Biochemistry: concepts and connections

Cover......Page 1
Title Page......Page 2
Copyright Page......Page 3
Brief Contents......Page 4
Contents......Page 5
Preface......Page 20
About the Authors......Page 23
Tools of Biochemistry:......Page 24
Foundation Figures......Page 25
Chapter 1: Biochemistry and the Language of Chemistry......Page 35
  The Origins of Biochemistry......Page 37
  Biochemistry as a Discipline and an Interdisciplinary Science......Page 39
  The Chemical Elements of Cells and Organisms......Page 40
  The Complexity and Size of Biological Molecules......Page 41
   The Biopolymers: Proteins, Nucleic Acids, and Carbohydrates......Page 42
 1.3. Distinguishing Characteristics of Living Systems......Page 44
 1.4. The Unit of Biological Organization: The Cell......Page 46
 1.5. Biochemistry and the Information Explosion......Page 47
Chapter 2: The Chemical Foundation of Life: Weak Interactions in an Aqueous Environment......Page 51
 2.1. The Importance of Noncovalent Interactions in Biochemistry......Page 53
 2.2. The Nature of Noncovalent Interactions......Page 54
  Charge–Charge Interactions......Page 55
  Van der Waals Interactions......Page 56
  Hydrogen Bonds......Page 57
  The Structure and Properties of Water......Page 59
  Water as a Solvent......Page 60
  Hydrophobic Molecules in Aqueous Solution......Page 61
 2.4. Acid–Base Equilibria......Page 62
  Ionization of Water and the Ion Product......Page 63
  The pH Scale and the Physiological pH Range......Page 64
  Weak Acid and Base Equilibria: Ka and pKa......Page 65
  Titration of Weak Acids: The Henderson–Hasselbalch Equation......Page 66
  Buffer Solutions......Page 67
  Molecules with Multiple Ionizing Groups......Page 68
  Solubility of Macroions and pH......Page 71
  The Influence of Small Ions: Ionic Strength......Page 73
 Tools of Biochemistry: 2A Electrophoresis and Isoelectric Focusing......Page 77
 Foundation Figure: Biomolecules: Structure and Function......Page 79
Chapter 3: The Energetics of Life......Page 81
  The First Law of Thermodynamics and Enthalpy......Page 83
  The Driving Force for a Process......Page 84
  Entropy......Page 85
  Free Energy Defined in Terms of Enthalpy and Entropy Changes in the System......Page 86
  The Interplay of Enthalpy and Entropy: A Summary......Page 87
  Equilibrium, Le Chatelier’s Principle, and the Standard State......Page 89
  .G versus .G°, Q versus K, and Homeostasis versus Equilibrium......Page 90
  Water, H+ in Buffered Solutions, and the “Biochemical Standard State”......Page 92
  Organic Phosphate Compounds as Energy Transducers......Page 93
   Free Energy and Concentration Gradients: A Close Look at Diffusion Through a Membrane......Page 96
   Quantification of Reducing Power: Standard Reduction Potential......Page 97
   Standard Free Energy Changes in Oxidation–Reduction Reactions......Page 99
  A Brief Overview of Free Energy Changes in Cells......Page 100
Chapter 4: Nucleic Acids......Page 105
  The Two Types of Nucleic Acid: DNA and RNA......Page 107
  Properties of the Nucleotides......Page 109
  Stability and Formation of the Phosphodiester Linkage......Page 110
  The Nature and Significance of Primary Structure......Page 112
  DNA as the Genetic Substance: Early Evidence......Page 113
   X-Ray Analysis of DNA Fibers......Page 114
  Semiconservative Nature of DNA Replication......Page 116
  Alternative Nucleic Acid Structures: B and A Helices......Page 117
   DNA Molecules......Page 119
   Circular DNA and Supercoiling......Page 120
   Single-Stranded Polynucleotides......Page 121
  Left-Handed DNA (Z-DNA)......Page 123
  Triple Helices......Page 124
  G-Quadruplexes......Page 125
 4.5. The Helix-to-Random Coil Transition: Nucleic Acid Denaturation......Page 126
  Replication: DNA to DNA......Page 127
