. Anemia of Inflammation	159
9. Iron Overload	159
9.1. General Comments on Iron Overload	160
9.2. Hemochromatosis	161
9.3. Iron Overload With Blood Transfusions	161
9.4. Iron Chelation Therapy	162
9.5. Hemosiderosis and Siderosis	162
9.6. Acute Iron Poisoning	162
Summary	162
Further Reading	163
Review Questions	163
16 Erythropoiesis, Hemoglobin Function, and the Complete Blood Count	164
Learning Objectives	164
Synopsis	164
1. Erythropoiesis	164
1.1. Location of Erythropoiesis	164
1.2. Major Stages in Erythropoiesis	164
1.3. Role of Erythropoietin in the Control of Red Blood Cell Production	165
1.4. Oxygen-Dependent Secretion of Erythropoietin	166
1.5. Clinical Uses of Recombinant Erythropoietin	166
2. Protein Composition of Hemoglobin	167
3. Oxygen Binding by Hemoglobin and Myoglobin	168
3.1. Cooperative Binding of O2 to Hemoglobin	168
3.2. Short-Term Regulation of the O2 Affinity of Hemoglobin	169
3.3. Long-Term Regulation of the O2 Affinity of Hemoglobin	170
3.4. Maternal-Fetal Exchange of O2	171
3.5. Binding of O2 to Myoglobin	171
4. Transport and Buffering Function of CO2 and HCO3− in Blood	171
5. Carbon Monoxyhemoglobin and Methemoglobin	172
5.1. Carbon Monoxyhemoglobin	172
5.2. Oxidation of Hemoglobin to Methemoglobin	172
6. Clinically Important Laboratory Data on Red Blood Cells	173
7. Color of Hemoglobins	175
7.1. Effect of Hemoglobin on Skin Color	175
7.2. Pulse Oximeter	175
Summary	176
Further Reading	177
Review Questions	177
17 Hemoglobinopathies	179
Learning Objectives	179
Synopsis	179
1. Link Between Malaria and Some Hemoglobinopathies	179
2. Thalassemias	179
2.1. General Comments About the Thalassemias	179
2.2. α-Thalassemia Trait, Hemoglobin H Disease, and Hemoglobin Barts Hydrops Fetalis Syndrome	180
2.3. β-Thalassemia	181
3. Sickle Cell Anemia and Hemoglobin S	182
3.1. Cause and the Genetics of Sickle Cell Anemia	182
3.2. Polymerization of Deoxyhemoglobin S	183
3.3. Vaso-Occlusive Episodes in Sickle Cell Anemia	184
4. Hemoglobin C, Hemoglobin SC, and Hemoglobin E Disease	185
5. Summary of the Causes and Manifestations of the Most Common Hemoglobinopathies	185
6. Hemoglobin Analysis for the Diagnosis of Hemoglobin Disorders	185
Summary	186
Further Reading	188
Review Questions	188
18 Carbohydrate Transport, Carbohydrate Malabsorption, and Lactose Intolerance	189
Learning Objectives	189
Synopsis	189
1. Classification of Carbohydrates	189
2. Digestion of Polysaccharides and Disaccharides in the Small Intestine	190
2.1. Structure of the Small Intestine	191
2.2. Hydrolysis of Polysaccharides and Disaccharides to Monosaccharides	191
3. Transport of Monosaccharides	192
3.1. Intestinal Monosaccharide Transport	192
3.2. Monosaccharide Transport in Tissues Other Than the Intestine	193
4. Bacterial Metabolism of Undigested Carbohydrates That Reach the Colon	194
5. Carbohydrate Malabsorption	196
5.1. General Comments	196
5.2. Pancreatic Insufficiency	196
5.3. Diminished Capacity of the Small Intestine to Degrade Carbohydrates	197
6. SGLT Inhibitors: Drugs That Inhibit Na+-Coupled Glucose Transport	198
Summary	198
Further Reading	199
Review Questions	199
19 Glycolysis and Its Regulation by Hormones and Hypoxia	200
Learning Objectives	200
Synopsis	200
1. Chemical Reactions of Glycolysis	200
2. Aerobic Versus Anaerobic Glycolysis	202
2.1. Production of NADH in Glycolysis	202
2.2. Cells Performing Anaerobic Glycolysis Release Lactic Acid	203
2.3. Aerobic Glycolysis: Cells Produce ATP From the Reducing Power of NADH	204
