《lehninger principles of biochemistry fourth edition P1119》求取 ⇩

1 The Foundations of Biochemistry1

1.1 Cellular Foundations3

Cells Are the Structural and Functional Units of All Living Organisms3

Cellular Dimensions Are Limited by Oxygen Diffusion4

There Are Three Distinct Domains of Life4

Escherichia coli Is the Most-Studied Prokaryotic Cell5

Eukaryotic Cells Have a Variety of Membranous Organelles,Which Can Be Isolated for Study6

The Cytoplasm Is Organized by the Cytoskeleton and Is Highly Dynamic9

Cells Build Supramolecular Structures10

In Vitro Studies May Overlook Important Interactions among Molecules11

1.2 Chemical Foundations12

Biomolecules Are Compounds of Carbon with a Variety of Functional Groups13

Cells Contain a Universal Set of Small Molecules14

Macromolecules Are the Major Constituents of Cells15

Box 1-1 Molecular Weight, Molecular Mass, and Their Correct Units15

Three-Dimensional Structure Is Described by Configuration and Conformation16

Box 1-2 Louis Pasteur and Optical Activlty: In Vino, Veritas19

Interactions between Biomolecules Are Stereospecific20

1.3 Physical Foundations21

Living Organisms Exist in a Dynamic Steady State, Never at Equilibrium with Their Surroundings21

Organisms Transform Energy and Matter from Their Surroundings22

The Flow of Electrons Provides Energy for Organisms22

Creating and Maintaining Order Requires Work and Energy23

Energy Coupling Links Reactions in Biology23

Box 1-3 Entropy: The Advantages of Belng Disorganized24

Keq and △G Are Measures of a Reaction's Tendency to Proceed Spontaneously26

Enzymes Promote Sequences of Chemical Reactions26

Metabolism Is Regulated to Achieve Balance and Economy27

1.4 Genetic Foundations28

Genetic Continuity Is Vested in Single DNA Molecules29

The Structure of DNA Allows for Its Replication and Repair with Near-Perfect Fidelity29

The Linear Sequence in DNA Encodes Proteins with Three-Dimensional Structures29

1.5 Evolutionary Foundations31

Changes in the Hereditary Instructions Allow Evolution31

Biomolecules First Arose by Chemical Evolution32

Chemical Evolution Can Be Simulated in the Laboratory32

RNA or Related Precursors May Have Been the First Genes and Catalysts32

Biological Evolution Began More Than Three and a Half Billion Years Ago34

The First Cell Was Probably a Chemoheterotroph34

Eukaryotic Cells Evolved from Prokaryotes in Several Stages34

Molecular Anatomy Reveals Evolutionary Relationships36

Functional Genomics Shows the Allocations of Genes to Specific Cellular Processes38

Genomic Comparisons Will Have Increasing Importance in Human Biology and Medicine38

Ⅰ STRUCTURE AND CATALYSIS45

2 Water47

2.1 Weak Interactions in Aqueous Systems47

Hydrogen Bonding Gives Water Its Unusual Properties47

Water Forms Hydrogen Bonds with Polar Solutes49

Water Interacts Electrostatically with Charged Solutes50

Entropy Increases as Crystalline Substances Dissolve51

Nonpolar Gases Are Poorly Soluble in Water52

Nonpolar Compounds Force Energetically Unfavorable Changes in the Structure of Water52

