lehninger principles of biochemistry fourth editionPDF电子书下载

1 The Foundations of Biochemistry 1

1.1 Cellular Foundations 3

Cells Are the Structural and Functional Units of All Living Organisms 3

Cellular Dimensions Are Limited by Oxygen Diffusion 4

There Are Three Distinct Domains of Life 4

Escherichia coli Is the Most-Studied Prokaryotic Cell 5

Eukaryotic Cells Have a Variety of Membranous Organelles,Which Can Be Isolated for Study 6

The Cytoplasm Is Organized by the Cytoskeleton and Is Highly Dynamic 9

Cells Build Supramolecular Structures 10

In Vitro Studies May Overlook Important Interactions among Molecules 11

1.2 Chemical Foundations 12

Biomolecules Are Compounds of Carbon with a Variety of Functional Groups 13

Cells Contain a Universal Set of Small Molecules 14

Macromolecules Are the Major Constituents of Cells 15

Box 1-1 Molecular Weight, Molecular Mass, and Their Correct Units 15

Three-Dimensional Structure Is Described by Configuration and Conformation 16

Box 1-2 Louis Pasteur and Optical Activlty: In Vino, Veritas 19

Interactions between Biomolecules Are Stereospecific 20

1.3 Physical Foundations 21

Living Organisms Exist in a Dynamic Steady State, Never at Equilibrium with Their Surroundings 21

Organisms Transform Energy and Matter from Their Surroundings 22

The Flow of Electrons Provides Energy for Organisms 22

Creating and Maintaining Order Requires Work and Energy 23

Energy Coupling Links Reactions in Biology 23

Box 1-3 Entropy: The Advantages of Belng Disorganized 24

Keq and △G Are Measures of a Reaction's Tendency to Proceed Spontaneously 26

Enzymes Promote Sequences of Chemical Reactions 26

Metabolism Is Regulated to Achieve Balance and Economy 27

1.4 Genetic Foundations 28

Genetic Continuity Is Vested in Single DNA Molecules 29

The Structure of DNA Allows for Its Replication and Repair with Near-Perfect Fidelity 29

The Linear Sequence in DNA Encodes Proteins with Three-Dimensional Structures 29

1.5 Evolutionary Foundations 31

Changes in the Hereditary Instructions Allow Evolution 31

Biomolecules First Arose by Chemical Evolution 32

Chemical Evolution Can Be Simulated in the Laboratory 32

RNA or Related Precursors May Have Been the First Genes and Catalysts 32

Biological Evolution Began More Than Three and a Half Billion Years Ago 34

The First Cell Was Probably a Chemoheterotroph 34

Eukaryotic Cells Evolved from Prokaryotes in Several Stages 34

Molecular Anatomy Reveals Evolutionary Relationships 36

Functional Genomics Shows the Allocations of Genes to Specific Cellular Processes 38

Genomic Comparisons Will Have Increasing Importance in Human Biology and Medicine 38

Ⅰ STRUCTURE AND CATALYSIS 45

2 Water 47

2.1 Weak Interactions in Aqueous Systems 47

Hydrogen Bonding Gives Water Its Unusual Properties 47

Water Forms Hydrogen Bonds with Polar Solutes 49

Water Interacts Electrostatically with Charged Solutes 50

Entropy Increases as Crystalline Substances Dissolve 51

Nonpolar Gases Are Poorly Soluble in Water 52

Nonpolar Compounds Force Energetically Unfavorable Changes in the Structure of Water 52

van der Waals Interactions Are Weak Interatomic Attractions 54

Weak Interactions Are Crucial to Macromolecular Structure and Function 54

Solutes Affect the Colligative Properties of Aqueous Solutions 56

Box 2-1 Touch Response in Plants: An Osmotic Event 59

2.2 Ionization of Water, Weak Acids, and Weak Bases 60

Pure Water Is Slightly Ionized 60

The Ionization of Water Is Expressed by an Equilibrium Constant 61

The pH Scale Designates the H+ and OH-Concentrations 61

Box 2-2 The Ion Product of Water: Two Illustrative Problems 62

Weak Acids and Bases Have Characteristic Dissociation Constants 63

Titration Curves Reveal the pKa of Weak Acids 64

2.3 Buffering against pH Changes in Biological Systems 65

Buffers Are Mixtures of Weak Acids and Their Conjugate Bases 66

A Simple Expression Relates pH, pKa, and Buffer Concentration 66

Weak Acids or Bases Buffer Cells and Tissues against pH Changes 67

Box 2-3 Solving Problems Using the Henderson-Hasseibalch Equation 67

Box 2-4 Blood, Lungs, and Buffer: The Bicarbonate Buffer System 69

2.4 Water as a Reactant 69

2.5 The Fitness of the Aqueous Environment for Living Organisms 70

3 Amino Acids, Peptides, and Proteins 75

3.1 Amino Acids 75

Amino Acids Share Common Structural Features 76

The Amino Acid Residues in Proteins Are L Stereoisomers 77

Amino Acids Can Be Classified by R Group 78

Uncommon Amino Acids Also Have Important Functions 80

Amino Acids Can Act as Acids and Bases 81

Box 3-1 Absorption of Light by Molecules: The Lambert-Beer Law 82

Amino Acids Have Characteristic Titration Curves 82

Titration Curves Predict the Electric Charge of Amino Acids 84

Amino Acids Differ in Their Acid-Base Properties 84

3.2 Peptides and Proteins 85

Peptides Are Chains of Amino Acids 85

Peptides Can Be Distinguished by Their Ionization Behavior 86

Biologically Active Peptides and Polypeptides Occur in a Vast Range of Sizes 86

Polypeptides Have Characteristic Amino Acid Compositions 87

Some Proteins Contain Chemical Groups Other Than Amino Acids 88

There Are Several Levels of Protein Structure 88

3.3 Working with Proteins 89

Proteins Can Be Separated and Purified 89

Proteins Can Be Separated and Characterized by Electrophoresis 92

Unseparated Proteins Can Be Quantified 94

3.4 The Covalent Structure of Proteins 96

The Function of a Protein Depends on Its Amino Acid Sequence 96

The Amino Acid Sequences of Millions of Proteins Have Been Determined 96

Short Polypeptides Are Sequenced Using Automated Procedures 97

Large Proteins Must Be Sequenced in Smaller Segments 99

Amino Acid Sequences Can Also Be Deduced by Other Methods 100

Box 3-2 Investigating Proteins with Mass Spectrometry 102

Small Peptides and Proteins Can Be Chemically Synthesized 104

Amino Acid Sequences Provide Important Biochemical Information 106

3.5 Protein Sequences and Evolution 106

Protein Sequences Can Elucidate the History of Life on Earth 107

4 The Three-Dimensional Structure of Proteins 116

4.1 Overview of Protein Structure 116

A Protein's Conformation Is Stabilized Largely by Weak Interactions 117

The Peptide Bond Is Rigid and Planar 118

4.2 Protein Secondary Structure 120

The α Helix Is a Common Protein Secondary Structure 120

Amino Acid Sequence Affects α Helix Stability 121

Box 4-1 Knowing the Right Hand from the Left 122

The β Conformation Organizes Polypeptide Chains into Sheets 123

β Turns Are Common in Proteins 123

Common Secondary Structures Have Characteristic Bond Angles and Amino Acid Content 124

4.3 Protein Tertiary and Quaternary Structures 125

Fibrous Proteins Are Adapted for a Structural Function 126

Box 4-2 Permanent Waving Is Biochemical Engineering 127

Structural Diversity Reflects Functional Diversity in Globular Proteins 129

Box 4-3 Why Sailors, Explorers, and College Students Should Eat Their Fresh Fruits and Vegetables 130