3. Basic Mechanisms in the Regulation of Glycolysis	204
3.1. Overview	204
3.2. Introduction to Insulin, Glucagon, Epinephrine, and Norepinephrine	204
3.3. Introduction to AMP-Dependent Protein Kinase	205
3.4. Regulation of Glucose Transport	205
3.5. Regulation of Hexokinase and Glucokinase Activities	205
3.6. Regulation of Phosphofructokinase 1	205
3.7. Regulation of Pyruvate Kinase	206
3.8. Summary of the Regulation of Flux in Glycolysis	206
4. Interactions of Glycolysis With Other Pathways	206
5. Tissue-Specific Regulation of Glycolysis	207
5.1. Regulation of Glycolysis in Red Blood Cells	207
5.2. Regulation of Glycolysis in the Brain	208
5.3. Regulation of Glycolysis in Adipocytes	208
5.4. Regulation of Glycolysis in Heart Muscle	209
5.5. Regulation of Glycolysis in Skeletal Muscle	209
5.6. Regulation of Glycolysis in the Liver	210
6. Common Laboratory Methods and Assays	211
6.1. Preservation of Metabolites in Blood Samples	211
6.2. Plasma or Serum Lactate Dehydrogenase	211
6.3. 2-Fluoro-Deoxyglucose Positron Emission Tomographic Scans	211
7. Diseases That Involve an Abnormal Flux in Glycolysis	211
7.1. Lactate Accumulation	211
7.2. Effect of Hypophosphatemia on Glycolysis	212
7.3. Hemolytic Anemias Due to Hereditary Deficiencies of Enzymes of Glycolysis	213
Summary	213
Further Reading	213
Review Questions	214
20 Fructose and Galactose Metabolism	215
Learning Objectives	215
Synopsis	215
1. Normal Metabolism of Fructose	215
1.1. Sources of Fructose	215
1.2. Uptake of Fructose	215
1.3. Metabolism of Dietary Fructose	215
2. Polyol Pathway and Its Role in Disease	216
3. Abnormal Fructose Absorption and Metabolism	217
3.1. Fructose Malabsorption	218
3.2. Fructosuria	218
3.3. Hereditary Fructose Intolerance	218
3.4. Concerns About High Fructose Consumption in the General Population	219
3.5. Problems With the Use of Fructose or Sorbitol in Medicine	220
4. Normal Metabolism of Galactose	220
5. Galactosemia	220
5.1. Classical Galactosemia	220
5.2. Nonclassical Galactosemia	221
6. Lactose Synthesis in the Lactating Breast	221
Summary	222
Further Reading	222
Review Questions	223
21 Pentose Phosphate Pathway, Oxidative Stress, and Glucose 6-Phosphate Dehydrogenase Deficiency	224
Learning Objectives	224
Synopsis	224
1. Steps of the Pentose Phosphate Pathway	224
1.1. General Comments	224
1.2. Oxidative Branch	224
1.3. Nonoxidative Branch	225
1.4. Independent Versus Joint Operation of the Branches	226
2. Processes That Use NADPH Inside Cells	226
2.1. Use of NADPH in Biosynthetic Pathways	226
2.2. NADPH Reduces Oxidized Glutathione	226
2.3. Removal of ROS and Repair of ROS-Induced Damage	227
3. Glucose 6-Phosphate Dehydrogenase Deficiency	229
Summary	231
Further Reading	231
Review Questions	231
22 Citric Acid Cycle and Thiamine Deficiency	232
Learning Objectives	232
Synopsis	232
1. Mitochondria Convert Pyruvate to Acetyl-CoA	232
2. Reactions of the Citric Acid Cycle	234
3. Oxaloacetate Helps Replenish Citric Acid Cycle Intermediates	234
4. Regulation of the Citric Acid Cycle and the Use of Pyruvate	236
5. Problems Associated With the Citric Acid Cycle	237
5.1. Inhibition of the Citric Acid Cycle Secondary to Impaired Oxidative Phosphorylation	237
5.2. Clinically Significant Vitamin Deficiencies	237
5.2.1. Overview	237
5.2.2. Deficiency of Thiamine (Vitamin B1)	237
5.2.3. Deficiency of Riboflavin (Vitamin B2)	239
5.2.4. Deficiency of Niacin (Vitamin B3, Nicotinic Acid)	239
