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Fundamentals of Biochemistry: Life at the Molecular Level, 3rd Edition
by
Voet, Donald J., Univ. of Pennsylvania; Voet, Judith G., Swarthmore College; Pratt, Charlotte W., Seattle Pacific University
Publisher: John Wiley & Sons
Publishing Date: 2008/01/14
eText ISBN-10
0-470-28367-X
eText ISBN-13
978-0-470-28367-7
Print ISBN-10
0-470-12930-1
Print ISBN-13
978-0-470-12930-2
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Fundamentals of Biochemistry: Life at the Molecular Level, 3rd Edition
by
Voet, Donald J., Univ. of Pennsylvania; Voet, Judith G., Swarthmore College; Pratt, Charlotte W., Seattle Pacific University
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Copyright, iv
About the Authors, v
Preface, xviii
Acknowledgments, xxi
Instructor and Student Re...
Guide to Media Resources,...
Part I. INTRODUCTION, 1
Part II. BIOMOLECULES, 39
Part III. ENZYMES, 322
Part IV. METABOLISM, 448
Part V. GENE EXPRESSION A...
APPENDICES, SP-1
Solutions to Problems, SP...
Glossary, G-1
Index, I-1
Table of Contents
Copyright, iv
About the Authors, v
Preface, xviii
Acknowledgments, xxi
Instructor and Student Resources, xxiii
Guide to Media Resources, xxv
Part I. INTRODUCTION, 1
1. Introduction to the Chemistry of Life, 1
1. The Origin of Life, 2
A. Biological Molecules Arose from Inorganic Materials, 2
B. Complex Self-replicating Systems Evolved from Simple Molecules, 3
2. Cellular Architecture, 5
A. Cells Carry Out Metabolic Reactions, 5
B. There Are Two Types of Cells: Prokaryotes and Eukaryotes, 7
C. Molecular Data Reveal Three Evolutionary Domains of Organisms, 9
BOX 1-1. PATHWAYS OF DISCOVERYLynn Margulis and the Theory of Endosymbiosis, 10
D. Organisms Continue to Evolve, 11
3. Thermodynamics, 11
A. The First Law of Thermodynamics States That Energy Is Conserved, 12
BOX 1-2. PERSPECTIVES IN BIOCHEMISTRYBiochemical Conventions, 13
B. The Second Law of Thermodynamics States That Entropy Tends to Increase, 13
C. The Free Energy Change Determines the Spontaneity of a Process, 14
D. Free Energy Changes Can Be Calculated from Equilibrium Concentrations, 15
E. Life Obeys the Laws of Thermodynamics, 17
2. Water, 22
1. Physical Properties of Water, 23
A. Water Is a Polar Molecule, 23
B. Hydrophilic Substances Dissolve in Water, 25
C. The Hydrophobic Effect Causes Nonpolar Substances to Aggregate in Water, 26
D. Water Moves by Osmosis and Solutes Move by Diffusion, 29
2. Chemical Properties of Water, 30
A. Water Ionizes to Form H
+
and OH
-
, 30
B. Acids and Bases Alter the pH, 32
C. Buffers Resist Changes in pH, 34
BOX 2-1. BIOCHEMISTRY IN HEALTH AND DISEASEThe Blood Buffering System, 36
Part II. BIOMOLECULES, 39
3. Nucleotides, Nucleic Acids, and Genetic Information, 39
1. Nucleotides, 40
2. Introduction to Nucleic Acid Structure, 43
A. Nucleic Acids Are Polymers of Nucleotides, 43
B. The DNA Forms a Double Helix, 44
C. RNA Is a Single-Stranded Nucleic Acid, 47
3. Overview of Nucleic Acid Function, 47
A. DNA Carries Genetic Information, 48
B. Genes Direct Protein Synthesis, 49
4. Nucleic Acid Sequencing, 50
A. Restriction Endonucleases Cleave DNA at Specific Sequences, 51
B. Electrophoresis Separates Nucleic Acid According to Size, 52
C. DNA Is Sequenced by the Chain-Terminator Method, 53
BOX 3-1. PATHWAYS OF DISCOVERYFrancis Collins and the Gene for Cystic Fibrosis, 56
D. Entire Genomes Have Been Sequenced, 57
E. Evolution Results from Sequence Mutations, 58
5. Manipulating DNA, 59
A. Cloned DNA Is an Amplified Copy, 60
B. DNA Libraries Are Collections of Cloned DNA, 62
C. DNA Is Amplified by the Polymerase Chain Reaction, 65
BOX 3-2. PERSPECTIVES IN BIOCHEMISTRYDNA Fingerprinting, 66
D. Recombinant DNA Technology Has Numerous Practical Applications, 67
BOX 3-3. PERSPECTIVES IN BIOCHEMISTRYEthical Aspects of Recombinant DNA Technology, 70
4. Amino Acids, 74
1. Amino Acid Structure, 74
BOX 4-1. PATHWAYS OF DISCOVERYWilliam C. Rose and the Discovery of Threonine, 75
A. Amino Acids Are Dipolar Ions, 75
B. Peptide Bonds Link Amino Acids, 78
C. Amino Acid Side Chains Are Nonpolar, Polar, or Charged, 78
D. The p
K
Values of Ionizable Groups Depend on Nearby Groups, 81
E. Amino Acid Names Are Abbreviated, 81
2. Stereochemistry, 82
BOX 4-2. PERSPECTIVES IN BIOCHEMISTRYThe
RS
System, 85
3. Amino Acid Derivatives, 86
A. Protein Side Chains May Be Modified, 86
B. Some Amino Acids Are Biologically Active, 86
BOX 4-3. PERSPECTIVES IN BIOCHEMISTRYGreen Fluorescent Protein, 87
5. Proteins: Primary Structure, 91
1. Polypeptide Diversity, 91
2. Protein Purification and Analysis, 94