Myoglobin Provided Early Clues about the Complexity of Globular Protein Structure 132

Globular Proteins Have a Variety of Tertiary Structures 134

Box 4-4 Methods for Determining the Three-Dimensional Structure of a Protein 136

Analysis of Many Globular Proteins Reveals Common Structural Patterns 138

Protein Motifs Are the Basis for Protein Structural Classification 141

Protein Quaternary Structures Range from Simple Dimers to Large Complexes 144

There Are Limits to the Size of Proteins 146

4.4 Protein Denaturation and Folding 147

Loss of Protein Structure Results in Loss of Function 147

Amino Acid Sequence Determines Tertiary Structure 148

Polypeptides Fold Rapidly by a Stepwise Process 148

Box 4-5 Death by Misfolding: The Prion Diseases 150

Some Proteins Undergo Assisted Folding 151

5 Protein Function 157

5.1 Reversible Binding of a Protein to a Ligand:Oxygen-Binding Proteins 158

Oxygen Can Be Bound to a Heme Prosthetic Group 158

Myoglobin Has a Single Binding Site for Oxygen 159

Protein-Ligand Interactions Can Be Described Quantitatively 160

Protein Structure Affects How Ligands Bind 162

Oxygen Is Transported in Blood by Hemoglobin 162

Hemoglobin Subunits Are Structurally Similar to Myoglobin 163

Hemoglobin Undergoes a Structural Change on Binding Oxygen 164

Hemoglobin Binds Oxygen Cooperatively 164

Cooperative Ligand Binding Can Be Described Quantitatively 167

Two Models Suggest Mechanisms for Cooperative Binding 167

Box 5-1 Carbon Monoxide: A Stealthy Killer 168

Hemoglobin Also Transports H+ and CO2 170

Oxygen Binding to Hemoglobin Is Regulated by 2,3-Bisphosphoglycerate 171

Sickle-Cell Anemia Is a Molecular Disease of Hemoglobin 172

5.2 Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins 174

The Immune Response Features a Specialized Array of Cells and Proteins 175

Self Is Distinguished from Nonself by the Display of Peptides on Cell Surfaces 176

Antibodies Have Two Identical Antigen-Binding Sites 178

Antibodies Bind Tightly and Specifically to Antigen 180

The Antibody-Antigen Interaction Is the Basis for a Variety of Important Analytical Procedures 180

5.3 Protein Interactions Modulated by Chemical Energy:Actin, Myosin, and Molecular Motors 182

The Major Proteins of Muscle Are Myosin and Actin 182

Additional Proteins Organize the Thin and Thick Filaments into Ordered Structures 184

Myosin Thick Filaments Slide along Actin Thin Filaments 185

6 Enzymes 190

6.1 An Introduction to Enzymes 191

Most Enzymes Are Proteins 191

Enzymes Are Classified by the Reactions They Catalyze 192

6.2 How Enzymes Work 193

Enzymes Affect Reaction Rates, Not Equilibria 193

Reaction Rates and Equilibria Have Precise Thermodynamic Definitions 195

A Few Principles Explain the Catalytic Power and Specificity of Enzymes 196

Weak Interactions between Enzyme and Substrate Are Optimized in the Transition State 196

Binding Energy Contributes to Reaction Specificity and Catalysis 198

Specific Catalytic Groups Contribute to Catalysis 200

6.3 Enzyme Kinetics As an Approach to Understanding Mechanism 202

Substrate Concentration Affects the Rate of Enzyme-Catalyzed Reactions 202

The Relationship between Substrate Concentration and Reaction Rate Can Be Expressed Quantitatively 203

Kinetic Parameters Are Used to Compare Enzyme Activities 205

Box 6-1 Transformations of the Michaelis-Menten Equation: The Double Reciprocal Plot 206

Many Enzymes Catalyze Reactions with Two or More Substrates 207

Pre-Steady State Kinetics Can Provide Evidence for Specific Reaction Steps 208

Enzymes Are Subject to Reversible or Irreversible Inhibition 209

Box 6-2 Kinetic Tests for Determining Inhibition Mechanisms 210

Enzyme Activity Depends on pH 212

6.4 Examples of Enzymatic Reactions 213

The Chymotrypsin Mechanism Involves Acylation and Deacylation of a Ser Residue 213

Hexokinase Undergoes Induced Fit on Substrate Binding 218

The Enolase Reaction Mechanism Requires Metal Ions 219

Box 6-3 Evidence for Enzyme-Transition State Complementarity 220

Lysozyme Uses Two Successive Nucleophilic Displacement Reactions 222

6.5 Regulatory Enzymes 225

Allosteric Enzymes Undergo Conformational Changes in Response to Modulator Binding 225

In Many Pathways a Regulated Step Is Catalyzed by an Allosteric Enzyme 226

The Kinetic Properties of Allosteric Enzymes Diverge from Michaelis-Menten Behavior 227

Some Regulatory Enzymes Undergo Reversible Covalent Modification 228

Phosphoryl Groups Affect the Structure and Catalytic Activity of Proteins 228

Multiple Phosphorylations Allow Exquisite Regulatory Control 230

Some Enzymes and Other Proteins Are Regulated by Proteolytic Cleavage of an Enzyme Precursor 231

Some Regulatory Enzymes Use Several Regulatory Mechanisms 232

7 Carbohydrates and Glycobiology 238

7.1 Monosaccharides and Disaccharides 239

The Two Families of Monosaccharides Are Aldoses and Ketoses 239

Monosaccharides Have Asymmetric Centers 239

The Common Monosaccharides Have Cyclic Structures 240

Organisms Contain a Variety of Hexose Derivatives 243

Monosaccharides Are Reducing Agents 244

Disaccharides Contain a Glycosidic Bond 245

7.2 Polysaccharides 247

Some Homopolysaccharides Are Stored Forms of Fuel 247

Some Homopolysaccharides Serve Structural Roles 248

Steric Factors and Hydrogen Bonding Influence Homopolysaccharide Folding 250

Bacterial and Algal Cell Walls Contain Structural Heteropolysaccharides 252

Glycosaminoglycans Are Heteropolysaccharides of the Extracellular Matrix 253

7.3 Glycoconjugates: Proteoglycans, Glycoproteins, and Glycolipids 255

Proteoglycans Are Glycosaminoglycan-Containing Macromolecules of the Cell Surface and Extracellular Matrix 256

Glycoproteins Have Covalently Attached Oligosaccharides 258

Glycolipids and Lipopolysaccharides Are Membrane Components 260

7.4 Carbohydrates as Informational Molecules: The Sugar Code 261

Lectins Are Proteins That Read the Sugar Code and Mediate Many Biological Processes 262

Lectin-Carbohydrate Interactions Are Very Strong and Highly Specific 264

7.5 Working with Carbohydrates 267

8 Nucleotides and Nucleic Acids 273

8.1 Some Basics 273

Nucleotides and Nucleic Acids Have Characteristic Bases and Pentoses 273

Phosphodiester Bonds Link Successive Nucleotides in Nucleic Acids 276

The Properties of Nucleotide Bases Affect the Three-Dimensional Structure of Nucleic Acids 278