5.2.5. Deficiency of Biotin	239
5.3. Pyruvate Carboxylase Deficiency	240
5.4. Acute Poisoning With Arsenic	240
5.5. Tumorigenic Mutations in Isocitrate Dehydrogenase, Succinate Dehydrogenase, or Fumarase	240
5.6. Deficiency of the Pyruvate Dehydrogenase Complex	242
Summary	242
Further Reading	243
Review Questions	243
23 Oxidative Phosphorylation and Mitochondrial Diseases	244
Learning Objectives	244
Synopsis	244
1. Oxidative Phosphorylation	244
1.1. Structure and Function of Mitochondria	244
1.2. Electron Transport Chain	245
1.3. Clinically Relevant Inhibitors of the Electron Transport Chain	245
1.4. ATP Synthase	247
1.5. Transport of Chemical Energy in the Form of ATP and Phosphocreatine	247
1.6. Uncouplers of Oxidative Phosphorylation	248
2. Interplay of Glycolysis, Citric Acid Cycle, and Oxidative Phosphorylation	248
3. Mitochondrial Dna and Its Inheritance	249
4. Diseases Involving Mitochondria	250
4.1. Overview	250
4.2. Diseases Associated With mtDNA Mutations	251
4.3. Diseases Associated With Dysfunctional Mitochondria Due to Mutation in the Nucleus	251
4.4. Idiopathic or Acquired Diseases of Mitochondria	252
Summary	252
Further Reading	253
Review Questions	253
24 Glycogen Metabolism and Glycogen Storage Diseases	254
Learning Objectives	254
Synopsis	254
1. Synthesis of Glycogen (Glycogenesis)	254
1.1. Structure and Role of Glycogen	254
1.2. Reactions of Glycogen Synthesis	254
1.3. Regulation of Glycogen Synthesis	255
2. Degradation of Glycogen (Glycogenolysis)	257
2.1. Degradation of Glycogen to Glucose 6-Phosphate and Glucose	257
2.2. Regulation of Glycogenolysis	257
3. Disorders of Glycogen Metabolism	259
3.1. Diabetes and Glycogen Metabolism	259
3.2. Fructose and Glycogen Metabolism	260
3.3. Glycogenoses	260
Summary	262
Further Reading	262
Review Questions	263
25 Gluconeogenesis and Fasting Hypoglycemia	264
Learning Objectives	264
Synopsis	264
1. Pathway of Gluconeogenesis	264
2. Substrate and Energy Sources for Gluconeogenesis	267
2.1. Lactate	267
2.2. Amino Acids	267
2.3. Glycerol	268
2.4. Fatty Acids as a Source of ATP	268
3. Regulation of Gluconeogenesis	268
4. Diseases Associated With an Abnormal Rate of Gluconeogenesis	270
4.1. Diseases Associated With Inadequate Gluconeogenesis	270
4.1.1. General Comments	270
4.1.2. Hyperinsulinemia	270
4.1.3. Hypocortisolism	270
4.1.4. Liver Disease	270
4.1.5. Impaired Production of ATP and Intermediates of Gluconeogenesis (Impaired Oxidation of Fatty Acids, Alcohol Intoxication, and Enzyme Deficiencies)	270
4.2. Diseases Associated With Excessive Gluconeogenesis	271
4.2.1. General Comments	271
4.2.2. Insulin Deficiency With Diabetes	271
4.2.3. Cushing Syndrome	271
4.2.4. Hyperthyroidism	272
4.2.5. Pheochromocytoma	272
4.2.6. Glucagonoma	272
Summary	272
Further Reading	273
Review Questions	273
26 Insulin and Counterregulatory Hormones	274
Learning Objectives	274
Synopsis	274
1. Structure of the Human Pancreas	274
2. Synthesis of Glucagon, Glucagon-Like Peptides, Insulin, Epinephrine, and Cortisol	274
2.1. Synthesis of Glucagon and Glucagon-Like Peptides	275
2.2. Synthesis of Insulin and Amylin	275
2.3. Synthesis of Epinephrine and Cortisol in the Adrenal Glands	276
3. Secretion of Glucagon, Glucagon-Like Peptides, Insulin, Epinephrine, and Cortisol	276
3.1. Secretion of Glucagon-Like Peptide 1	276
3.2. Secretion of Glucagon	277
3.3. Secretion of Insulin	277
3.3.1. Stimulatory Effect of Glucose	277