  Translation: RNA to Protein......Page 128
 Tools of Biochemistry: 4A Manipulating DNA......Page 132
 Tools of Biochemistry: 4B An Introduction to X-Ray Diffraction......Page 137
Chapter 5: Introduction to Proteins: The Primary Level of Protein Structure......Page 141
  Stereochemistry of the a-Amino Acids......Page 144
   Amino Acids with Nonpolar Aromatic Side Chains......Page 148
   Amino Acids with Positively Charged (Basic) Side Chains......Page 149
 5.2. Peptides and the Peptide Bond......Page 150
  The Structure of the Peptide Bond......Page 151
  Peptides......Page 152
  Polypeptides as Polyampholytes......Page 153
 5.3. Proteins: Polypeptides of Defined Sequence......Page 154
  The Genetic Code......Page 156
  Posttranslational Processing of Proteins......Page 157
 5.5. From Gene Sequence to Protein Function......Page 158
 5.6. Protein Sequence Homology......Page 160
 Tools of Biochemistry: 5A Protein Expression and Purification......Page 164
 Tools of Biochemistry: 5B Mass, Sequence, and Amino Acid Analyses of Purified Proteins......Page 171
Chapter 6: The Three-Dimensional Structure of Proteins......Page 177
  Theoretical Descriptions of Regular Polypeptide Structures......Page 179
  Describing the Structures: Helices and Sheets......Page 181
  Amphipathic Helices and Sheets......Page 182
  Ramachandran Plots......Page 183
  The Keratins......Page 185
  Fibroin......Page 186
  Collagen......Page 187
  Different Modes of Display Aid Our Understanding of Protein Structure......Page 189
  Varieties of Globular Protein Structure: Patterns of Main-Chain Folding......Page 190
  The Information for Protein Folding......Page 194
  Conformational Entropy......Page 195
  The Hydrophobic Effect......Page 196
  Disulfide Bonds and Protein Stability......Page 197
  Prosthetic Groups, Ion-Binding, and Protein Stability......Page 198
  Kinetics of Protein Folding......Page 199
  The “Energy Landscape” Model of Protein Folding......Page 200
  Chaperones Faciliate Protein Folding in Vivo......Page 201
  Protein Misfolding and Disease......Page 203
  Prediction of Secondary Structure......Page 204
  Symmetry in Multisubunit Proteins: Homotypic Protein–Protein Interactions......Page 205
  Heterotypic Protein–Protein Interactions......Page 207
 Tools of Biochemistry: 6A Spectroscopic Methods for Studying Macromolecular Conformation in Solution......Page 211
 Tools of Biochemistry: 6B Determining Molecular Masses and the Number of Subunits in a Protein Molecule......Page 218
 Foundation Figure: Protein Structure and Function......Page 221
Chapter 7: Protein Function and Evolution......Page 223
 7.2. The Adaptive Immune Response......Page 225
 7.3. The Structure of Antibodies......Page 226
 7.4 Antibody:Antigen Interactions......Page 228
  Shape and Charge Complementarity......Page 229
  Generation of Antibody Diversity......Page 230
 7.6. The Challenge of Developing an AIDS Vaccine......Page 231
 7.7. Antibodies and Immunoconjugates as Potential Cancer Treatments......Page 232
 7.8. Oxygen Transport from Lungs to Tissues: Protein Conformational Change Enhances Function......Page 233
 7.9. The Oxygen-Binding Sites in Myoglobin and Hemoglobin......Page 234
  Analysis of Oxygen Binding by Myoglobin......Page 236
  Cooperative Binding and Allostery......Page 237
  Changes in Hemoglobin Structure Accompanying Oxygen Binding......Page 239
  A Closer Look at the Allosteric Change in Hemoglobin......Page 241
  Response to pH Changes: The Bohr Effect......Page 244
  Response to Chloride Ion at the a-Globin N-Terminus......Page 245
  2,3-Bisphosphoglycerate......Page 246
  The Structure of Eukaryotic Genes: Exons and Introns......Page 247
  Substitution of DNA Nucleotides......Page 248
  Evolution of the Myoglobin–Hemoglobin Family of Proteins......Page 249