8.2 Nucleic Acid Structure 279

DNA Stores Genetic Information 280

DNA Molecules Have Distinctive Base Compositions 281

DNA Is a Double Helix 282

DNA Can Occur in Different Three-Dimensional Forms 283

Certain DNA Sequences Adopt Unusual Structures 285

Messenger RNAs Code for Polypeptide Chains 287

Many RNAs Have More Complex Three-Dimensional Structures 288

8.3 Nucleic Acid Chemistry 291

Double-Helical DNA and RNA Can Be Denatured 291

Nucleic Acids from Different Species Can Form Hybrids 292

Nucleotides and Nucleic Acids Undergo Nonenzymatic Transformations 293

Some Bases of DNA Are Methylated 296

The Sequences of Long DNA Strands Can Be Determined 296

The Chemical Synthesis of DNA Has Been Automated 298

8.4 Other Functions of Nucleotides 300

Nucleotides Carry Chemical Energy in Cells 300

Adenine Nucleotides Are Components of Many Enzyme Cofactors 301

Some Nucleotides Are Regulatory Molecules 302

9 DNA-Based Information Technologies 306

9.1 DNA Cloning: The Basics 306

Restriction Endonucleases and DNA Ligase Yield Recombinant DNA 307

Cloning Vectors Allow Amplification of Inserted DNA Segments 311

Specific DNA Sequences Are Detectable by Hybridization 314

Expression of Cloned Genes Produces Large Quantities of Protein 315

Alterations in Cloned Genes Produce Modified Proteins 316

9.2 From Genes to Genomes 317

DNA Libraries Provide Specialized Catalogs of Genetic Information 318

The Polymerase Chain Reaction Amplifies Specific DNA Sequences 319

Genome Sequences Provide the Ultimate Genetic Libraries 321

Box 9-1 A Potent Weapon In Forensic Medicine 322

9.3 From Genomes to Proteomes 325

Sequence or Structural Relationships Provide Information on Protein Function 325

Cellular Expression Patterns Can Reveal the Cellular Function of a Gene 326

Detection of Protein-Protein Interactions Helps to Define Cellular and Molecular Function 327

9.4 Genome Alterations and New Products of Biotechnology 330

A Bacterial Plant Parasite Aids Cloning in Plants 330

Manipulation of Animal Cell Genomes Provides Information on Chromosome Structure and Gene Expression 333

New Technologies Promise to Expedite the Discovery of New Pharmaceuticals 335

Box 9-2 The Human Genome and Human Gene Therapy 336

Recombinant DNA Technology Yields New Products and Challenges 338

10 Lipids 343

10.1 Storage Lipids 343

Fatty Acids Are Hydrocarbon Derivatives 343

Triacylglycerols Are Fatty Acid Esters of Glycerol 345

Triacylglycerols Provide Stored Energy and Insulation 346

Many Foods Contain Triacylglycerols 346

Box 10-1 Sperm Whales: Fatheads of the Deep 347

Waxes Serve as Energy Stores and Water Repellents 348

10.2 Structural Lipids in Membranes 348

Glycerophospholipids Are Derivatives of Phosphatidic Acid 349

Some Phospholipids Have Ether-Linked Fatty Acids 349

Chloroplasts Contain Galactolipids and Sulfolipids 351

Archaebacteria Contain Unique Membrane Lipids 352

Sphingolipids Are Derivatives of Sphingosine 352

Sphingolipids at Cell Surfaces Are Sites of Biological Recognition 353

Phospholipids and Sphingolipids Are Degraded in Lysosomes 354

Sterols Have Four Fused Carbon Rings 354

Box 10-2 Inherited Human Diseases Resulting from Abnormal Accumulations of Membrane Lipids 356

10.3 Lipids as Signals, Cofactors, and Pigments 357

Phosphatidylinositols and Sphingosine Derivatives Act as Intracellular Signals 357

Eicosanoids Carry Messages to Nearby Cells 358

Steroid Hormones Carry Messages between Tissues 359

Plants Use Phosphatidylinositols, Steroids, and Eicosanoidlike Compounds in Signaling 360

Vitamins A and D Are Hormone Precursors 360

Vitamins E and K and the Lipid Quinones Are Oxidation-Reduction Cofactors 362

Dolichols Activate Sugar Precursor for Biosynthesis 363

10.4 Working with Lipids 363

Lipid Extraction Requires Organic Solvents 364

Adsorption Chromatography Separates Lipids of Different Polarity 365

Gas-Liquid Chromatography Resolves Mixtures of Volatile Lipid Derivatives 365

Specific Hydrolysis Aids in Determination of Lipid Structure 365

Mass Spectrometry Reveals Complete Lipid Structure 365

11 Biological Membranes and Transport 369

11.1 The Composition and Architecture of Membranes 370

Each Type of Membrane Has Characteristic Lipids and Proteins 370

All Biological Membranes Share Some Fundamental Properties 371

A Lipid Bilayer Is the Basic Structural Element of Membranes 371

Peripheral Membrane Proteins Are Easily Solubilized 373

Many Membrane Proteins Span the Lipid Bilayer 373

Integral Proteins Are Held in the Membrane by Hydrophobic Interactions with Lipids 375

The Topology of an Integral Membrane Protein Can Be Predicted from Its Sequence 376

Covalently Attached Lipids Anchor Some Membrane Proteins 378

11.2 Membrane Dynamics 380

Acyl Groups in the Bilayer Interior Are Ordered to Varying Degrees 380

Transbilayer Movement of Lipids Requires Catalysis 381

Lipids and Proteins Diffuse Laterally in the Bilayer 382

Box 11-1 Atomic Force Microscopy to Visualize Membrane Proteins 384

Sphingolipids and Cholesterol Cluster Together in Membrane Rafts 383

Caveolins Define a Special Class of Membrane Rafts 385

Certain Integral Proteins Mediate Cell-Cell Interactions and Adhesion 385

Membrane Fusion Is Central to Many Biological Processes 387

11.3 Solute Transport across Membranes 389

Passive Transport Is Facilitated by Membrane Proteins 389

Transporters Can Be Grouped into Superfamilies Based onTheir Structures 391

The Glucose Transporter of Erythrocytes Mediates Passive Transport 393

The Chloride-Bicarbonate Exchanger Catalyzes Electroneutral Cotransport of Anions across the Plasma Membrane 395

Box 11-2 Defective Glucose and Water Transport In Two Forms of Diabetes 396

Active Transport Results in Solute Movement against a Concentration or Electrochemical Gradient 397

P-Type ATPases Undergo Phosphorylation during Their Catalytic Cycles 398

P-Type Ca 2+ Pumps Maintain a Low Concentration of Calcium in the Cytosol 400

F-Type ATPases Are Reversible, ATP-Driven Proton Pumps 401

ABC Transporters Use ATP to Drive the Active Transport of a Wide Variety of Substrates 402

Ion Gradients Provide the Energy for Secondary Active Transport 402

Box 11-3 A Defective Ion Channel in Cystic Fibrosis 403

Aquaporins Form Hydrophilic Transmembrane Channels for the Passage of Water 406

Ion-Selective Channels Allow Rapid Movement of Ions across Membranes 408

Ion-Channel Function Is Measured Electrically 408

The Structure of a K+ Channel Reveals the Basis for Its Specificity 409

The Neuronal Na+ Channel Is a Voltage-Gated Ion Channel 410

The Acetylcholine Receptor Is a Ligand-Gated Ion Channel 411

Defective Ion Channels Can Have Adverse Physiological Consequences 415

12 Biosignaling 421

12.1 Molecular Mechanisms of Signal Transduction 422

Box 12-1 Scatchard Analysis Quantifies the Receptor-Ligand Interaction 423

12.2 Gated Ion Channels 425

Ion Channels Underlie Electrical Signaling in Excitable Cells 425

The Nicotinic Acetylcholine Receptor Is a Ligand-Gated Ion Channel 426

Voltage-Gated Ion Channels Produce Neuronal Action Potentials 427

Neurons Have Receptor Channels That Respond to Different Neurotransmitters 428

12.3 Receptor Enzymes 429

The Insulin Receptor Is a Tyrosine-Specific Protein Kinase 429

Receptor Guanylyl Cyclases Generate the Second Messenger cGMP 433

12.4 G Protein-Coupled Receptors and Second Messengers 435

The β-Adrenergic Receptor System Acts through the Second Messenger cAMP 435

The β-Adrenergic Receptor Is Desensitized by Phosphotylation 439

Cyclic AMP Acts as a Second Messenger for a Number of Regulatory Molecules 441

Two Second Messengers Are Derived from Phosphatidylinositols 442

Calcium Is a Second Messenger in Many Signal Transductions 442

Box 12-2 FRET: Biochemistry Vlsuallzed in a Living Cell 446

12.5 Multivalent Scaffold Proteins and Membrane Rafts 448

Protein Modules Bind Phosphorylated Tyr, Ser, or Thr Residues in Partner Proteins 448