3.3.2. Amplification of Glucose-Induced Insulin Secretion	279
3.3.3. Inhibition of Insulin Secretion by Catecholamines	279
3.4. Secretion of Epinephrine and Norepinephrine	279
3.5. Secretion of Cortisol	280
4. Effects of Insulin and Counterregulatory Hormones on Tissues	280
4.1. Biological Effects of Glucagon-Like Peptides	280
4.2. Biological Effects of Glucagon	280
4.3. Biological Effects of Insulin	281
4.4. Biological Effects of Epinephrine and Norepinephrine	282
4.5. Biological Effects of Cortisol	282
5. Physiological and Pathological Changes in Insulin Sensing	282
5.1. General Commen+ts About Insulin Resistance	282
5.2. Polycystic Ovary Syndrome	283
6. Pathology of the Secretion of Insulin and Counterregulatory Hormones	284
6.1. Disorders Associated With Hypoglycemia	284
6.1.1. Insulinoma	284
6.1.2. Multiple Endocrine Neoplasia	284
6.1.3. Congenital Hyperinsulinism	285
6.1.4. Adrenal Insufficiency	285
6.2. Disorders Associated With Hyperglycemia	285
6.2.1. Diabetes Due to Heritable β-Cell Abnormalities	285
6.2.2. Hyperglycemia Due to Glucagonoma	285
6.2.3. Hyperglycemia Due to Pheochromocytoma or Cushing Syndrome	286
Summary	286
Further Reading	286
Review Questions	287
27 Fatty Acids, Ketone Bodies, and Ketoacidosis	288
Learning Objectives	288
Synopsis	288
1. Use and Nomenclature of Fatty Acids	288
2. Fatty Acid Synthesis	290
3. Fatty Acid Activation, Elongation, and Desaturation	292
4. Fatty Acid Oxidation	293
5. Synthesis and Degradation of Ketone Bodies	295
5.1. Ketone Body Synthesis (Ketogenesis)	295
5.2. Oxidation of Ketone Bodies by Extra-Hepatic Tissues	296
5.3. Laboratory Tests for Ketone Bodies	296
5.4. Ketosis, Ketonemia, and Ketonuria	297
6. Overview of Fuel Use by Tissues	297
7. Metabolic Disturbances of Fatty Acid and Ketone Body Metabolism	297
7.1. Hypoketotic Hypoglycemia and Disorders of Fatty Acid Oxidation	297
7.2. Diseases of Very-Long-Chain Fatty Acid Oxidation in Peroxisomes	298
7.3. Ketoacidosis	298
Summary	299
Further Reading	300
Review Questions	300
28 Triglycerides and Hypertriglyceridemia	301
Learning Objectives	301
Synopsis	301
1. Structure and Role of Triglycerides	301
2. Digestion of Triglycerides and Absorption of Fatty Acids and Monoglycerides	302
2.1. Partial Digestion of Triglycerides in the Stomach	302
2.2. Digestion of Triglycerides in the Intestine	303
2.3. Absorption of Fatty Acids and Monoglycerides	303
3. Production and Export of Triglycerides From the Intestine, Liver, and Mammary Glands	303
3.1. Triglycerides Made in the Intestine	303
3.2. Triglycerides Made in the Liver	304
3.3. Triglycerides Made in the Lactating Mammary Glands	304
4. Removal of Triglycerides From Chylomicrons and VLDL, and Deposition of Triglycerides Inside Adipocytes	304
4.1. Removal of Triglycerides From Chylomicrons and VLDL	304
4.2. Deposition of Triglycerides Inside Adipocytes	305
5. Hydrolysis of Stored Triglycerides	306
5.1. Lipolysis	306
5.2. Hydrolysis of Triglycerides in Muscles	307
5.3. Daily Course of Triglycerides and Fatty Acids in the Blood	307
6. Laboratory Determinations	307
7. Absorption, Transport, and Storage of the Fat-Soluble Vitamins a, D, E, and K	307
8. Disorders of Triglyceride Metabolism	309
8.1. Hypertriglyceridemia	309
8.2. Fatty Liver	310
8.3. Fat Malabsorption	310
8.4. Abetalipoproteinemia and Hypobetalipoproteinemia	310
Summary	311
Further Reading	311
Review Questions	312
29 Cholesterol Metabolism and Hypercholesterolemia	313
Learning Objectives	313
Synopsis	313