A. Purifying a Protein Requires a Strategy, 94
B. Salting Out Separates Proteins by Their Solubility, 97
C. Chromatography Involves Interaction with Mobile and Stationary Phases, 98
D. Electrophoresis Separates Molecules According to Charge and Size, 101
3. Protein Sequencing, 104
A. The First Step Is to Separate Subunits, 104
BOX 5-1. PATHWAYS OF DISCOVERYFrederick Sanger and Protein Sequencing, 105
B. The Polypeptide Chains Are Cleaved, 107
C. Edman Degradation Removes a Peptide’s First Amino Acid Residue, 109
D. Mass Spectrometry Determines the Molecular Masses of Peptides, 110
E. Reconstructed Protein Sequences Are Stored in Databases, 112
4. Protein Evolution, 114
A. Protein Sequences Reveal Evolutionary Relationships, 114
B. Proteins Evolve by the Duplication of Genes or Gene Segments, 117
6. Proteins: Three-Dimensional Structure, 125
1. Secondary Structure, 127
A. The Planar Peptide Group Limits Polypeptide Conformations, 127
B. The Most Common Regular Secondary Structures Are the α Helix and the β Sheet, 129
BOX 6-1. PATHWAYS OF DISCOVERYLinus Pauling and Structural Biochemistry, 130
C. Fibrous Proteins Have Repeating Secondary Structures, 134
BOX 6-2. BIOCHEMISTRY IN HEALTH AND DISEASECollagen Diseases, 137
D. Most Proteins Include Nonrepetitive Structure, 139
2. Tertiary Structure, 140
A. Most Protein Structures Have Been Determined by X-Ray Crystallography or Nuclear Magnetic Resonance, 141
B. Side Chain Location Varies with Polarity, 145
C. Tertiary Structures Contain Combinations of Secondary Structure, 146
D. Structure Is Conserved More than Sequence, 150
E. Structural Bioinformatics Provides Tools for Storing, Visualizing, and Comparing Protein Structural Information, 151
3. Quaternary Structure and Symmetry, 154
4. Protein Stability, 156
A. Proteins Are Stabilized by Several Forces, 156
B. Proteins Can Undergo Denaturation and Renaturation, 158
BOX 6-3. PERSPECTIVES IN BIOCHEMISTRYThermostable Proteins, 159
5. Protein Folding, 161
A. Proteins Follow Folding Pathways, 161
BOX 6-4. PERSPECTIVES IN BIOCHEMISTRYProtein Structure Prediction and Protein Design, 163
B. Molecular Chaperones Assist Protein Folding, 165
C. Some Diseases Are Caused by Protein Misfolding, 168
7. Protein Function: Myoglobin and Hemoglobin, Muscle Contraction, and Antibodies, 176
1. Oxygen Binding to Myoglobin and Hemoglobin, 177
A. Myoglobin Is a Monomeric Oxygen-Binding Protein, 177
B. Hemoglobin Is a Tetramer with Two Conformations, 181
BOX 7-1. PERSPECTIVES IN BIOCHEMISTRYOther Oxygen-Transport Proteins, 181
BOX 7-2. PATHWAYS OF DISCOVERYMax Perutz and the Structure and Function of Hemoglobin, 182
C. Oxygen Binds Cooperatively to Hemoglobin, 184
D. Hemoglobin’s Two Conformations Exhibit Different Affinities for Oxygen, 186
BOX 7-3. BIOCHEMISTRY IN HEALTH AND DISEASEHigh-Altitude Adaptation, 192
E. Mutations May Alter Hemoglobin’s Structure and Function, 194
2. Muscle Contraction, 197
A. Muscle Consists of Interdigitated Thick and Thin Filaments, 198
BOX 7-4. PATHWAYS OF DISCOVERYHugh Huxley and the Sliding Filament Model, 200
B. Muscle Contraction Occurs When Myosin Heads Walk Up Thin Filaments, 205
C. Actin Forms Microfilaments in Nonmuscle Cells, 207
3. Antibodies, 209
A. Antibodies Have Constant and Variable Regions, 210
B. Antibodies Recognize a Huge Variety of Antigens, 212
BOX 7-5. PERSPECTIVES IN BIOCHEMISTRYMonoclonal Antibodies, 213
8. Carbohydrates, 219
1. Monosaccharides, 220
A. Monosaccharides Are Aldoses or Ketoses, 220
B. Monosaccharides Vary in Configuration and Conformation, 221
C. Sugars Can Be Modified and Covalently Linked, 224
2. Polysaccharides, 226
A. Lactose and Sucrose Are Disaccharides, 227
BOX 8-1. BIOCHEMISTRY IN HEALTH AND DISEASELactose Intolerance, 227
BOX 8-2. PERSPECTIVES IN BIOCHEMISTRYArtificial Sweeteners, 228
B. Cellulose and Chitin Are Structural Polysaccharides, 228
C. Starch and Glycogen Are Storage Polysaccharides, 230
D. Glycosaminoglycans Form Highly Hydrated Gels, 232
3. Glycoproteins, 234
A. Proteoglycans Contain Glycosaminoglycans, 234
B. Bacterial Cell Walls Are Made of Peptidoglycan, 235
BOX 8-3. BIOCHEMISTRY IN HEALTH AND DISEASEPeptidoglycan-Specific Antibiotics, 238
C. Many Eukaryotic Proteins Are Glycosylated, 238
D. Oligosaccharides May Determine Glycoprotein Structure, Function, and Recognition, 240
9. Lipids and Biological Membranes, 245
1. Lipid Classification, 246
A. The Properties of Fatty Acids Depend on Their Hydrocarbon Chains, 246
B. Triacylglycerols Contain Three Esterified Fatty Acids, 248
C. Glycerophospholipids Are Amphiphilic, 249