  Pathological Effects of Variant Hemoglobins......Page 251
 7.15. Protein Function Requiring Large Conformational Changes: Muscle Contraction......Page 253
  Myosin......Page 254
 7.18. The Mechanism of Contraction......Page 256
  Regulation of Contraction: The Role of Calcium......Page 259
 Tools of Biochemistry: 7A Immunological Methods......Page 263
Chapter 8: Enzymes: Biological Catalysts......Page 265
 8.2. The Diversity of Enzyme Function......Page 267
   First-Order Reactions......Page 268
  Transition States and Reaction Rates......Page 270
  Transition State Theory Applied to Enzymatic Catalysis......Page 272
 8.4. How Enzymes Act as Catalysts: Principles and Examples......Page 273
  Mechanisms for Achieving Rate Acceleration......Page 274
  Case Study #1: Lysozyme......Page 276
  Case Study #2: Chymotrypsin, a Serine Protease......Page 278
  Coenzyme Function in Catalysis......Page 281
  Metal Ions in Enzymes......Page 282
  Reaction Rate for a Simple Enzyme-Catalyzed Reaction: Michaelis–Menten Kinetics......Page 283
  Interpreting KM, kcat, and kcat/KM......Page 285
  Analysis of Kinetic Data: Testing the Michaelis–Menten Model......Page 286
  Competitive Inhibition......Page 287
  Uncompetitive Inhibition......Page 289
  Mixed Inhibition......Page 291
  Irreversible Inhibition......Page 292
   Qualitative Interpretation of Km and Vmax: Application to Multisubstrate Reaction Mechanisms......Page 293
  Feedback Control......Page 295
   Homoallostery......Page 296
  Aspartate Carbamoyltransferase: An Example of an Allosteric Enzyme......Page 297
 8.9. Covalent Modifications Used to Regulate Enzyme Activity......Page 299
  Pancreatic Proteases: Activation by Irreversible Protein Backbone Cleavage......Page 300
 8.10. Nonprotein Biocatalysts: Catalytic Nucleic Acids......Page 301
 Tools of Biochemistry: 8A How to Measure the Rates of Enzyme-Catalyzed Reactions......Page 306
 Foundation Figure: Regulation of Enzyme Activity......Page 309
Chapter 9: Carbohydrates: Sugars, Saccharides, Glycans......Page 311
   Alternative Designations for Enantiomers: d–l and R–S......Page 314
   Tetrose Diastereomers......Page 315
   Pentose Rings......Page 316
   Hexose Rings......Page 318
  Phosphate Esters......Page 320
  Glycosides......Page 321
   Distinguishing Features of Different Disaccharides......Page 322
   Writing the Structure of Disaccharides......Page 323
  Stability and Formation of the Glycosidic Bond......Page 324
 9.4. Polysaccharides......Page 325
  Storage Polysaccharides......Page 326
   Cellulose......Page 327
   Chitin......Page 328
   Nonstructural Roles of Glycosaminoglycans......Page 329
  Bacterial Cell Wall Polysaccharides; Peptidoglycan......Page 330
   O-Linked Glycans......Page 331
  Blood Group Antigens......Page 332
  Influenza Neuraminidase, a Target for Antiviral Drugs......Page 333
 Tools of Biochemistry: 9A The Emerging Field of Glycomics......Page 336
Chapter 10: Lipids, Membranes, and Cellular Transport......Page 337
  Fatty Acids......Page 339
  Triacylglycerols: Fats......Page 341
 10.2. The Lipid Constituents of Biological Membranes......Page 342
  Glycerophospholipids......Page 343
  Sphingolipids and Glycosphingolipids......Page 344
  Cholesterol......Page 345
 10.3. The Structure and Properties of Membranes and Membrane Proteins......Page 346
   Motion in Synthetic Membranes......Page 347
  The Asymmetry of Membranes......Page 348
  Characteristics of Membrane Proteins......Page 349
  Insertion of Proteins into Membranes......Page 350
  Evolution of the Fluid Mosaic Model of Membrane Structure......Page 352
  The Thermodynamics of Transport......Page 354
  Nonmediated Transport: Diffusion......Page 355
   Carriers......Page 356
   Permeases......Page 357
   Pore-Facilitated Transport......Page 358
  Ion Selectivity and Gating......Page 359