Membrane Rafts and Caveolae May Segregate Signaling Proteins 451

12.6 Signaling in Microorganisms and Plants 452

Bacterial Signaling Entails Phosphorylation in a Two-Component System 452

Signaling Systems of Plants Have Some of the Same Components Used by Microbes and Mammals 452

Plants Detect Ethylene through a Two-Component System and a MAPK Cascade 454

Receptorlike Protein Kinases Transduce Signals from Peptides and Brassinosteroids 455

12.7 Sensory Transduction in Vision, Olfaction, and Gustation 456

Light Hyperpolarizes Rod and Cone Cells of the Vertebrate Eye 456

Light Triggers Conformational Changes in the Receptor Rhodopsin 457

Excited Rhodopsin Acts through the G Protein Transducin to Reduce the cGMP Concentration 457

Amplification of the Visual Signal Occurs in the Rod and Cone Cells 458

The Visual Signal Is Quickly Terminated 458

Rhodopsin Is Desensitized by Phosphorylation 459

Cone Cells Specialize in Color Vision 460

Vertebrate Olfaction and Gustation Use Mechanisms Similar to the Visual System 460

Box 12-3 Color Blindness: John Dalton's Experiment from the Grave 461

G Protein-Coupled Serpentine Receptor Systems Share Several Features 462

Disruption of G-Protein Signaling Causes Disease 464

12.8 Regulation of Transcription by Steroid Hormones 465

12.9 Regulation of the Cell Cycle by Protein Kinases 466

The Cell Cycle Has Four Stages 466

Levels of Cyclin-Dependent Protein Kinases Oscillate 467

CDKs Regulate Cell Division by Phosphorylating Critical Proteins 470

12.10 Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death 471

Oncogenes Are Mutant Forms of the Genes for Proteins That Regulate the Cell Cycle 471

Defects in Tumor Suppressor Genes Remove Normal Restraints on Cell Division 472

Apoptosis Is Programmed Cell Suicide 473

Ⅱ BIOENERGETICS AND METABOLISM 481

13 Principles of Bioenergetics 489

13.1 Bioenergetics and Thermodynamics 490

Biological Energy Transformations Obey the Laws of Thermodynamics 490

Cells Require Sources of Free Energy 491

The Standard Free-Energy Change Is Directly Related to the Equilibrium Constant 491

Actual Free-Energy Changes Depend on Reactant and Product Concentrations 493

Standard Free-Energy Changes Are Additive 494

13.2 Phosphoryl Group Transfers and ATP 496

The Free-Energy Change for ATP Hydrolysis Is Large and Negative 496

Other Phosphorylated Compounds and Thioesters Also Have Large Free Energies of Hydrolysis 497

Box 13-1 The Free Energy of Hydrolysis of ATP within Cells: The Real Cost of Doing Metabolic Business 498

ATP Provides Energy by Group Transfers, Not by Simple Hydrolysis 500

ATP Donates Phosphoryl, Pyrophosphoryl, and Adenylyl Groups 502

Box 13-2 Firefly Flashes: Glowing Reports of ATP 503

Assembly of Informational Macromolecules Requires Energy 504

ATP Energizes Active Transport and Muscle Contraction 504

Transphosphorylations between Nucleotides Occur in All Cell Types 505

Inorganic Polyphosphate Is a Potential Phosphoryl Group Donor 506

Biochemical and Chemical Equations Are Not Identical 506

13.3 Biological Oxidation-Reduction Reactions 507

The Flow of Electrons Can Do Biological Work 507

Oxidation-Reduction Can Be Described as Half-Reactions 508

Biological Oxidations Often Involve Dehydrogenation 508

Reduction Potentials Measure Affinity for Electrons 509

Standard Reduction Potentials Can Be Used to Calculate the Free-Energy Change 510

Cellular Oxidation of Glucose to Carbon Dioxide Requires Specialized Electron Carriers 512

A Few Types of Coenzymes and Proteins Serve as Universal Electron Carriers 512

NADH and NADPH Act with Dehydrogenases as Soluble Electron Carriers 512

Dietary Deficiency of Niacin, the Vitamin Form of NAD and NADP, Causes Pellagra 514

Flavin Nucleotides Are Tightly Bound in Flavoproteins 515

14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway 521

14.1 Glycolysis 522

An Overview: Glycolysis Has Two Phases 523

The Preparatory Phase of Glycolysis Requires ATP 525

The Payoff Phase of Glycolysis Produces ATP and NADH 529

The Overall Balance Sheet Shows a Net Gain of ATP 533

Glycolysis Is under Tight Regulation 533

Cancerous Tissue Has Deranged Glucose Catabolism 533

14.2 Feeder Pathways for Glycolysis 534

Glycogen and Starch Are Degraded by Phosphorolysis 534

Dietary Polysaccharides and Disaccharides Undergo Hydrolysis to Monosaccharides 535

Other Monosaccharides Enter the Glycolytic Pathway at Several Points 536

14.3 Fates of Pyruvate under Anaerobic Conditions:Fermentation 538

Pyruvate Is the Terminal Electron Acceptor in Lactic Acid Fermentation 538

Ethanol Is the Reduced Product in Ethanol Fermentation 538

Box 14-1 Athletes, Alligators, and Coelacanths: Glycolysis at Limiting Concentrations of Oxygen 539

Thiamine Pyrophosphate Carries “Active Aldehyde” Groups 540

Fermentations Yield a Variety of Common Foods and Industrial Chemicals 541

Box 14-2 Brewing Beer 542

14.4 Gluconeogenesis 543

Conversion of Pyruvate to Phosphoenolpyruvate Requires Two Exergonic Reactions 544

Conversion of Fructose 1,6-Bisphosphate to Fructose 6-Phosphate Is the Second Bypass 547

Conversion of Glucose 6-Phosphate to Glucose Is the Third Bypass 547

Gluconeogenesis Is Energetically Expensive, But Essential 548

Citric Acid Cycle Intermediates and Many Amino Acids Are Glucogenic 548

Glycolysis and Gluconeogenesis Are Regulated Reciprocally 548

14.5 Pentose Phosphate Pathway of Glucose Oxidation 549

The Oxidative Phase Produces Pentose Phosphates and NADPH 550

Box 14-3 Why Pythagoras Wouldn't Eat Falafel: Glucose 6-Phosphate Dehydrogenase Deficiency 551

The Nonoxidative Phase Recycles Pentose Phosphates to Glucose 6-Phosphate 552

Wernicke-Korsakoff Syndrome Is Exacerbated by a Defect in Transketolase 554

Glucose 6-Phosphate Is Partitioned between Glycolysis and the Pentose Phosphate Pathway 554

15 Principles of Metabolic Regulation:Glucose and Glycogen 560

15.1 The Metabolism of Glycogen in Animals 562

Glycogen Breakdown Is Catalyzed by Glycogen Phosphorylase 562

Glucose 1-Phosphate Can Enter Glycolysis or, in Liver,Replenish Blood Glucose 563