BOX 9-1. BIOCHEMISTRY IN HEALTH AND DISEASELung Surfactant, 250
D. Sphingolipids Are Amino Alcohol Derivatives, 252
E. Steroids Contain Four Fused Rings, 254
F. Other Lipids Perform a Variety of Metabolic Roles, 257
2. Lipid Bilayers, 260
A. Bilayer Formation Is Driven by the Hydrophobic Effect, 260
B. Lipid Bilayers Have Fluidlike Properties, 261
3. Membrane Proteins, 263
A. Integral Membrane Proteins Interact with Hydrophobic Lipids, 263
BOX 9-2. PATHWAYS OF DISCOVERYRichard Henderson and the Structure of Bacteriorhodopsin, 266
B. Lipid-Linked Proteins Are Anchored to the Bilayer, 267
C. Peripheral Proteins Associate Loosely with Membranes, 269
4. Membrane Structure and Assembly, 269
A. The Fluid Mosaic Model Accounts for Lateral Diffusion, 270
B. The Membrane Skeleton Helps Define Cell Shape, 272
C. Membrane Lipids Are Distributed Asymmetrically, 274
D. The Secretory Pathway Generates Secreted and Transmembrane Proteins, 278
E. Intracellular Vesicles Transport Proteins, 282
F. Proteins Mediate Vesicle Fusion, 287
BOX 9-3. BIOCHEMISTRY IN HEALTH AND DISEASETetanus and Botulinum Toxins Specifically Cleave SNAREs, 288
10. Membrane Transport, 295
1. Thermodynamics of Transport, 296
2. Passive-Mediated Transport, 297
A. Ionophores Carry Ions across Membranes, 297
B. Porins Contain β Barrels, 298
C. Ion Channels Are Highly Selective, 299
D. Aquaporins Mediate the Transmembrane Movement of Water, 306
E. Transport Proteins Alternate between Two Conformations, 307
BOX 10-1. PERSPECTIVES IN BIOCHEMISTRYGap Junctions, 308
BOX 10-2. PERSPECTIVES IN BIOCHEMISTRYDifferentiating Mediated and Nonmediated Transport, 309
3. Active Transport, 311
A. The (Na
+
–K
+
)–ATPase Transports Ions in Opposite Directions, 311
BOX 10-3. BIOCHEMISTRY IN HEALTH AND DISEASEThe Action of Cardiac Glycosides, 313
B. The Ca
2+
–ATPase Pumps Ca
2+
Out of the Cytosol, 313
C. ABC Transporters Are Responsible for Drug Resistance, 314
D. Active Transport May Be Driven by Ion Gradients, 316
Part III. ENZYMES, 322
11. Enzymatic Catalysis, 322
1. General Properties of Enzymes, 323
A. Enzymes Are Classified by the Type of Reaction They Catalyze, 324
B. Enzymes Act on Specific Substrates, 325
C. Some Enzymes Require Cofactors, 326
2. Activation Energy and the Reaction Coordinate, 328
3. Catalytic Mechanisms, 330
A. Acid–Base Catalysis Occurs by Proton Transfer, 331
BOX 11-1. PERSPECTIVES IN BIOCHEMISTRYEffects of pH on Enzyme Activity, 332
B. Covalent Catalysis Usually Requires a Nucleophile, 333
C. Metal Ion Cofactors Act as Catalysts, 335
D. Catalysis Can Occur through Proximity and Orientation Effects, 336
E. Enzymes Catalyze Reactions by Preferentially Binding the Transition State, 338
4. Lysozyme, 339
A. Lysozyme’s Catalytic Site Was Identified through Model Building, 340
BOX 11-2. PERSPECTIVES IN BIOCHEMISTRYObserving Enzyme Action by X-Ray Crystallography, 342
B. The Lysozyme Reaction Proceeds via a Covalent Intermediate, 343
5. Serine Proteases, 347
A. Active Site Residues Were Identified by Chemical Labeling, 348
B. X-Ray Structures Provided Information about Catalysis, Substrate Specificity, and Evolution, 348
BOX 11-3. BIOCHEMISTRY IN HEALTH AND DISEASENerve Poisons, 349
C. Serine Proteases Use Several Catalytic Mechanisms, 352
D. Zymogens Are Inactive Enzyme Precursors, 357
BOX 11-4. BIOCHEMISTRY IN HEALTH AND DISEASEThe Blood Coagulation Cascade, 358
12. Enzyme Kinetics, Inhibition, and Control, 363
1. Reaction Kinetics, 364
A. Chemical Kinetics Is Described by Rate Equations, 364
B. Enzyme Kinetics Often Follows the Michaelis–Menten Equation, 366
BOX 12-1. PERSPECTIVES IN BIOCHEMISTRYIsotopic Labeling, 367
BOX 12-2. PATHWAYS OF DISCOVERYJ.B.S. Haldane and Enzyme Action, 369
BOX 12-3. PERSPECTIVES IN BIOCHEMISTRYKinetics and Transition State Theory, 372
C. Kinetic Data Can Provide Values of
V
max
and
K
M
, 372
D. Bisubstrate Reactions Follow One of Several Rate Equations, 375
2. Enzyme Inhibition, 377
A. Competitive Inhibition Involves Inhibitor Binding at an Enzyme’s Substrate Binding Site, 377
B. Uncompetitive Inhibition Involves Inhibitor Binding to the Enzyme–Substrate Complex, 381
C. Mixed Inhibition Involves Inhibitor Binding to Both the Free Enzyme and the Enzyme–Substrate Complex, 382
BOX 12-4. BIOCHEMISTRY IN HEALTH AND DISEASEHIV Enzyme Inhibitors, 384
3. Control of Enzyme Activity, 386
A. Allosteric Control Involves Binding at a Site Other Than the Active Site, 386
B. Control by Covalent Modification Often Involves Protein Phosphorylation, 390
4. Drug Design, 394
A. Drug Discovery Employs a Variety of Techniques, 394