 10.5. Ion Pumps: Direct Coupling of ATP Hydrolysis to Transport......Page 361
 10.6. Ion Transporters and Disease......Page 363
 10.7. Cotransport Systems......Page 364
  The Resting Potential......Page 365
  The Action Potential......Page 366
  Toxins and Neurotransmission......Page 367
 Foundation Figure: Targeting Pain and Inflammation through Drug Design......Page 371
Chapter 11: Chemical Logic of Metabolism......Page 373
 11.1. A First Look at Metabolism......Page 375
  Central Pathways of Energy Metabolism......Page 376
  Distinct Pathways for Biosynthesis and Degradation......Page 379
  Nucleophilic Substitutions......Page 380
  Carbonyl Condensations......Page 381
  Oxidation as a Metabolic Energy Source......Page 383
   Energy Yields, Respiratory Quotients, and Reducing Equivalents......Page 384
  ATP as a Free Energy Currency......Page 385
   Metabolite Concentrations and Solvent Capacity......Page 387
   Thermodynamic Properties of ATP......Page 388
   Kinetic Control of Substrate Cycles......Page 389
   Other High-Energy Phosphate Compounds......Page 390
  Control of Enzyme Levels......Page 391
  Compartmentation......Page 392
  Hormonal Regulation......Page 393
  Distributive Control of Metabolism......Page 394
   Whole Cells......Page 395
  Metabolic Probes......Page 396
 Tools of Biochemistry: 11A Metabolomics......Page 400
 Tools of Biochemistry: 11B Radioactive and Stable Isotopes......Page 403
 Foundation Figure: Enzyme Kinetics and Drug Action......Page 405
Chapter 12: Carbohydrate Metabolism: Glycolysis, Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway......Page 407
  Anaerobic and Aerobic Glycolysis......Page 410
   Reaction 1: The First ATP Investment......Page 412
   Reaction 4: Cleavage to Two Triose Phosphates......Page 414
   Reaction 5: Isomerization of Dihydroxyacetone Phosphate......Page 415
   Reaction 7: The First Substrate-Level Phosphorylation......Page 416
   Reaction 8: Preparing for Synthesis of the Next High-Energy Compound......Page 417
   Reaction 10: The Second Substrate-Level Phosphorylation......Page 418
  Lactate Metabolism......Page 419
  Ethanol Metabolism......Page 421
 12.4. Energy and Electron Balance Sheets......Page 422
  Physiological Need for Glucose Synthesis in Animals......Page 423
   Bypass 1: Conversion of Pyruvate to Phosphoenolpyruvate......Page 424
   Bypass 3: Conversion of Glucose-6-phosphate to Glucose......Page 425
   Lactate......Page 426
  The Pasteur Effect......Page 427
  Reciprocal Regulation of Glycolysis and Gluconeogenesis......Page 428
  Fructose-2,6-bisphosphate and the Control of Glycolysis and Gluconeogenesis......Page 429
  Regulation at the Hexokinase/Glucose-6-Phosphatase Substrate Cycle......Page 432
  Disaccharide Metabolism......Page 433
   Hydrolytic and Phosphorolytic Cleavages......Page 434
  Glycogen Breakdown......Page 435
   Biosynthesis of UDP-Glucose......Page 436
   The Glycogen Synthase Reaction......Page 437
  Structure of Glycogen Phosphorylase......Page 438
  Proteins in the Glycogenolytic Cascade......Page 439
  Nonhormonal Control of Glycogenolysis......Page 440
  Control of Glycogen Synthase Activity......Page 441
  Congenital Defects of Glycogen Metabolism in Humans......Page 442
 12.10. A Biosynthetic Pathway That Oxidizes Glucose: The Pentose Phosphate Pathway......Page 443
   Production of Six-Carbon and Three-Carbon Sugar Phosphates......Page 444
   Tailoring the Pentose Phosphate Pathway to Specific Needs......Page 446
   Regulation of the Pentose Phosphate Pathway......Page 447
  Human Genetic Disorders Involving Pentose Phosphate Pathway Enzymes......Page 448
Chapter 13: The Citric Acid Cycle......Page 453
  The Three Stages of Respiration......Page 456
  Chemical Strategy of the Citric Acid Cycle......Page 457