1. Absorption of Cholesterol	313
2. De Novo Synthesis of Cholesterol	315
2.1. Pathway for the Biosynthesis of Cholesterol	315
2.2. Regulation of Cholesterol Synthesis	316
3. Transport of Cholesterol via the Blood	316
3.1. Transport of Cholesterol From the Liver to Peripheral Cells	317
3.2. Export of Cholesterol From Peripheral Cells (Reverse Cholesterol Transport)	317
3.3. Treatment of a Low Concentration of HDL Cholesterol	318
3.4. Laboratory Measurements of Cholesterol-Containing Lipoproteins	318
4. Bile Metabolism	319
4.1. Production of Bile and Recirculation of Bile Salts and Cholesterol	319
4.2. Diseases of Bile Metabolism	321
5. Hypercholesterolemia	322
5.1. Blood Cholesterol Concentration and the Risk of Coronary Artery Disease	322
5.2. Familial Hypercholesterolemia	323
5.3. Other Causes of Hypercholesterolemia	324
5.4. Lowering the Concentration of LDL Cholesterol	324
6. Combined Hyperlipidemia	325
6.1. Familial Combined Hyperlipidemia	325
6.2. Familial Dysbetalipoproteinemia	325
Summary	325
Further Reading	326
Review Questions	326
30 Metabolism of Ethanol and the Consequences of Alcohol Dependence Syndrome	328
Learning Objectives	328
Synopsis	328
1. Effects of Alcohol Use on the Health of the Public	328
2. Metabolism of Ethanol	329
2.1. Metabolism of Ethanol to Acetate	329
2.2. Oxidation of Acetate to CO2	330
3. Acute Effect of Ethanol on Pathways of Metabolism	330
3.1. Effect of Ethanol on Gluconeogenesis	330
3.2. Effect of Ethanol on Fatty Acid Metabolism	331
3.3. Effect of Ethanol on the Production of Uric Acid	332
3.4. Treatment of Acute Ethanol Intoxication in the Clinic	332
4. Effects of Chronic Ethanol Intake on Organ Function	332
4.1. General Comments About Alcohol Dependence Syndrome	332
4.2. Effects of Ethanol and Acetaldehyde on Proteins and DNA	333
4.3. Drugs That Help Patients Free Themselves From Alcohol Dependence	333
4.4. Effect of Ethanol on the Liver	334
4.5. Effect of Ethanol on Cancer Risk	334
4.6. Effect of Ethanol on the Heart	335
4.7. Effect of Ethanol on the Fetus	335
Summary	336
Further Reading	336
Review Questions	336
31 Steroid Hormones and Vitamin D	338
Learning Objectives	338
Synopsis	338
1. General Properties and Synthesis of Steroid Hormones	338
1.1. Structure and Properties of Steroid Hormones	338
1.2. Common Pathway of Steroid Hormone Synthesis	338
2. Sex Steroids	339
2.1. Common Pathways for the Biosynthesis of Sex Steroids	339
2.2. Biosynthesis of Sex Steroids in Men	340
2.3. 46,XY Disorder of Sex Development	340
2.4. Biosynthesis of Sex Steroids in Women	343
3. Glucocorticoids	344
4. Mineralocorticoids	347
4.1. Synthesis of Aldosterone	348
4.2. Disorders of Aldosterone Synthesis	348
5. Vitamin D	350
Summary	351
Further Reading	352
Review Questions	352
32 Eicosanoids	353
Learning Objectives	353
Synopsis	353
1. Eicosanoid Families	353
2. Prostaglandins and Thromboxanes	354
2.1. Synthesis of Prostanoids	354
2.2. Prostanoid Receptors	355
2.3. Physiological Roles of Prostaglandins D2, E2, and F2	355
2.4. Roles of Thromboxane A2 and Prostacyclin	355
3. Leukotrienes and Lipoxins	356
3.1. Leukotrienes	356
3.2. Lipoxins	357
Summary	358
Further Reading	359
Review Questions	359
33 Signaling	360
Learning Objectives	360
Synopsis	360
1. Principles of Signaling	360
2. G Protein–Coupled Receptor Signaling	360
3. Growth Factor Receptors That Are Receptor Tyrosine Kinases	362
3.1. Normal Receptor Tyrosine Kinase Signaling	363
3.2. Neurofibromatosis, Noonan Syndrome, and Cowden Syndrome	364