B. A Drug’s Bioavailability Depends on How It Is Absorbed and Transported in the Body, 396
C. Clinical Trials Test for Efficacy and Safety, 396
D. Cytochromes P450 Are Often Implicated in Adverse Drug Reactions, 398
13. Biochemical Signaling, 405
1. Hormones, 406
A. Pancreatic Islet Hormones Control Fuel Metabolism, 407
BOX 13-1. PATHWAYS OF DISCOVERYRosalyn Yalow and the Radioimmunoassay (RIA), 408
B. Epinephrine and Norepinephrine Prepare the Body for Action, 409
C. Steroid Hormones Regulate a Wide Variety of Metabolic and Sexual Processes, 410
D. Growth Hormone Binds to Receptors in Muscle, Bone, and Cartilage, 411
2. Receptor Tyrosine Kinases, 412
A. Receptor Tyrosine Kinases Transmit Signals across the Cell Membrane, 413
BOX 13-2. PERSPECTIVES IN BIOCHEMISTRYReceptor–Ligand Binding Can Be Quantitated, 414
B. Kinase Cascades Relay Signals to the Nucleus, 416
BOX 13-3. BIOCHEMISTRY IN HEALTH AND DISEASEOncogenes and Cancer, 421
C. Some Receptors Are Associated with Nonreceptor Tyrosine Kinases, 422
D. Protein Phosphatases Are Signaling Proteins in Their Own Right, 425
3. Heterotrimeric G Proteins, 428
A. G Protein–Coupled Receptors Contain Seven Transmembrane Helices, 429
B. Heterotrimeric G Proteins Dissociate on Activation, 430
C. Adenylate Cyclase Synthesizes cAMP to Activate Protein Kinase A, 432
D. Phosphodiesterases Limit Second Messenger Activity, 435
BOX 13-4. BIOCHEMISTRY IN HEALTH AND DISEASEDrugs and Toxins That Affect Cell Signaling, 435
4. The Phosphoinositide Pathway, 436
A. Ligand Binding Results in the Cytoplasmic Release of the Second Messengers IP
3
and Ca
2+
, 437
B. Calmodulin Is a Ca
2+
-Activated Switch, 438
C. DAG Is a Lipid-Soluble Second Messenger That Activates Protein Kinase C, 440
D. Epilog: Complex Systems Have Emergent Properties, 442
BOX 13-5. BIOCHEMISTRY IN HEALTH AND DISEASEAnthrax, 444
Part IV. METABOLISM, 448
14. Introduction to Metabolism, 448
1. Overview of Metabolism, 449
A. Nutrition Involves Food Intake and Use, 449
B. Vitamins and Minerals Assist Metabolic Reactions, 450
C. Metabolic Pathways Consist of Series of Enzymatic Reactions, 451
BOX 14-1. PERSPECTIVES IN BIOCHEMISTRYOxidation States of Carbon, 453
BOX 14-2. PERSPECTIVES IN BIOCHEMISTRYMapping Metabolic Pathways, 454
D. Thermodynamics Dictates the Direction and Regulatory Capacity of Metabolic Pathways, 455
E. Metabolic Flux Must Be Controlled, 457
2. “High-Energy” Compounds, 459
BOX 14-3. PATHWAYS OF DISCOVERYFritz Lipmann and “High-Energy” Compounds, 460
A. ATP Has a High Phosphoryl Group-Transfer Potential, 460
BOX 14-4. PERSPECTIVES IN BIOCHEMISTRYATP and Δ
G
, 462
B. Coupled Reactions Drive Endergonic Processes, 462
C. Some Other Phosphorylated Compounds Have High Phosphoryl Group-Transfer Potentials, 464
D. Thioesters Are Energy-Rich Compounds, 468
3. Oxidation–Reduction Reactions, 469
A. NAD
+
and FAD Are Electron Carriers, 469
B. The Nernst Equation Describes Oxidation–Reduction Reactions, 470
C. Spontaneity Can Be Determined by Measuring Reduction Potential Differences, 472
4. Experimental Approaches to the Study of Metabolism, 475
A. Labeled Metabolites Can Be Traced, 475
B. Studying Metabolic Pathways Often Involves Perturbing the System, 477
C. Systems Biology Has Entered the Study of Metabolism, 477
15. Glucose Catabolism, 485
1. Overview of Glycolysis, 486
BOX 15-1. PATHWAYS OF DISCOVERYOtto Warburg and Studies of Metabolism, 488
2. The Reactions of Glycolysis, 489
A. Hexokinase Uses the First ATP, 489
B. Phosphoglucose Isomerase Converts Glucose-6-Phosphate to Fructose-6-Phosphate, 490
C. Phosphofructokinase Uses the Second ATP, 491
D. Aldolase Converts a 6-Carbon Compound to Two 3-Carbon Compounds, 492
E. Triose Phosphate Isomerase Interconverts Dihydroxyacetone Phosphate and Glyceraldehyde-3-Phosphate, 494
F. Glyceraldehyde-3-Phosphate Dehydrogenase Forms the First “High-Energy” Intermediate, 497
G. Phosphoglycerate Kinase Generates the First ATP, 499
H. Phosphoglycerate Mutase Interconverts 3-Phosphoglycerate and 2-Phosphoglycerate, 499
I. Enolase Forms the Second “High-Energy” Intermediate, 500
J. Pyruvate Kinase Generates the Second ATP, 501
BOX 15-2. PERSPECTIVES IN BIOCHEMISTRYSynthesis of 2,3-Bisphosphoglycerate in Erythrocytes and Its Effect on the Oxygen Carrying Capacity of the Blood, 502
3. Fermentation: The Anaerobic Fate of Pyruvate, 504
A. Homolactic Fermentation Converts Pyruvate to Lactate, 505
B. Alcoholic Fermentation Converts Pyruvate to Ethanol and CO
2
, 506
C. Fermentation Is Energetically Favorable, 509