  Overview of Pyruvate Oxidation and the Pyruvate Dehydrogenase Complex......Page 459
  Coenzymes Involved in Pyruvate Oxidation and the Citric Acid Cycle......Page 460
  Coenzyme A: Activation of Acyl Groups......Page 461
  Flavin Adenine Dinucleotide (FAD)......Page 462
  Action of the Pyruvate Dehydrogenase Complex......Page 464
  Step 1: Introduction of Two Carbon Atoms as Acetyl-CoA......Page 466
  Step 2: Isomerization of Citrate......Page 467
  Step 4: Conservation of Energy in NADH by a Second Oxidative Decarboxylation......Page 468
  Step 5: A Substrate-Level Phosphorylation......Page 469
  Step 8: An Oxidation that Regenerates Oxaloacetate......Page 470
 13.5. Regulation of Pyruvate Dehydrogenase and the Citric Acid Cycle......Page 471
  Control of Pyruvate Oxidation......Page 472
 13.6. Organization and Evolution of the Citric Acid Cycle......Page 473
 13.8. Anaplerotic Sequences: The Need to Replace Cycle Intermediates......Page 474
  Reactions Involving Amino Acids......Page 475
 13.9. The Glyoxylate Cycle: An Anabolic Variant of the Citric Acid Cycle......Page 476
 Tools of Biochemistry: 13A Detecting and Analyzing Protein–Protein Interactions......Page 481
Chapter 14: Electron Transport, Oxidative Phosphorylation, and Oxygen Metabolism......Page 483
 14.2. Free Energy Changes in Biological Oxidations......Page 486
   Coenzyme Q......Page 489
   Cytochromes......Page 490
   NADH–Coenzyme Q Reductase (Complex I)......Page 491
   Succinate–Coenzyme Q Reductase (Complex II; Succinate Dehydrogenase)......Page 493
   Coenzyme Q:Cytochrome c Oxidoreductase (Complex III)......Page 494
   Cytochrome c Oxidase (Complex IV)......Page 495
  The P/O Ratio: Energetics of Oxidative Phosphorylation......Page 496
  Oxidative Reactions That Drive ATP Synthesis......Page 497
  Mechanism of Oxidative Phosphorylation: Chemiosmotic Coupling......Page 498
   An Intact Inner Membrane Is Required for Oxidative Phosphorylation......Page 499
   Discovery and Reconstitution of ATP Synthase......Page 500
  Mechanism of ATP Synthesis......Page 502
 14.5. Respiratory States and Respiratory Control......Page 505
  Transport of Substrates and Products into and out of Mitochondria......Page 508
  Shuttling Cytoplasmic Reducing Equivalents into Mitochondria......Page 509
 14.8. The Mitochondrial Genome, Evolution, and Disease......Page 510
  Cytochrome P450 Monooxygenase......Page 512
   Dealing with Oxidative Stress......Page 513
 Foundation Figure: Intermediary Metabolism......Page 517
Chapter 15: Photosynthesis......Page 519
 15.1. The Basic Processes of Photosynthesis......Page 523
 15.2. The Chloroplast......Page 524
   The Light-Absorbing Pigments......Page 525
   The Light-Gathering Structures......Page 526
  Photochemistry in Plants and Algae: Two Photosystems in Series......Page 528
   Photosystem II: The Splitting of Water......Page 530
   Photosystem I: Production of NADPH......Page 532
   Summation of the Two Systems: The Overall Reaction and NADPH and ATP Generation......Page 533
  Evolution of Photosynthesis......Page 535
 15.4. The Carbon Reactions: The Calvin Cycle......Page 536
   Incorporation of CO2 into a Three-Carbon Sugar......Page 537
  Stage II: Regeneration of the Acceptor......Page 538
  Regulation of Photosynthesis......Page 539
 15.6. Photorespiration and the C4 Cycle......Page 540
Chapter 16: Lipid Metabolism......Page 545
  Fat Digestion and Absorption......Page 548
   Classification and Functions of Lipoproteins......Page 550
   Transport and Utilization of Lipoproteins......Page 551
  Cholesterol Transport and Utilization in Animals......Page 552
   The LDL Receptor and Cholesterol Homeostasis......Page 553
   Cholesterol, LDL, and Atherosclerosis......Page 555
  Early Experiments......Page 556
  Fatty Acid Activation and Transport into Mitochondria......Page 558