The Sugar Nucleotide UDP-Glucose Donates Glucose for Glycogen Synthesis 565

Box 15-1 Carl and Gerty Cori: Pioneers in Glycogen Metabollsm and Disease 566

Glycogenin Primes the Initial Sugar Residues in Glycogen 569

15.2 Regulation of Metabolic Pathways 571

Living Cells Maintain a Dynamic Steady State 571

Regulatory Mechanisms Evolved under Strong Selective Pressures 571

Regulatory Enzymes Respond to Changes in Metabolite Concentration 572

Enzyme Activity Can Be Altered in Several Ways 574

15.3 Coordinated Regulation of Glycolysis and Gluconeogenesis 575

Hexokinase Isozymes of Muscle and Liver Are Affected Differently by Their Product, Glucose 6-Phosphate 576

Box 15-2 Isozymes: Different Proteins That Catalyze the Same Reaction 577

Phosphofructokinase-1 Is under Complex Allosteric Regulation 578

Pyruvate Kinase Is Allosterically Inhibited by ATP 579

Gluconeogenesis Is Regulated at Several Steps 580

Fructose 2,6-Bisphosphate Is a Potent Regulator of Glycolysis and Gluconeogenesis 581

Are Substrate Cycles Futile? 583

Xylulose 5-Phosphate Is a Key Regulator of Carbohydrate and Fat Metabolism 583

15.4 Coordinated Regulation of Glycogen Synthesis and Breakdown 583

Glycogen Phosphorylase Is Regulated Allosterically and Hormonally 583

Glycogen Synthase Is Also Regulated by Phosphorylation and Dephosphorylation 586

Glycogen Synthase Kinase 3 Mediates the Actions of Insulin 586

Phosphoprotein Phosphatase 1 Is Central to Glycogen Metabolism 588

Transport into Cells Can Limit Glucose Utilization 588

Allosteric and Hormonal Signals Coordinate Carbohydrate Metabolism 588

Carbohydrate and Lipid Metabolism Are Integrated by Hormonal and Allosteric Mechanisms 590

Insulin Changes the Expression of Many Genes Involved in Carbohydrate and Fat Metabolism 590

15.5 Analysis of Metabolic Control 591

The Contribution of Each Enzyme to Flux through a Pathway Is Experimentally Measurable 592

The Control Coefficient Quantifies the Effect of a Change in Enzyme Activity on Metabolite Flux through a Pathway 592

The Elasticity Coefficient Is Related to an Enzyme's Responsiveness to Changes in Metabolite or Regulator Concentrations 593

The Response Coefficient Expresses the Effect of an Outside Controller on Flux through a Pathway 593

Metabolic Control Analysis Has Been Applied to Carbohydrate Metabolism, with Surprising Results 593

Box 15-3 Metabolic Control Analysis: Quantitative Aspects 594

Metabolic Control Analysis Suggests a General Method for Increasing Flux through a Pathway 596

16 The Citric Acid Cycle 601

16.1 Production of Acetyl-CoA （Activated Acetate） 602

Pyruvate Is Oxidized to Acetyl-CoA and CO2 602

The Pyruvate Dehydrogenase Complex Requires Five Coenzymes 603

The Pyruvate Dehydrogenase Complex Consists of Three Distinct Enzymes 604

In Substrate Channeling, Intermediates Never Leave the Enzyme Surface 605

16.2 Reactions of the Citric Acld Cycle 606

The Citric Acid Cycle Has Eight Steps 608

Box 16-1 Synthases and Synthetases; Llgases and Lyases; Klnases,Phosphatases, and Phosphorylases: Yes, the Names Are Confusing! 613

The Energy of Oxidations in the Cycle Is Efficiently Conserved 614

Box 16-2 Cltrate: A Symmetrlcal Molecule That Reacts Asymmetrlcally 614

Why Is the Oxidation of Acetate So Complicated? 615

Citric Acid Cycle Components Are Important Biosynthetic Intermediates 616

Anaplerotic Reactions Replenish Citric Acid Cycle Intermediates 616

Box 16-3 Citrate Synthase, Soda Pop, and the World Food Supply 618

Biotin in Pyruvate Carboxylase Carries CO2 Groups 618

16.3 Regulation of the Citric Acid Cycle 621

Production of Acetyl-CoA by the Pyruvate Dehydrogenase Complex Is Regulated by Allosteric and Covalent Mechanisms 621

The Citric Acid Cycle Is Regulated at Its Three Exergonic Steps 622

Substrate Channeling through Multienzyme Complexes May Occur in the Citric Acid Cycle 622

16.4 The Glyoxylate Cycle 623

The Glyoxylate Cycle Produces Four-Carbon Compounds from Acetate 623

The Citric Acid and Glyoxylate Cycles Are Coordinately Regulated 624

17 Fatty Acid Catabolism 631

17.1 Digestion, Mobilization, and Transport of Fats 632

Dietary Fats Are Absorbed in the Small Intestine 632

Hormones Trigger Mobilization of Stored Triacylglycerols 634

Fatty Acids Are Activated and Transported into Mitochondria 634

17.2 Oxidation of Fatty Acids 637

The β Oxidation of Saturated Fatty Acids Has Four Basic Steps 637

The Four β-Oxidation Steps Are Repeated to Yield Acetyl-CoA and ATP 639

Acetyl-CoA Can Be Further Oxidized in the Citric Acid Cycle 639

Oxidation of Unsaturated Fatty Acids Requires Two Additional Reactions 639

Box 17-1 Fat Bears Carry Out β Oxldatlon In Thelr Sleep 640

Complete Oxidation of Odd-Number Fatty Acids Requires Three Extra Reactions 642

Fatty Acid Oxidation Is Tightly Regulated 642

Genetic Defects in Fatty Acyl-CoA Dehydrogenases Cause Serious Disease 643

Box 17-2 Coenzyme B12: A Radlcal Solutlon to a Perplexing Problem 644

Peroxisomes Also Carry Out β Oxidation 646

Plant Peroxisomes and Glyoxysomes Use Acetyl-CoA from β Oxidation as a Biosynthetic Precursor 647

The β-Oxidation Enzymes of Different Organelles Have Diverged during Evolution 647

The ω Oxidation of Fatty Acids Occurs in the Endoplasmic Reticulum 647

Phytanic Acid Undergoes α Oxidation in Peroxisomes 649

17.3 Ketone Bodies 650

Ketone Bodies, Formed in the Liver, Are Exported to Other Organs as Fuel 650

Ketone Bodies Are Overproduced in Diabetes and during Starvation 652

18 Amino Acid Oxidation and the Production of Urea 656

18.1 Metabolic Fates of Amino Groups 657

Dietary Protein Is Enzymatically Degraded to Amino Acids 658

Pyridoxal Phosphate Participates in the Transfer of α-Amino Groups to α-Ketoglutarate 660