BOX 15-3. PERSPECTIVES IN BIOCHEMISTRYGlycolytic ATP Production in Muscle, 510
4. Regulation of Glycolysis, 510
A. Phosphofructokinase Is the Major Flux-Controlling Enzyme of Glycolysis in Muscle, 511
B. Substrate Cycling Fine-Tunes Flux Control, 514
5. Metabolism of Hexoses Other than Glucose, 516
A. Fructose Is Converted to Fructose-6-Phosphate or Glyceraldehyde-3-Phosphate, 516
B. Galactose Is Converted to Glucose-6-Phosphate, 518
C. Mannose Is Converted to Fructose-6-Phosphate, 520
6. The Pentose Phosphate Pathway, 520
A. Oxidative Reactions Produce NADPH in Stage 1, 522
B. Isomerization and Epimerization of Ribulose-5-Phosphate Occur in Stage 2, 523
C. Stage 3 Involves Carbon–Carbon Bond Cleavage and Formation, 523
D. The Pentose Phosphate Pathway Must Be Regulated, 524
BOX 15-4. BIOCHEMISTRY IN HEALTH AND DISEASEGlucose-6-Phosphate Dehydrogenase Deficiency, 526
16. Glycogen Metabolism and Gluconeogenesis, 530
1. Glycogen Breakdown, 532
BOX 16-1. PATHWAYS OF DISCOVERYCarl and Gerty Cori and Glucose Metabolism, 533
A. Glycogen Phosphorylase Degrades Glycogen to Glucose-1-Phosphate, 534
B. Glycogen Debranching Enzyme Acts as a Glucosyltransferase, 536
C. Phosphoglucomutase Interconverts Glucose-1-Phosphate and Glucose-6-Phosphate, 537
BOX 16-2. BIOCHEMISTRY IN HEALTH AND DISEASEGlycogen Storage Diseases, 538
2. Glycogen Synthesis, 540
A. UDP–Glucose Pyrophosphorylase Activates Glucosyl Units, 540
B. Glycogen Synthase Extends Glycogen Chains, 541
C. Glycogen Branching Enzyme Transfers Seven-Residue Glycogen Segments, 543
BOX 16-3. PERSPECTIVES IN BIOCHEMISTRYOptimizing Glycogen Structure, 544
3. Control of Glycogen Metabolism, 545
A. Glycogen Phosphorylase and Glycogen Synthase Are Under Allosteric Control, 545
B. Glycogen Phosphorylase and Glycogen Synthase Undergo Control by Covalent Modification, 545
C. Glycogen Metabolism Is Subject to Hormonal Control, 550
4. Gluconeogenesis, 552
A. Pyruvate Is Converted to Phosphoenolpyruvate in Two Steps, 554
B. Hydrolytic Reactions Bypass Irreversible Glycolytic Reactions, 557
C. Gluconeogenesis and Glycolysis Are Independently Regulated, 558
5. Other Carbohydrate Biosynthetic Pathways, 560
BOX 16-4. PERSPECTIVES IN BIOCHEMISTRYLactose Synthesis, 560
17. Citric Acid Cycle, 566
1. Overview of the Citric Acid Cycle, 567
BOX 17-1. PATHWAYS OF DISCOVERYHans Krebs and the Citric Acid Cycle, 569
2. Synthesis of Acetyl-Coenzyme A, 570
A. Pyruvate Dehydrogenase Is a Multienzyme Complex, 570
B. The Pyruvate Dehydrogenase Complex Catalyzes Five Reactions, 572
BOX 17-2. BIOCHEMISTRY IN HEALTH AND DISEASEArsenic Poisoning, 576
3. Enzymes of the Citric Acid Cycle, 576
A. Citrate Synthase Joins an Acetyl Group to Oxaloacetate, 577
B. Aconitase Interconverts Citrate and Isocitrate, 578
C. NAD
+
-Dependent Isocitrate Dehydrogenase Releases CO
2
, 579
D. α-Ketoglutarate Dehydrogenase Resembles Pyruvate Dehydrogenase, 580
E. Succinyl-CoA Synthetase Produces GTP, 580
F. Succinate Dehydrogenase Generates FADH
2
, 582
G. Fumarase Produces Malate, 583
H. Malate Dehydrogenase Regenerates Oxaloacetate, 583
4. Regulation of the Citric Acid Cycle, 583
A. Pyruvate Dehydrogenase Is Regulated by Product Inhibition and Covalent Modification, 585
B. Three Enzymes Control the Rate of the Citric Acid Cycle, 585
5. Reactions Related to the Citric Acid Cycle, 588
A. Other Pathways Use Citric Acid Cycle Intermediates, 588
B. Some Reactions Replenish Citric Acid Cycle Intermediates, 589
C. The Glyoxylate Cycle Shares Some Steps with the Citric Acid Cycle, 590
BOX 17-3. PERSPECTIVES IN BIOCHEMISTRYEvolution of the Citric Acid Cycle, 592
18. Electron Transport and Oxidative Phosphorylation, 596
1. The Mitochondrion, 597
A. Mitochondria Contain a Highly Folded Inner Membrane, 597
B. Ions and Metabolites Enter Mitochondria via Transporters, 599
2. Electron Transport, 600
A. Electron Transport Is an Exergonic Process, 601
B. Electron Carriers Operate in Sequence, 602
C. Complex I Accepts Electrons from NADH, 604
D. Complex II Contributes Electrons to Coenzyme Q, 609
BOX 18-1. PERSPECTIVES IN BIOCHEMISTRYCytochromes Are Electron-Transport Heme Proteins, 610
E. Complex III Translocates Protons via the Q Cycle, 611
F. Complex IV Reduces Oxygen to Water, 615
3. Oxidative Phosphorylation, 618
A. The Chemiosmotic Theory Links Electron Transport to ATP Synthesis, 618
BOX 18-2. PATHWAYS OF DISCOVERYPeter Mitchell and the Chemiosmotic Theory, 619
BOX 18-3. PERSPECTIVES IN BIOCHEMISTRYBacterial Electron Transport and Oxidative Phosphorylation, 621
B. ATP Synthase Is Driven by the Flow of Protons, 622