  The ß-Oxidation Pathway......Page 559
   Reaction 4: Thiolytic Cleavage......Page 560
  Energy Yield from Fatty Acid Oxidation......Page 561
  Oxidation of Unsaturated Fatty Acids......Page 562
  Control of Fatty Acid Oxidation......Page 563
  Ketogenesis......Page 564
  Relationship of Fatty Acid Synthesis to Carbohydrate Metabolism......Page 565
   Synthesis of Malonyl-CoA......Page 566
   Malonyl-CoA to Palmitate......Page 567
   Multifunctional Proteins in Fatty Acid Synthesis......Page 569
   Transport of Acetyl Units and Reducing Equivalents into the Cytosol......Page 570
  Fatty Acid Desaturation......Page 571
  Control of Fatty Acid Synthesis......Page 572
 16.4. Biosynthesis of Triacylglycerols......Page 573
 16.5. Glycerophospholipids......Page 574
 16.6. Sphingolipids......Page 575
  Steroids: Some Structural Considerations......Page 576
   Early Studies of Cholesterol Biosynthesis......Page 577
   Stage 3: Cyclization of Squalene to Lanosterol and Its Conversion to Cholesterol......Page 578
   Control of Cholesterol Biosynthesis......Page 579
   Vitamin D......Page 581
   Vitamin A......Page 583
 16.8. Eicosanoids: Prostaglandins, Thromboxanes, and Leukotrienes......Page 584
Chapter 17: Interorgan and Intracellular Coordination of Energy Metabolism in Vertebrates......Page 589
   Brain......Page 591
   Blood......Page 593
  Actions of the Major Hormones......Page 594
   Glucagon......Page 595
   AMP-Activated Protein Kinase (AMPK)......Page 596
   Mammalian Target of Rapamycin (mTOR)......Page 597
   Sirtuins......Page 598
   Endocrine Regulation of Energy Homeostasis......Page 599
 17.3. Responses to Metabolic Stress: Starvation, Diabetes......Page 600
  Starvation......Page 601
  Diabetes......Page 602
 Foundation Figure: Energy Regulation......Page 607
Chapter 18: Amino Acid and Nitrogen Metabolism......Page 609
  Biological Nitrogen Fixation......Page 612
  Glutamate Dehydrogenase: Reductive Amination of a-Ketoglutarate......Page 614
  Metabolic Consequences of the Absence of Nitrogen Storage Compounds......Page 615
  Intracellular Proteases and Sites of Turnover......Page 616
  Pyridoxal Phosphate......Page 617
   Discovery and Chemistry of Folic Acid......Page 619
   Tetrahydrofolate in the Metabolism of One-Carbon Units......Page 620
  B12 Coenzymes......Page 622
  Transamination Reactions......Page 623
  Transport of Ammonia to the Liver......Page 624
  The Krebs–Henseleit Urea Cycle......Page 625
  Pyruvate Family of Glucogenic Amino Acids......Page 627
  a-Ketoglutarate Family of Glucogenic Amino Acids......Page 628
  Acetoacetate/Acetyl-CoA Family of Ketogenic Amino Acids......Page 629
   Phenylalanine and Tyrosine Degradation......Page 631
  Biosynthetic Capacities of Organisms......Page 632
   Synthesis of Serine and Glycine from 3-Phosphoglycerate......Page 633
   Synthesis of Valine, Leucine, and Isoleucine from Pyruvate......Page 634
  S-Adenosylmethionine and Biological Methylation......Page 635
  Tryptophan and Tyrosine Are Precursors of Neurotransmitters and Biological Regulators......Page 637
Chapter 19: Nucleotide Metabolism......Page 643
  Biosynthetic Routes: De Novo and Salvage Pathways......Page 645
  PRPP, a Central Metabolite in De Novo and Salvage Pathways......Page 646
  Synthesis of the Purine Ring......Page 647
  Synthesis of ATP and GTP from Inosine Monophosphate......Page 649
  Uric Acid, a Primary End Product......Page 650
   Gout......Page 651
   Severe Combined Immunodeficiency Disease......Page 652
  De Novo Biosynthesis of UTP and CTP......Page 653
  Glutamine-Dependent Amidotransferases......Page 654
  Reduction of Ribonucleotides to Deoxyribonucleotides......Page 655
   Regulation of Ribonucleotide Reductase Activity......Page 656
  Biosynthesis of Thymine Deoxyribonucleotides......Page 659