Glutamate Releases its Amino Group as Ammonia in the Liver 661

Glutamine Transports Ammonia in the Bloodstream 662

Box 18-1 Assays for Tissue Damage 664

Alanine Transports Ammonia from Skeletal Muscles to the Liver 664

Ammonia Is Toxic to Animals 665

18.2 Nitrogen Excretion and the Urea Cycle 665

Urea Is Produced from Ammonia in Five Enzymatic Steps 667

The Citric Acid and Urea Cycles Can Be Linked 668

The Activity of the Urea Cycle Is Regulated at Two Levels 669

Pathway Interconnections Reduce the Energetic Cost of Urea Synthesis 669

Genetic Defects in the Urea Cycle Can Be Life-Threatening 669

18.3 Pathways of Amino Acid Degradation 671

Some Amino Acids Are Converted to Glucose, Others to Ketone Bodies 671

Several Enzyme Cofactors Play Important Roles in Amino Acid Catabolism 672

Six Amino Acids Are Degraded to Pyruvate 674

Seven Amino Acids Are Degraded to Acetyl-CoA 677

Phenylalanine Catabolism Is Genetically Defective in Some People 679

Five Amino Acids Are Converted to α-Ketoglutarate 681

Four Amino Acids Are Converted to Succinyl-CoA 682

Branched-Chain Amino Acids Are Not Degraded in the Liver 683

Box 18-2 Sclentlflc Sleuths Solve a Murder Mystery 684

Asparagine and Aspartate Are Degraded to Oxaloacetate 685

19 Oxidative Phosphorylation and Photophosphorylation 690

OXIDATIVE PHOSPHORYLATION 691

19.1 Electron-Transfer Reactions in Mitochondria 691

Electrons Are Funneled to Universal Electron Acceptors 692

Electrons Pass through a Series of Membrane-Bound Carriers 693

Electron Carriers Function in Multienzyme Complexes 696

The Energy of Electron Transfer Is Efficiently Conserved in a Proton Gradient 701

Plant Mitochondria Have Alternative Mechanisms for Oxidizing NADH 704

19.2 ATP Synthesis 704

Box 19-1 Hot, Stlnklng Plants and Alternatlve Resplratory Pathways 706

ATP Synthase Has Two Functional Domains,Fo and F1 708

ATP Is Stabilized Relative to ADP on the Surface of F1 708

The Proton Gradient Drives the Release of ATP from the Enzyme Surface 709

Each β Subunit of ATP Synthase Can Assume Three Different Conformations 709

Rotational Catalysis Is Key to the Binding-Change Mechanism for ATP Synthesis 711

Chemiosmotic Coupling Allows Nonintegral Stoichiometries of O2 Consumption and ATP Synthesis 712

The Proton-Motive Force Energizes Active Transport 713

Shuttle Systems Indirectly Convey Cytosolic NADH into Mitochondria for Oxidation 714

19.3 Regulation of Oxidative Phosphorylation 716

Oxidative Phosphorylation Is Regulated by Cellular Energy Needs 716

An Inhibitory Protein Prevents ATP Hydrolysis during Ischemia 717

Uncoupled Mitochondria in Brown Fat Produce Heat 717

ATP-Producing Pathways Are Coordinately Regulated 718

19.4 Mitochondrial Genes: Their Origin and the Effects of Mutations 719

Mutations in Mitochondrial Genes Cause Human Disease 719

Mitochondria Evolved from Endosymbiotic Bacteria 72119.5 The Role of Mitochondria in Apoptosis and OxidativeStress 721PHOTOSYNTHESIS: HARVESTING LIGHT ENERGY 72319.6 General Features of Photophosphorylation 723

Photosynthesis in Plants Takes Place in Chloroplasts 724

Light Drives Electron Flow in Chloroplasts 724

19.7 Light Absorption 725

Chlorophylls Absorb Light Energy for Photosynthesis 725

Accessory Pigments Extend the Range of Light Absorption 728

Chlorophyll Funnels the Absorbed Energy to Reaction Centers by Exciton Transfer 728

19.8 The Central Photochemical Event: Light-Driven Electron Flow 730

Bacteria Have One of Two Types of Single Photochemical Reaction Center 730

Kinetic and Thermodynamic Factors Prevent the Dissipation of Energy by Internal Conversion 732

In Plants, Two Reaction Centers Act in Tandem 733

Antenna Chlorophylls Are Tightly Integrated with Electron Carriers 734

Spatial Separation of Photosystems Ⅰ and Ⅱ Prevents Exciton Larceny 736

The Cytochrome b6 f Complex Links Photosystems Ⅱ and I 737

Cyanobacteria Use the Cytochrome b6 f Complex and Cytochrome c6 in Both Oxidative Phosphorylation and Photophosphorylation 738

Water Is Split by the Oxygen-Evolving Complex 738

19.9 ATP Synthesis by Photophosphorylation 740

A Proton Gradient Couples Electron Flow and Photophosphorylation 740

The Approximate Stoichiometry of Photophosphorylation Has Been Established 741

Cyclic Electron Flow Produces ATP but Not NADPH or O2 741

The ATP Synthase of Chloroplasts Is Like That of Mitochondria 742

Chloroplasts Evolved from Endosymbiotic Bacteria 742

Diverse Photosynthetic Organisms Use Hydrogen Donors Other Than Water 743

In Halophilic Bacteria, a Single Protein Absorbs Light and Pumps Protons to Drive ATP Synthesis 743

20 Carbohydrate Biosynthesis in Plants and Bacteria 751

20.1 Photosynthetic Carbohydrate Synthesis 751

Plastids Are Organelles Unique to Plant Cells and Algae 752

Carbon Dioxide Assimilation Occurs in Three Stages 753

Synthesis of Each Triose Phosphate from CO2 Requires Six NADPH and Nine ATP 762

A Transport System Exports Triose Phosphates from the Chloroplast and Imports Phosphate 763

Four Enzymes of the Calvin Cycle Are Indirectly Activated by Light 764

20.2 Photorespiration and the C4 and CAM Pathways 766

Photorespiration Results from Rubisco's Oxygenase Activity 766

The Salvage of Phosphoglycolate Is Costly 767

In C4 Plants, CO2 Fixation and Rubisco Activity Are Spatially Separated 769

In CAM Plants, CO2 Capture and Rubisco Action Are Temporally Separated 770

20.3 Biosynthesis of Starch and Sucrose 771

ADP-Glucose Is the Substrate for Starch Synthesis in Plant Plastids and for Glycogen Synthesis in Bacteria 771

UDP-Glucose Is the Substrate for Sucrose Synthesis in the Cytosol of Leaf Cells 771

Conversion of Triose Phosphates to Sucrose and Starch Is Tightly Regulated 772

20.4 Synthesis of Cell Wall Polysaccharides: Plant Cellulose and Bacterial Peptidoglycan 775

Cellulose Is Synthesized by Supramolecular Structures in the Plasma Membrane 775

Lipid-Linked Oligosaccharides Are Precursors for Bacterial Cell Wall Synthesis 777

Box 20-1 The Magic Bullet versus the Bulletproof Vest: Penicillin and β-Lactamase 779

20.5 Integration of Carbohydrate Metabolism in the Plant Cell 780

Gluconeogenesis Converts Fats and Proteins to Glucose in Germinating Seeds 780

Pools of Common Intermediates Link Pathways in Different Organelles 781

21 Lipid Biosynthesis 787

21.1 Biosynthesis of Fatty Acids and Eicosanoids 787

Malonyl-CoA Is Formed from Acetyl-CoA and Bicarbonate 787

Fatty Acid Synthesis Proceeds in a Repeating Reaction Sequence 788

The Fatty Acid Synthase Complex Has Seven Different Active Sites 789

Fatty Acid Synthase Receives the Acetyl and Malonyl Groups 790

The Fatty Acid Synthase Reactions Are Repeated to Form Palmitate 791

The Fatty Acid Synthase of Some Organisms Consists of Multifunctional Proteins 794

Fatty Acid Synthesis Occurs in the Cytosol of Many Organisms but in the Chloroplasts of Plants 794

Acetate Is Shuttled out of Mitochondria as Citrate 794

Fatty Acid Biosynthesis Is Tightly Regulated 795

Long-Chain Saturated Fatty Acids Are Synthesized from Palmitate 797

Desaturation of Fatty Acids Requires a Mixed-Function Oxidase 798

Box 21-1 Mixed-Function Oxidases, Oxygenases, and Cytochrome P-450 798

Eicosanoids Are Formed from 20-Carbon Polyunsaturated Fatty Acids 800

Box 21-2 Relief Is in （the Active） Site: Cyclooxygenase Isozymes and the Search for a Better Aspirin 802