C. The P/O Ratio Relates the Amount of ATP Synthesized to the Amount of Oxygen Reduced, 629
D. Oxidative Phosphorylation Can Be Uncoupled from Electron Transport, 630
4. Control of Oxidative Metabolism, 631
A. The Rate of Oxidative Phosphorylation Depends on the ATP and NADH Concentrations, 631
BOX 18-4. PERSPECTIVES IN BIOCHEMISTRYUncoupling in Brown Adipose Tissue Generates Heat, 632
B. Aerobic Metabolism Has Some Disadvantages, 634
BOX 18-5. BIOCHEMISTRY IN HEALTH AND DISEASEOxygen Deprivation in Heart Attack and Stroke, 635
19. Photosynthesis, 640
1. Chloroplasts, 641
A. The Light Reactions Take Place in the Thylakoid Membrane, 641
B. Pigment Molecules Absorb Light, 643
2. The Light Reactions, 645
A. Light Energy Is Transformed to Chemical Energy, 645
B. Electron Transport in Photosynthetic Bacteria Follows a Circular Path, 647
C. Two-Center Electron Transport Is a Linear Pathway That Produces O
2
and NADPH, 650
D. The Proton Gradient Drives ATP Synthesis by Photophosphorylation, 661
BOX 19-1. PERSPECTIVES IN BIOCHEMISTRYSegregation of PSI and PSII, 662
3. The Dark Reactions, 663
A. The Calvin Cycle Fixes CO
2
, 663
B. Calvin Cycle Products Are Converted to Starch, Sucrose, and Cellulose, 668
C. The Calvin Cycle Is Controlled Indirectly by Light, 670
D. Photorespiration Competes with Photosynthesis, 671
20. Lipid Metabolism, 677
1. Lipid Digestion, Absorption, and Transport, 678
A. Triacylglycerols Are Digested before They Are Absorbed, 678
B. Lipids Are Transported as Lipoproteins, 680
2. Fatty Acid Oxidation, 685
A. Fatty Acids Are Activated by Their Attachment to Coenzyme A, 686
B. Carnitine Carries Acyl Groups across the Mitochondrial Membrane, 686
C. β Oxidation Degrades Fatty Acids to Acetyl-CoA, 688
D. Oxidation of Unsaturated Fatty Acids Requires Additional Enzymes, 690
E. Oxidation of Odd-Chain Fatty Acids Yields Propionyl-CoA, 692
BOX 20-1. BIOCHEMISTRY IN HEALTH AND DISEASEVitamin B
12
Deficiency, 696
BOX 20-2. PATHWAYS OF DISCOVERYDorothy Crowfoot Hodgkin and the Structure of Vitamin B
12
, 697
F. Peroxisomal β Oxidation Differs from Mitochondrial β Oxidation, 698
3. Ketone Bodies, 698
4. Fatty Acid Biosynthesis, 701
A. Mitochondrial Acetyl-CoA Must Be Transported into the Cytosol, 701
B. Acetyl-CoA Carboxylase Produces Malonyl-CoA, 702
C. Fatty Acid Synthase Catalyzes Seven Reactions, 703
D. Fatty Acids May Be Elongated and Desaturated, 707
BOX 20-3. PERSPECTIVES IN BIOCHEMISTRYTriclosan: An Inhibitor of Fatty Acid Synthesis, 708
E. Fatty Acids Are Esterified to Form Triacylglycerols, 711
5. Regulation of Fatty Acid Metabolism, 711
6. Synthesis of Other Lipids, 714
A. Glycerophospholipids Are Built from Intermediates of Triacylglycerol Synthesis, 714
B. Sphingolipids Are Built from Palmitoyl-CoA and Serine, 717
C. C
20
Fatty Acids Are the Precursors of Prostaglandins, 718
BOX 20-4. BIOCHEMISTRY IN HEALTH AND DISEASESphingolipid Degradation and Lipid Storage Diseases, 720
7. Cholesterol Metabolism, 721
A. Cholesterol Is Synthesized from Acetyl-CoA, 721
B. HMG-CoA Reductase Controls the Rate of Cholesterol Synthesis, 725
C. Abnormal Cholesterol Transport Leads to Atherosclerosis, 727
21. Amino Acid Metabolism, 732
1. Protein Degradation, 732
A. Lysosomes Degrade Many Proteins, 732
B. Ubiquitin Marks Proteins for Degradation, 733
C. The Proteasome Unfolds and Hydrolyzes Ubiquitinated Polypeptides, 734
2. Amino Acid Deamination, 738
A. Transaminases Use PLP to Transfer Amino Groups, 738
B. Glutamate Can Be Oxidatively Deaminated, 742
3. The Urea Cycle, 743
A. Five Enzymes Carry out the Urea Cycle, 743
B. The Urea Cycle Is Regulated by Substrate Availability, 747
4. Breakdown of Amino Acids, 747
A. Alanine, Cysteine, Glycine, Serine, and Threonine Are Degraded to Pyruvate, 748
B. Asparagine and Aspartate Are Degraded to Oxaloacetate, 751
C. Arginine, Glutamate, Glutamine, Histidine, and Proline Are Degraded to α-Ketoglutarate, 751
D. Isoleucine, Methionine, and Valine Are Degraded to Succinyl-CoA, 753
BOX 21-1. BIOCHEMISTRY IN HEALTH AND DISEASEHomocysteine, a Marker of Disease, 755
E. Leucine and Lysine Are Degraded Only to Acetyl-CoA and/or Acetoacetate, 758
F. Tryptophan Is Degraded to Alanine and Acetoacetate, 758
G. Phenylalanine and Tyrosine Are Degraded to Fumarate and Acetoacetate, 760
BOX 21-2. BIOCHEMISTRY IN HEALTH AND DISEASEPhenylketonuria and Alcaptonuria Result from Defects in Phenylalanine Degradation, 762
5. Amino Acid Biosynthesis, 763
A. Nonessential Amino Acids Are Synthesized from Common Metabolites, 764
B. Plants and Microorganisms Synthesize the Essential Amino Acids, 769