  Salvage Routes to Deoxyribonucleotides......Page 660
  Thymidylate Synthase: A Target Enzyme for Chemotherapy......Page 662
 19.6. Virus-Directed Alterations of Nucleotide Metabolism......Page 664
 19.7. Other Medically Useful Analogs......Page 665
Chapter 20: Mechanisms of Signal Transduction......Page 669
 20.1. An Overview of Hormone Action......Page 671
  Hierarchical Nature of Hormonal Control......Page 672
   Receptors and Adenylate Cyclase as Distinct Components of Signal Transduction Systems......Page 673
   Structural Analysis of G Protein-Coupled Receptors......Page 674
   Actions of G Proteins......Page 675
   The Versatility of G Proteins......Page 676
  Effectors......Page 677
   Cyclic GMP and Nitric Oxide......Page 678
   Phosphoinositides......Page 679
 20.3. Receptor Tyrosine Kinases and Insulin Signaling......Page 681
 20.4. Hormones and Gene Expression: Nuclear Receptors......Page 683
  Viral and Cellular Oncogenes......Page 686
  Oncogenes in Human Tumors......Page 687
  The Cancer Genome Mutational Landscape......Page 688
  The Cholinergic Synapse......Page 689
  Fast and Slow Synaptic Transmission......Page 690
  Actions of Specific Neurotransmitters......Page 691
  Peptide Neurotransmitters and Neurohormones......Page 692
 Foundation Figure: Cell Signaling and Protein Regulation......Page 695
Chapter 21: Genes, Genomes, and Chromosomes......Page 697
  Bacterial Genomes— The Nucleoid......Page 699
  Genome Sizes......Page 700
   Satellite DNA......Page 701
   Introns......Page 702
  The Nucleus......Page 703
  Chromatin......Page 704
  The Nucleosome......Page 705
 21.4. Nucleotide Sequence Analysis of Genomes......Page 707
  Restriction and Modification......Page 708
  Properties of Restriction and Modification Enzymes......Page 709
  Determining Genome Nucleotide Sequences......Page 710
   The Principle of Southern Analysis......Page 711
   Locating Genes on the Human Genome......Page 713
   Size of the Human Genome......Page 714
  Tools of Biochemistry: 21A Polymerase Chain Reaction......Page 717
Chapter 22: DNA Replication......Page 719
 22.1. Early Insights into DNA Replication......Page 721
 22.2. DNA Polymerases: Enzymes Catalyzing Polynucleotide Chain Elongation......Page 722
   Structure of DNA Polymerase I......Page 723
  Structure and Mechanism of DNA Polymerases......Page 724
  Genetic Maps of E. coli and Bacteriophage T4......Page 725
   Discontinuous DNA Synthesis......Page 726
   Proteins at the Replication Fork......Page 728
   The DNA Polymerase III Holoenzyme......Page 729
   Single-Stranded DNA-Binding Proteins: Maintaining Optimal Template Conformation......Page 730
  Helicases: Unwinding DNA Ahead of the Fork......Page 731
   Actions of Type I and Type II Topoisomerases......Page 732
  A Model of the Replisome......Page 734
  Other Eukaryotic Replication Proteins......Page 735
  Replication of Chromatin......Page 736
  Initiation of E. coli DNA Replication at ori c......Page 737
  Linear Virus Genome Replication......Page 738
  Telomerase......Page 739
  3' Exonucleolytic Proofreading......Page 740
  Polymerase Insertion Specificity......Page 741
  Ribonucleotide Incorporation and Genomic Stability......Page 742
  Replication of Retroviral Genomes......Page 743
Chapter 23: DNA Repair, Recombination, and Rearrangement......Page 747
  Types and Consequences of DNA Damage......Page 749
   O6-Alkylguanine Alkyltransferase......Page 751
  Nucleotide Excision Repair: Excinucleases......Page 752
   Replacement of Uracil in DNA by BER......Page 754
  Mismatch Repair......Page 755
  Double-Strand Break Repair......Page 757
  Translesion Synthesis and the DNA Damage Response......Page 758
  Site-Specific Recombination......Page 759
   Models for Recombination......Page 760
   Proteins Involved in Homologous Recombination......Page 761