21.2 Biosynthesis of Triacylglycerols 804

Triacylglycerols and Glycerophospholipids Are Synthesized from the Same Precursors 804

Triacylglycerol Biosynthesis in Animals Is Regulated by Hormones 804

Adipose Tissue Generates Glycerol 3-phosphate by Glyceroneogenesis 806

21.3 Biosynthesis of Membrane Phospholipids 808

Cells Have Two Strategies for Attaching Phospholipid Head Groups 809

Phospholipid Synthesis in E.coli Employs CDP-Diacylglycerol 811

Eukaryotes Synthesize Anionic Phospholipids from CDP-Diacylglycerol 811

Eukaryotic Pathways to Phosphatidylserine,Phosphatidylethanolamine, and Phosphatidylcholine Are Interrelated 812

Plasmalogen Synthesis Requires Formation of an Ether-Linked Fatty Alcohol 813

Sphingolipid and Glycerophospholipid Synthesis Share Precursors and Some Mechanisms 813

Polar Lipids Are Targeted to Specific Cellular Membranes 814

21.4 Biosynthesis of Cholesterol, Steroids, and Isoprenoids 816

Cholesterol Is Made from Acetyl-CoA in Four Stages 816

Cholesterol Has Several Fates 820

Cholesterol and Other Lipids Are Carried on Plasma Lipoproteins 820

Box 21-3 ApoE Alleles Predict Incidence of Alzheimer's Disease 824

Cholesteryl Esters Enter Cells by Receptor-Mediated Endocytosis 824

Cholesterol Biosynthesis Is Regulated at Several Levels 825

Steroid Hormones Are Formed by Side-Chain Cleavage and Oxidation of Cholesterol 827

Intermediates in Cholesterol Biosynthesis Have Many Alternative Fates 828

22 Biosynthesis of Amino Acids, Nucleotides,and Related Molecules 833

22.1 Overview of Nitrogen Metabolism 834

The Nitrogen Cycle Maintains a Pool of Biologically Available Nitrogen 834

Nitrogen Is Fixed by Enzymes of the Nitrogenase Complex 834

Ammonia Is Incorporated into Biomolecules through Glutamate and Glutamine 837

Glutamine Synthetase Is a Primary Regulatory Point in Nitrogen Metabolism 838

Several Classes of Reactions Play Special Roles in the Biosynthesis of Amino Acids and Nucleotides 840

22.2 Biosynthesis of Amino Acids 841

α-Ketoglutarate Gives Rise to Glutamate, Glutamine, Proline,and Arginine 842

Serine, Glycine, and Cysteine Are Derived from 3-Phospho-glycerate 842

Three Nonessential and Six Essential Amino Acids Are Synthesized from Oxaloacetate and Pyruvate 845

Chorismate Is a Key Intermediate in the Synthesis of Tryptophan, Phenylalanine, and Tyrosine 849

Histidine Biosynthesis Uses Precursors of Purine Biosynthesis 851

Amino Acid Biosynthesis Is under Allosteric Regulation 851

22.3 Molecules Derived from Amino Acids 854

Glycine Is a Precursor of Porphyrins 854

Heme Is the Source of Bile Pigments 854

Box 22-1 Blochemistry of Kings and Vampires 857

Amino Acids Are Precursors of Creatine and Glutathione 857

D-Amino Acids Are Found Primarily in Bacteria 858

Aromatic Amino Acids Are Precursors of Many Plant Substances 859

Biological Amines Are Products of Amino Acid Decarboxylation 859

Arginine Is the Precursor for Biological Synthesis of Nitric Oxide 860

Box 22-2 Curing African Sleeping Sickness wlth a Biochemical Trojan Horse 862

22.4 Biosynthesis and Degradation of Nucleotides 862

De Novo Purine Nucleotide Synthesis Begins with PRPP 864

Purine Nucleotide Biosynthesis Is Regulated by Feedback Inhibition 866

Pyrimidine Nucleotides Are Made from Aspartate, PRPP, and Carbamoyl Phosphate 867

Pyrimidine Nucleotide Biosynthesis Is Regulated by Feedback Inhibition 868

Nucleoside Monophosphates Are Converted to Nucleoside Triphosphates 868

Ribonucleotides Are the Precursors of Deoxyribonucleotides 869

Thymidylate Is Derived from dCDP and dUMP 872

Degradation of Purines and Pyrimidines Produces Uric Acid and Urea, Respectively 873

Purine and Pyrimidine Bases Are Recycled by Salvage Pathways 875

Excess Uric Acid Causes Gout 875

Many Chemotherapeutic Agents Target Enzymes in the Nucleotide Biosynthetic Pathways 876

23 Hormonal Regulation and Integration of Mammalian Metabolism 881

23.1 Hormones: Diverse Structures for Diverse Functions 881

The Discovery and Purification of Hormones Require a Bioassay 882

Box 23-1 How Is a Hormone Dlscovered? The Arduous Path to Purlfied Insulin 883

Hormones Act through Specific High-Affinity Cellular Receptors 884

Hormones Are Chemically Diverse 886

Hormone Release Is Regulated by a Hierarchy of Neuronal and Hormonal Signals 889

23.2 Tissue-Specific Metabolism: The Dlvision of Labor 892

The Liver Processes and Distributes Nutrients 893

Adipose Tissue Stores and Supplies Fatty Acids 897

Muscles Use ATP for Mechanical Work 898

The Brain Uses Energy for Transmission of Electrical Impulses 900

Blood Carries Oxygen, Metabolites, and Hormones 900

23.3 Hormonal Regulatlon of Fuel Metabollsm 902

The Pancreas Secretes Insulin or Glucagonin Response to Changes in Blood Glucose 902

Insulin Counters High Blood Glucose 904

Glucagon Counters Low Blood Glucose 904

During Fasting and Starvation, Metabolism Shifts to Provide Fuel for the Brain 906

Epinephrine Signals Impending Activity 908

Cortisol Signals Stress, Including Low Blood Glucose 909

Diabetes Mellitus Arises from Defects in Insulin Production or Action 909

23.4 Obesity and the Regulation of Body Mass 910

The Lipostat Theory Predicts the Feedback Regulation of Adipose Tissue 910

Leptin Stimulates Production of Anorexigenic Peptide Hormones 912

Leptin Triggers a Signaling Cascade That Regulates Gene Expression 913

The Leptin System May Have Evolved to Regulate the Starvation Response 913

Insulin Acts in the Arcuate Nucleus to Regulate Eating and Energy Conservation 914

Adiponectin Acts through AMPK 914

Diet Regulates the Expression of Genes Central to Maintaining Body Mass 915

Short-Term Eating Behavior Is Set by Ghrelin and PYY3-36 916

Ⅲ INFORMATION PATHWAYS 921

24 Genes and Chromosomes 923

24.1 Chromosomal Elements 924

Genes Are Segments of DNA That Code for Polypeptide Chains and RNAs 924

DNA Molecules Are Much Longer Than the Cellular Packages That Contain Them 925

Eukaryotic Genes and Chromosomes Are Very Complex 928

24.2 DNA Supercoiling 930

Most Cellular DNA Is Underwound 932

DNA Underwinding Is Defined by Topological Linking Number 933

Topoisomerases Catalyze Changes in the Linking Number of DNA 935

DNA Compaction Requires a Special Form of Supercoiling 937

24.3 The Structure of Chromosomes 938

Chromatin Consists of DNA and Proteins 938

Histones Are Small, Basic Proteins 939

Nucleosomes Are the Fundamental Organizational Units of Chromatin 940

Nucleosomes Are Packed into Successively Higher Order Structures 942

Condensed Chromosome Structures Are Maintained by SMC Proteins 943

Bacterial DNA Is Also Highly Organized 943

25 DNA Metabolism 948

25.1 DNA Replication 950

DNA Replication Follows a Set of Fundamental Rules 950

DNA Is Degraded by Nucleases 952

DNA Is Synthesized by DNA Polymerases 952

Replication Is Very Accurate 954

E.coli Has at Least Five DNA Polymerases 955

DNA Replication Requires Many Enzymes and Protein Factors 957

Replication of the E.coli Chromosome Proceeds in Stages 958

Bacterial Replication Is Organized in Membrane-Bound Replication Factories 963

Replication in Eukaryotic Cells Is More Complex 964

25.2 DNA Repair 966

Mutations Are Linked to Cancer 966

All Cells Have Multiple DNA Repair Systems 967

Box 25-1 DNA Repair and Cancer 970

The Interaction of Replication Forks with DNA Damage Can Lead to Error-Prone Translesion DNA Synthesis 976