6. Other Products of Amino Acid Metabolism, 774
A. Heme Is Synthesized from Glycine and Succinyl-CoA, 775
BOX 21-3. BIOCHEMISTRY IN HEALTH AND DISEASEThe Porphyrias, 778
B. Amino Acids Are Precursors of Physiologically Active Amines, 780
C. Nitric Oxide Is Derived from Arginine, 781
7. Nitrogen Fixation, 782
A. Nitrogenase Reduces N
2
to NH
3
, 783
B. Fixed Nitrogen Is Assimilated into Biological Molecules, 786
22. Mammalian Fuel Metabolism: Integration and Regulation, 791
1. Organ Specialization, 792
A. The Brain Requires a Steady Supply of Glucose, 793
B. Muscle Utilizes Glucose, Fatty Acids, and Ketone Bodies, 794
C. Adipose Tissue Stores and Releases Fatty Acids and Hormones, 795
D. Liver Is the Body’s Central Metabolic Clearinghouse, 796
E. Kidney Filters Wastes and Maintains Blood pH, 798
F. Blood Transports Metabolites in Interorgan Metabolic Pathways, 798
2. Hormonal Control of Fuel Metabolism, 799
3. Metabolic Homeostasis: The Regulation of Energy Metabolism, Appetite, and Body Weight, 804
A. AMP-Dependent Protein Kinase Is the Cell’s Fuel Gauge, 804
B. Adiponectin Regulates AMPK Activity, 806
C. Leptin Is a Satiety Hormone, 806
D. Ghrelin and PYY
3–36
Act as Short-Term Regulators of Appetite, 807
E. Energy Expenditure Can Be Controlled by Adaptive Thermogenesis, 808
4. Disturbances in Fuel Metabolism, 809
A. Starvation Leads to Metabolic Adjustments, 809
B. Diabetes Mellitus Is Characterized by High Blood Glucose Levels, 811
BOX 22-1. PATHWAYS OF DISCOVERYFrederick Banting and Charles Best and the Discovery of Insulin, 812
C. Obesity Is Usually Caused by Excessive Food Intake, 814
Part V. GENE EXPRESSION AND REPLICATION, 817
23. Nucleotide Metabolism, 817
1. Synthesis of Purine Ribonucleotides, 818
A. Purine Synthesis Yields Inosine Monophosphate, 818
B. IMP Is Converted to Adenine and Guanine Ribonucleotides, 821
C. Purine Nucleotide Biosynthesis Is Regulated at Several Steps, 822
D. Purines Can Be Salvaged, 823
2. Synthesis of Pyrimidine Ribonucleotides, 824
A. UMP Is Synthesized in Six Steps, 824
B. UMP Is Converted to UTP and CTP, 826
C. Pyrimidine Nucleotide Biosynthesis Is Regulated at ATCase or Carbamoyl Phosphate Synthetase II, 827
3. Formation of Deoxyribonucleotides, 828
A. Ribonucleotide Reductase Converts Ribonucleotides to Deoxyribonucleotides, 828
B. dUMP Is Methylated to Form Thymine, 834
BOX 23-1. BIOCHEMISTRY IN HEALTH AND DISEASEInhibition of Thymidylate Synthesis in Cancer Therapy, 838
4. Nucleotide Degradation, 839
A. Purine Catabolism Yields Uric Acid, 839
B. Some Animals Degrade Uric Acid, 842
BOX 23-2. PATHWAYS OF DISCOVERYGertrude Elion and Purine Derivatives, 844
C. Pyrimidines Are Broken Down to Malonyl-CoA and Methylmalonyl-CoA, 845
24. Nucleic Acid Structure, 848
1. The DNA Helix, 849
A. DNA Can Adopt Different Conformations, 849
BOX 24-1. PATHWAYS OF DISCOVERYRosalind Franklin and the Structure of DNA, 850
B. DNA Has Limited Flexibility, 855
C. DNA Can Be Supercoiled, 857
D. Topoisomerases Alter DNA Supercoiling, 859
2. Forces Stabilizing Nucleic Acid Structures, 864
A. DNA Can Undergo Denaturation and Renaturation, 864
BOX 24-2. BIOCHEMISTRY IN HEALTH AND DISEASEInhibitors of Topoisomerases as Antibiotics and Anticancer Chemotherapeutic Agents, 865
B. Nucleic Acids Are Stabilized by Base Pairing, Stacking, and Ionic Interactions, 866
C. RNA Structures Are Highly Variable, 868
BOX 24-3. PERSPECTIVES IN BIOCHEMISTRYThe RNA World, 871
3. Fractionation of Nucleic Acids, 872
A. Nucleic Acids Can Be Purified by Chromatography, 872
B. Electrophoresis Separates Nucleic Acids by Size, 872
4. DNA–Protein Interactions, 874
A. Restriction Endonucleases Distort DNA on Binding, 875
B. Prokaryotic Repressors Often Include a DNA-Binding Helix, 876
C. Eukaryotic Transcription Factors May Include Zinc Fingers or Leucine Zippers, 879
5. Eukaryotic Chromosome Structure, 883
A. Histones Are Positively Charged, 884
B. DNA Coils around Histones to Form Nucleosomes, 884
C. Chromatin Forms Higher-Order Structures, 887
25. DNA Replication, Repair, and Recombination, 893
1. Overview of DNA Replication, 894
2. Prokaryotic DNA Replication, 896
A. DNA Polymerases Add the Correctly Paired Nucleotide, 896
BOX 25-1. PATHWAYS OF DISCOVERYArthur Kornberg and DNA Polymerase I, 898
B. Replication Initiation Requires Helicase and Primase, 903
C. The Leading and Lagging Strands Are Synthesized Simultaneously, 904
D. Replication Terminates at Specific Sites, 908
E. DNA Is Replicated with High Fidelity, 909
3. Eukaryotic DNA Replication, 910
A. Eukaryotes Use Several DNA Polymerases, 910