  Immunoglobulin Synthesis: Generating Antibody Diversity......Page 763
  Transposable Genetic Elements......Page 765
  Retroviruses......Page 766
  Gene Amplification......Page 767
 Tools of Biochemistry: 23A Manipulating the Genome......Page 771
 Foundation Figure: Antibody Diversity and Use as Therapeutics......Page 773
Chapter 24: Transcription and Posttranscriptional Processing......Page 775
  The Predicted Existence of Messenger RNA......Page 777
  T2 Bacteriophage and the Demonstration of Messenger RNA......Page 778
  RNA Dynamics in Uninfected Cells......Page 779
  Biological Role of RNA Polymerase......Page 780
  Structure of RNA Polymerase......Page 781
  Initiation of Transcription: Interactions with Promoters......Page 782
  Initiation and Elongation: Incorporation of Ribonucleotides......Page 783
  Punctuation of Transcription: Termination......Page 784
   Factor-Independent Termination......Page 785
 24.4. Transcription in Eukaryotic Cells......Page 786
  RNA Polymerase III: Transcription of Small RNA Genes......Page 787
  RNA Polymerase II: Transcription of Structural Genes......Page 788
  Chromatin Structure and Transcription......Page 789
  Bacterial mRNA Turnover......Page 790
   tRNA Processing......Page 791
   Splicing......Page 792
  Alternative Splicing......Page 794
 Tools of Biochemistry: 24A Analyzing the Transcriptome......Page 797
 Tools of Biochemistry: 24B Chromatin Immunoprecipitation......Page 798
Chapter 25: Information Decoding: Translation and Posttranslational Protein Processing......Page 799
 25.1. An Overview of Translation......Page 801
  How the Code Was Deciphered......Page 802
  Features of the Code......Page 803
  The Wobble Hypothesis......Page 804
  Punctuation: Stopping and Starting......Page 805
  Transfer RNA......Page 806
  Aminoacyl-tRNA Synthetases: The First Step in Protein Synthesis......Page 808
  The Ribosome and Its Associated Factors......Page 810
   Components of Ribosomes......Page 811
   Internal Structure of the Ribosome......Page 812
  Initiation......Page 815
  Elongation......Page 816
  Termination......Page 818
  Suppression of Nonsense Mutations......Page 819
 25.5. Inhibition of Translation by Antibiotics......Page 820
 25.6. Translation in Eukaryotes......Page 821
 25.8. The Final Stages in Protein Synthesis: Folding and Covalent Modification......Page 822
  Covalent Modification......Page 823
  Proteins Synthesized in the Cytoplasm......Page 824
  Role of the Golgi Complex......Page 826
Chapter 26: Regulation of Gene Expression......Page 829
  The Lactose Operon—Earliest Insights into Transcriptional Regulation......Page 831
   The Repressor Binding Site......Page 833
   The CRP–DNA Complex......Page 835
   Bacteriophage .: Multiple Operators, Dual Repressors, Interspersed Promoters and Operators......Page 836
   The SOS Regulon: Activation of Multiple Operons by a Common Set of Environmental Signals......Page 838
   Biosynthetic Operons: Ligand-Activated Repressors and Attenuation......Page 839
  Chromatin and Transcription......Page 841
  Transcriptional Control Sites and Genes......Page 842
  Nucleosome Remodeling Complexes......Page 843
  Regulation of the Elongation Cycle by RNA Polymerase Phosphorylation......Page 844
  DNA Methylation in Eukaryotes......Page 845
  Genomic Distribution of Methylated Cytosines......Page 846
  Regulation of Bacterial Translation......Page 847
   Phosphorylation of Eukaryotic Initiation Factors......Page 848
  MicroRNAs......Page 849
 26.6. Riboswitches......Page 850
 26.7. RNA Editing......Page 851
 Foundation Figure: Information Flow in Biological Systems......Page 855
Appendix I: Answers to Selected Problems......Page 858
Appendix II: References......Page 877
Credits......Page 890
Index......Page 894
Back Cover......Page 934