25.3 DNA Recombination 978

Homologous Genetic Recombination Has Several Functions 979

Recombination during Meiosis Is Initiated with Double-Strand Breaks 980

Recombination Requires a Host of Enzymes and Other Proteins 982

All Aspects of DNA Metabolism Come Together to Repair Stalled Replication Forks 984

Site-Specific Recombination Results in Precise DNA Rearrangements 984

Complete Chromosome Replication Can Require Site-Specific Recombination 988

Transposable Genetic Elements Move from One Location to Another 988

Immunoglobulin Genes Assemble by Recombination 990

26 RNA Metabolism 995

26.1 DNA-Dependent Synthesis of RNA 996

RNA Is Synthesized by RNA Polymerases 996

RNA Synthesis Begins at Promoters 998

Transcription Is Regulated at Several Levels 1001

Specific Sequences Signal Termination of RNA Synthesis 1001

Box 26-1 RNA Polymerase Leaves Its Footprint on a Promoter 1002

Eukaryotic Cells Have Three Kinds of Nuclear RNA Polymerases 1003

RNA Polymerase Ⅱ Requires Many Other Protein Factors for Its Activity 1003

DNA-Dependent RNA Polymerase Undergoes Selective Inhibition 1006

26.2 RNA Processing 1007

Eukaryotic mRNAs Are Capped at the 5' End 1008

Both Introns and Exons Are Transcribed from DNA into RNA 1008

RNA Catalyzes the Splicing of Introns 1009

Eukaryotic mRNAs Have a Distinctive 3' End Structure 1011

A Gene Can Give Rise to Multiple Products by Differential RNA Processing 1014

Ribosomal RNAs and tRNAs Also Undergo Processing 1014

RNA Enzymes Are the Catalysts of Some Events in RNA Metabolism 1017

Cellular mRNAs Are Degraded at Different Rates 1020

Polynucleotide Phosphorylase Makes Random RNA-like Polymers 1020

26.3 RNA-Dependent Synthesis of RNA and DNA 1021

Reverse Transcriptase Produces DNA from Viral RNA 1021

Some Retroviruses Cause Cancer and AIDS 1023

Many Transposons, Retroviruses, and Introns May Have a Common Evolutionary Origin 1023

Box 26-2 Fighting AIDS with Inhibitors of HIV Reverse Transcriptase 1024

Telomerase Is a Specialized Reverse Transcriptase 1025

Some Viral RNAs Are Replicated by RNA-Dependent RNA Polymerase 1027

RNA Synthesis Offers Important Clues to Biochemical Evolution 1027

Box 26-3 The SELEX Method for Generating RNA Polymers with New Functlons 1030

27 Protein Metabolism 1034

27.1 The Genetic Code 1034

The Genetic Code Was Cracked Using Artificial mRNA Templates 1035

Wobble Allows Some tRNAs to Recognize More than One Codon 1039

Box 27-1 Changing Horses in Midstream: Translational Frameshiftlng and mRNA Editing 1040

Box 27-2 Exceptions That Prove the Rule: Natural Variations In the Genetic Code 1042

27.2 Protein Synthesis 1044

Protein Biosynthesis Takes Place in Five Stages 1044

The Ribosome Is a Complex Supramolecular Machine 1045

Box 27-3 From an RNA World to a Protein World 1048

Transfer RNAs Have Characteristic Structural Features 1049

Stage 1: Aminoacyl-tRNA Synthetases Attach the Correct Amino Acids to Their tRNAs 1051

Stage 2: A Specific Amino Acid Initiates Protein Synthesis 1054

Stage 3: Peptide Bonds Are Formed in the Elongation Stage 1058

Stage 4: Termination of Polypeptide Synthesis Requires a Special Signal 1061

Stage 5: Newly Synthesized Polypeptide Chains Undergo Folding and Processing 1062

Box 27-4 Induced Varlatlon in the Genetlc Code: Nonsense Suppresslon 1065

Protein Synthesis Is Inhibited by Many Antibiotics and Toxins 1065

27.3 Protein Targeting and Degradation 1068

Post translational Modification of Many Eukaryotic Proteins Begins in the Endoplasmic Reticulum 1068

Glycosylation Plays a Key Role in Protein Targeting 1069

Signal Sequences for Nuclear Transport Are Not Cleaved 1071

Bacteria Also Use Signal Sequences for Protein Targeting 1072

Cells Import Proteins by Receptor-Mediated Endocytosis 1074

Protein Degradation Is Mediated by Specialized Systems in All Cells 1075

28 Regulation of Gene Expression 1081

28.1 Principles of Gene Regulation 1082

RNA Polymerase Binds to DNA at Promoters 1082

Transcription Initiation Is Regulated by Proteins That Bind to or Near Promoters 1083

Many Prokaryotic Genes Are Clustered and Regulated in Operons 1085

The lac Operon Is Subject to Negative Regulation 1085

Regulatory Proteins Have Discrete DNA-Binding Domains 1087

Regulatory Proteins Also Have Protein-Protein Interaction Domains 1090

28.2 Regulation of Gene Expression in Prokaryotes 1092

The lac Operon Undergoes Positive Regulation 1093

Many Genes for Amino Acid Biosynthetic Enzymes Are Regulated by Transcription Attenuation 1094

Induction of the SOS Response Requires Destruction of Repressor Proteins 1097

Synthesis of Ribosomal Proteins Is Coordinated with rRNA Synthesis 1098

Some Genes Are Regulated by Genetic Recombination 1100

28.3 Regulation of Gene Expression in Eukaryotes 1102

Transcriptionally Active Chromatin Is Structurally Distinct from Inactive Chromatin 1102

Chromatin Is Remodeled by Acetylation and Nucleosomal Displacements 1103

Many Eukaryotic Promoters Are Positively Regulated 1103

DNA-Binding Transactivators and Coactivators Facilitate Assembly of the General Transcription Factors 1104

The Genes of Galactose Metabolism in Yeast Are Subject to Both Positive and Negative Regulation 1106

DNA-Binding Transactivators Have a Modular Structure 1106

Eukaryotic Gene Expression Can Be Regulated by Intercellular and Intracellular Signals 1108

Regulation Can Result from Phosphorylation of Nuclear Transcription Factors 1109

Many Eukaryotic mRNAs Are Subject to Translational Repression 1109

Posttranscriptional Gene Silencing Is Mediated by RNA Interference 1110

Development Is Controlled by Cascades of Regulatory Proteins 1111

Appendix A Common Abbreviations in the Biochemical Research Literature A-1 1148

Appendix B Abbreviated Solutions to Problems AS-1 1152

Glossary G-1 1121

Credits C-1 1139

Index I-1 1174