Summary	365
Further Reading	366
Review Questions	366
34 Digestion of Dietary Protein and Net Synthesis of Protein in the Body	367
Learning Objectives	367
Synopsis	367
1. Digestion of Protein in the Stomach	367
2. Digestion of Protein in the Intestine	370
2.1. Normal Protein Digestion in the Intestine	370
2.2. Diseases Associated With Impaired Digestion of Protein	372
3. Transport of Amino Acids and Small Peptides	373
3.1. Normal Transport of Amino Acids in the Intestinal Epithelium and in Other Cells	374
3.2. Diseases Due to Deficiencies of Amino Acid Transporters	374
4. Synthesis of Body Protein	375
4.1. Daily Turnover of Body Protein	375
4.2. Essential and Nonessential Amino Acids	375
4.3. Regulation of the Concentration of Amino Acids in Blood and of Protein Synthesis	376
Summary	378
Further Reading	378
Review Questions	378
35 Protein Degradation, Amino Acid Metabolism, and Nitrogen Balance	380
Learning Objectives	380
Synopsis	380
1. Degradation of Body Protein	380
1.1. General Comments	380
1.2. Degradation of Proteins by Proteasomes	380
1.3. Regulation of Protein Degradation via Proteasomes	382
1.4. Degradation of Proteins by Lysosomes	382
2. Elimination of Amino Acid Nitrogen	382
2.1. Production of Ammonium Ions From Amino Acids	383
2.2. Excretion of Ammonium Ions Into the Urine	383
2.3. Transamination	384
2.4. Role of Glutamine in Nitrogen Metabolism	384
2.5. Elimination of Nitrogen via the Urea Cycle	385
3. Deficiencies of Nitrogen Elimination	387
3.1. General Comments	388
3.2. Nitrogen Elimination in Patients With Liver Failure or Kidney Failure	388
3.3. Inborn Deficiencies That Affect the Urea Cycle	388
4. Summary of the Metabolism of Amino Acids	390
4.1. Overview	390
4.2. Normal Metabolism of Phenylalanine, Tyrosine, and Tryptophan	390
4.3. Hyperphenylalaninemias (Including Phenylketonuria)	393
4.4. Disorders of Pigmentation	394
4.5. Disorders of Tyrosine Degradation	395
4.6. Maple Syrup Disease and the Degradation of Branched-Chain Amino Acids	396
5. Nitrogen Balance	397
5.1. Concept of Nitrogen Balance	397
5.2. Nitrogen Balance in Health and Illness	398
Summary	399
Further Reading	400
Review Questions	400
36 One-Carbon Metabolism, Folate Deficiency, and Cobalamin Deficiency	402
Learning Objectives	402
Synopsis	402
1. Sources and Absorption of Dietary Folates	402
1.1. Structure of Folates	402
1.2. Absorption of Folates in the Intestine and Transport in the Blood	402
2. Loading Tetrahydrofolates With One-Carbon Groups	404
2.1. Glycine and Serine as Sources of One-Carbon Groups	404
2.2. Other Sources of One-Carbon Groups and Folates	405
3. Use of One-Carbon Groups on Tetrahydrofolates	405
3.1. Overview	405
3.2. Synthesis of Inosine Monophosphate and Deoxythymidine Monophosphate	405
3.3. Transfer of Methyl Groups to the Activated Methyl Group Cycle	405
3.4. Detoxification of Methanol	405
4. The Activated Methyl Group Cycle	406
4.1. Reactions of the Activated Methyl Group Cycle	406
4.2. Use of Methyl Groups From the Activated Methyl Group Cycle	407
5. Absorption of Cobalamin	407
6. Enzymes That Use Cobalamin as a Cofactor	409
6.1. Methionine Synthase	409
6.2. Methylmalonyl-CoA Mutase	409
7. Megaloblastic Anemia Due to Folate Deficiency or Cobalamin Deficiency	409
7.1. Folate Deficiency	409
7.2. Cobalamin Deficiency	410
8. Other Diseases Linked to Folates	412
8.1. Neural Tube Defects and Other Folate-Dependent Congenital Anomalies	412
8.2. Folates and Cancer	413