B. Eukaryotic DNA Is Replicated from Multiple Origins, 911
BOX 25-2. PERSPECTIVES IN BIOCHEMISTRYReverse Transcriptase, 912
C. Telomerase Extends Chromosome Ends, 914
BOX 25-3. BIOCHEMISTRY IN HEALTH AND DISEASETelomerase, Aging, and Cancer, 915
4. DNA Damage, 916
A. Environmental and Chemical Agents Generate Mutations, 916
BOX 25-4. PERSPECTIVES IN BIOCHEMISTRYDNA Methylation, 918
B. Many Mutagens Are Carcinogens, 919
5. DNA Repair, 920
A. Some Damage Can Be Directly Reversed, 920
B. Base Excision Repair Requires a Glycosylase, 921
BOX 25-5. PERSPECTIVES IN BIOCHEMISTRYWhy Doesn’t DNA Contain Uracil?, 921
C. Nucleotide Excision Repair Removes a Segment of a DNA Strand, 923
D. Mismatch Repair Corrects Replication Errors, 924
E. Some DNA Repair Mechanisms Introduce Errors, 925
6. Recombination, 926
A. Homologous Recombination Involves Several Protein Complexes, 926
B. DNA Can Be Repaired by Recombination, 932
C. Transposition Rearranges Segments of DNA, 934
26. Transcription and RNA Processing, 942
1. Prokaryotic RNA Transcription, 943
A. RNA Polymerase Resembles Other Polymerases, 943
B. Transcription Is Initiated at a Promoter, 943
C. The RNA Chain Grows from the 5′ to 3′ End, 947
BOX 26-1. PERSPECTIVES IN BIOCHEMISTRYCollisions between DNA Polymerase and RNA Polymerase, 949
D. Transcription Terminates at Specific Sites, 950
2. Transcription in Eukaryotes, 952
A. Eukaryotes Have Several RNA Polymerases, 953
BOX 26-2. BIOCHEMISTRY IN HEALTH AND DISEASEInhibitors of Transcription, 954
B. Each Polymerase Recognizes a Different Type of Promoter, 958
C. Transcription Factors Are Required to Initiate Transcription, 960
3. Posttranscriptional Processing, 965
A. Messenger RNAs Undergo 5′ Capping, Addition of a 3′ Tail, and Splicing, 965
BOX 26-3. PATHWAYS OF DISCOVERYRichard Roberts and Phillip Sharp and the Discovery of Introns, 968
B. Ribosomal RNA Precursors May Be Cleaved, Modified, and Spliced, 976
C. Transfer RNAs Are Processed by Nucleotide Removal, Addition, and Modification, 980
27. Protein Synthesis, 985
1. The Genetic Code, 986
A. Codons Are Triplets That Are Read Sequentially, 986
B. The Genetic Code Was Systematically Deciphered, 987
C. The Genetic Code Is Degenerate and Nonrandom, 988
BOX 27-1. PERSPECTIVES IN BIOCHEMISTRYEvolution of the Genetic Code, 990
2. Transfer RNA and Its Aminoacylation, 991
A. All tRNAs Have a Similar Structure, 991
B. Aminoacyl–tRNA Synthetases Attach Amino Acids to tRNAs, 994
C. A tRNA May Recognize More than One Codon, 998
BOX 27-2. PERSPECTIVES IN BIOCHEMISTRYExpanding the Genetic Code, 1000
3. Ribosomes, 1000
A. The Prokaryotic Ribosome Consists of Two Subunits, 1001
B. The Eukaryotic Ribosome Is Larger and More Complex, 1007
4. Translation, 1008
A. Chain Initiation Requires an Initiator tRNA and Initiation Factors, 1010
B. The Ribosome Decodes the mRNA, Catalyzes Peptide Bond Formation, Then Moves to the Next Codon, 1014
BOX 27-3. BIOCHEMISTRY IN HEALTH AND DISEASEThe Effects of Antibiotics on Protein Synthesis, 1024
C. Release Factors Terminate Translation, 1026
5. Posttranslational Processing, 1028
A. Ribosome-Associated Chaperones Help Proteins Fold, 1028
B. Newly Synthesized Proteins May Be Covalently Modified, 1029
28. Regulation of Gene Expression, 1037
1. Genome Organization, 1038
A. Gene Number Varies among Organisms, 1038
B. Some Genes Occur in Clusters, 1042
C. Eukaryotic Genomes Contain Repetitive DNA Sequences, 1043
BOX 28-1. BIOCHEMISTRY IN HEALTH AND DISEASETrinucleotide Repeat Diseases, 1044
2. Regulation of Prokaryotic Gene Expression, 1046
A. The
lac
Operon Is Controlled by a Repressor, 1046
B. Catabolite-Repressed Operons Can Be Activated, 1050
C. Attenuation Regulates Transcription Termination, 1051
D. Riboswitches Are Metabolite-Sensing RNAs, 1054
3. Regulation of Eukaryotic Gene Expression, 1055
A. Chromatin Structure Influences Gene Expression, 1055
BOX 28-2. PERSPECTIVES IN BIOCHEMISTRYX Chromosome Inactivation, 1057
B. Eukaryotes Contain Multiple Transcriptional Activators, 1067
C. Posttranscriptional Control Mechanisms Include RNA Degradation, 1073
BOX 28-3. PERSPECTIVES IN BIOCHEMISTRYNonsense-Mediated Decay, 1074
D. Antibody Diversity Results from Somatic Recombination and Hypermutation, 1077
4. The Cell Cycle, Cancer, and Apoptosis, 1081
A. Progress through the Cell Cycle Is Tightly Regulated, 1081
B. Tumor Suppressors Prevent Cancer, 1084
C. Apoptosis Is an Orderly Process, 1086
D. Development Has a Molecular Basis, 1090
APPENDICES, SP-1
Solutions to Problems, SP-1
Glossary, G-1
Index, I-1
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