9. Transsulfuration Pathway and Metabolism of Cysteine	413
Summary	414
Further Reading	415
Review Questions	415
37 Pyrimidine Nucleotides and Chemotherapy	416
Learning Objectives	416
Synopsis	416
1. De Novo Synthesis of Uridine Monophosphate, a Precursor for All Pyrimidine Nucleotides	416
2. Synthesis and Uses of UTP and CTP	418
3. Reduction of Ribonucleotides to Deoxyribonucleotides	418
4. Synthesis of dTMP	419
5. Chemotherapeutic Agents That Interfere With dTMP Synthesis	419
5.1. 5-Fluorouracil and Related Drugs	419
5.2. Pemetrexed	421
5.3. Methotrexate	421
6. Degradation of Pyrimidine Nucleotides	423
Summary	423
Further Reading	424
Review Questions	424
38 Gout and Other Diseases Related to the Metabolism of Purine Nucleotides	425
Learning Objectives	425
Synopsis	425
1. De Novo Synthesis of Purine Nucleotides	425
2. Degradation and Salvage of Purine Nucleotides	427
2.1. Degradation of AMP and GMP to Hypoxanthine and Guanine	427
2.2. Degradation of Hypoxanthine to Xanthine and Urate	428
2.3. Excretion of Urate by the Kidneys	429
2.4. Salvage of Hypoxanthine and Guanine	430
2.5. Balancing the Production of IMP From Salvage and De Novo Synthesis	431
2.6. Daily Purine Turnover and Urate Excretion	431
3. Hyperuricemia	431
3.1. Plasma Urate as a Function of Gender and Age	432
3.2. Overproduction of Urate	432
3.3. Underexcretion of Urate	432
3.4. Plasma Urate and Preeclampsia	433
3.5. Crystallization of Urate	433
3.6. Tumor Lysis Syndrome	433
4. Gout	434
4.1. General Comments About Gout	434
4.2. Acute Gouty Arthritis	434
4.3. Uric Acid and Sodium Urate in Nephrolithiasis	436
5. Thiopurines	436
Summary	437
Further Reading	437
Review Questions	438
39 Diabetes	439
Learning Objectives	439
Synopsis	439
1. Overview of the Classification of Diabetes	439
2. Metabolism During Severe Insulin Deficiency	440
2.1. Diabetic Ketoacidosis	440
2.2. Hyperosmolar Hyperglycemic State	442
3. Diagnosis of Diabetes	442
4. Pathogenesis, Diagnosis, and Treatment of Type 1 Diabetes	443
4.1. Definitions	443
4.2. Pathogenesis, Heredity, and Diagnosis	443
4.3. Treatment of Type 1 Diabetes	444
5. Pathogenesis, Diagnosis, and Treatment of Type 2 Diabetes	446
5.1. Pathogenesis	446
5.2. Diagnosis	447
5.3. Treatment	448
6. MODY	450
7. Gestational Diabetes	450
8. Complications of Diabetes	451
8.1. General Comments	451
8.2. Clinical Aspects of Complications of Diabetes	452
8.3. Potential Biochemical Causes of Complications of Diabetes	454
8.3.1. Nonenzymatic Glycation	454
8.3.2. Damage by Reactive Oxygen Species	455
8.3.3. Deregulation of Metabolism	455
Summary	456
Further Reading	457
Review Questions	457
Answers to Review Questions	459
Chapter 1	459
Chapter 2	459
Chapter 3	459
Chapter 4	459
Chapter 5	459
Chapter 6	459
Chapter 7	459
Chapter 8	459
Chapter 9	460
Chapter 10	460
Chapter 11	460
Chapter 12	460
Chapter 13	460
Chapter 14	460
Chapter 15	460
Chapter 16	460
Chapter 17	461
Chapter 18	461
Chapter 19	461
Chapter 20	461
Chapter 21	461
Chapter 22	462
Chapter 23	462
Chapter 24	462
Chapter 25	462
Chapter 26	462
Chapter 27	462
Chapter 28	462
Chapter 29	462
Chapter 30	462
Chapter 31	463
Chapter 32	463
Chapter 33	463
Chapter 34	463
Chapter 35	463
Chapter 36	463
Chapter 37	463
Chapter 38	464
Chapter 39	464
Index	465
A	465
B	466
C	467
D	468
E	469
F	470
G	471
H	472
I	473
J	474
K	474
L	474
M	475
N	476
O	477
P	477
Q	479
R	479
S	480
T	481
U	481
V	482
W	482
X	482
Z	482

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