van der Waals Interactions Are Weak Interatomic Attractions54

Weak Interactions Are Crucial to Macromolecular Structure and Function54

Solutes Affect the Colligative Properties of Aqueous Solutions56

Box 2-1 Touch Response in Plants: An Osmotic Event59

2.2 Ionization of Water, Weak Acids, and Weak Bases60

Pure Water Is Slightly Ionized60

The Ionization of Water Is Expressed by an Equilibrium Constant61

The pH Scale Designates the H+ and OH-Concentrations61

Box 2-2 The Ion Product of Water: Two Illustrative Problems62

Weak Acids and Bases Have Characteristic Dissociation Constants63

Titration Curves Reveal the pKa of Weak Acids64

2.3 Buffering against pH Changes in Biological Systems65

Buffers Are Mixtures of Weak Acids and Their Conjugate Bases66

A Simple Expression Relates pH, pKa, and Buffer Concentration66

Weak Acids or Bases Buffer Cells and Tissues against pH Changes67

Box 2-3 Solving Problems Using the Henderson-Hasseibalch Equation67

Box 2-4 Blood, Lungs, and Buffer: The Bicarbonate Buffer System69

2.4 Water as a Reactant69

2.5 The Fitness of the Aqueous Environment for Living Organisms70

3 Amino Acids, Peptides, and Proteins75

3.1 Amino Acids75

Amino Acids Share Common Structural Features76

The Amino Acid Residues in Proteins Are L Stereoisomers77

Amino Acids Can Be Classified by R Group78

Uncommon Amino Acids Also Have Important Functions80

Amino Acids Can Act as Acids and Bases81

Box 3-1 Absorption of Light by Molecules: The Lambert-Beer Law82

Amino Acids Have Characteristic Titration Curves82

Titration Curves Predict the Electric Charge of Amino Acids84

Amino Acids Differ in Their Acid-Base Properties84

3.2 Peptides and Proteins85

Peptides Are Chains of Amino Acids85

Peptides Can Be Distinguished by Their Ionization Behavior86

Biologically Active Peptides and Polypeptides Occur in a Vast Range of Sizes86

Polypeptides Have Characteristic Amino Acid Compositions87

Some Proteins Contain Chemical Groups Other Than Amino Acids88

There Are Several Levels of Protein Structure88

3.3 Working with Proteins89

Proteins Can Be Separated and Purified89

Proteins Can Be Separated and Characterized by Electrophoresis92

Unseparated Proteins Can Be Quantified94

3.4 The Covalent Structure of Proteins96

The Function of a Protein Depends on Its Amino Acid Sequence96

The Amino Acid Sequences of Millions of Proteins Have Been Determined96

Short Polypeptides Are Sequenced Using Automated Procedures97

Large Proteins Must Be Sequenced in Smaller Segments99

Amino Acid Sequences Can Also Be Deduced by Other Methods100

Box 3-2 Investigating Proteins with Mass Spectrometry102

Small Peptides and Proteins Can Be Chemically Synthesized104

Amino Acid Sequences Provide Important Biochemical Information106

3.5 Protein Sequences and Evolution106

Protein Sequences Can Elucidate the History of Life on Earth107

4 The Three-Dimensional Structure of Proteins116

4.1 Overview of Protein Structure116

A Protein's Conformation Is Stabilized Largely by Weak Interactions117

The Peptide Bond Is Rigid and Planar118

4.2 Protein Secondary Structure120

The α Helix Is a Common Protein Secondary Structure120

Amino Acid Sequence Affects α Helix Stability121

Box 4-1 Knowing the Right Hand from the Left122

The β Conformation Organizes Polypeptide Chains into Sheets123

β Turns Are Common in Proteins123

Common Secondary Structures Have Characteristic Bond Angles and Amino Acid Content124

4.3 Protein Tertiary and Quaternary Structures125

Fibrous Proteins Are Adapted for a Structural Function126

Box 4-2 Permanent Waving Is Biochemical Engineering127

Structural Diversity Reflects Functional Diversity in Globular Proteins129

Box 4-3 Why Sailors, Explorers, and College Students Should Eat Their Fresh Fruits and Vegetables130

Myoglobin Provided Early Clues about the Complexity of Globular Protein Structure132

Globular Proteins Have a Variety of Tertiary Structures134

Box 4-4 Methods for Determining the Three-Dimensional Structure of a Protein136

Analysis of Many Globular Proteins Reveals Common Structural Patterns138

Protein Motifs Are the Basis for Protein Structural Classification141

Protein Quaternary Structures Range from Simple Dimers to Large Complexes144

There Are Limits to the Size of Proteins146

4.4 Protein Denaturation and Folding147

Loss of Protein Structure Results in Loss of Function147

Amino Acid Sequence Determines Tertiary Structure148

Polypeptides Fold Rapidly by a Stepwise Process148

Box 4-5 Death by Misfolding: The Prion Diseases150

Some Proteins Undergo Assisted Folding151

5 Protein Function157

5.1 Reversible Binding of a Protein to a Ligand:Oxygen-Binding Proteins158

Oxygen Can Be Bound to a Heme Prosthetic Group158

Myoglobin Has a Single Binding Site for Oxygen159

Protein-Ligand Interactions Can Be Described Quantitatively160

Protein Structure Affects How Ligands Bind162

Oxygen Is Transported in Blood by Hemoglobin162

Hemoglobin Subunits Are Structurally Similar to Myoglobin163

Hemoglobin Undergoes a Structural Change on Binding Oxygen164

Hemoglobin Binds Oxygen Cooperatively164

Cooperative Ligand Binding Can Be Described Quantitatively167

Two Models Suggest Mechanisms for Cooperative Binding167

Box 5-1 Carbon Monoxide: A Stealthy Killer168

Hemoglobin Also Transports H+ and CO2170

Oxygen Binding to Hemoglobin Is Regulated by 2,3-Bisphosphoglycerate171

Sickle-Cell Anemia Is a Molecular Disease of Hemoglobin172

5.2 Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins174

The Immune Response Features a Specialized Array of Cells and Proteins175

Self Is Distinguished from Nonself by the Display of Peptides on Cell Surfaces176

Antibodies Have Two Identical Antigen-Binding Sites178

Antibodies Bind Tightly and Specifically to Antigen180

The Antibody-Antigen Interaction Is the Basis for a Variety of Important Analytical Procedures180

5.3 Protein Interactions Modulated by Chemical Energy:Actin, Myosin, and Molecular Motors182

The Major Proteins of Muscle Are Myosin and Actin182

Additional Proteins Organize the Thin and Thick Filaments into Ordered Structures184

Myosin Thick Filaments Slide along Actin Thin Filaments185

6 Enzymes190

6.1 An Introduction to Enzymes191

Most Enzymes Are Proteins191

Enzymes Are Classified by the Reactions They Catalyze192

6.2 How Enzymes Work193

Enzymes Affect Reaction Rates, Not Equilibria193

Reaction Rates and Equilibria Have Precise Thermodynamic Definitions195

A Few Principles Explain the Catalytic Power and Specificity of Enzymes196

Weak Interactions between Enzyme and Substrate Are Optimized in the Transition State196

Binding Energy Contributes to Reaction Specificity and Catalysis198

Specific Catalytic Groups Contribute to Catalysis200

6.3 Enzyme Kinetics As an Approach to Understanding Mechanism202

Substrate Concentration Affects the Rate of Enzyme-Catalyzed Reactions202

The Relationship between Substrate Concentration and Reaction Rate Can Be Expressed Quantitatively203

Kinetic Parameters Are Used to Compare Enzyme Activities205

Box 6-1 Transformations of the Michaelis-Menten Equation: The Double Reciprocal Plot206

Many Enzymes Catalyze Reactions with Two or More Substrates207

Pre-Steady State Kinetics Can Provide Evidence for Specific Reaction Steps208

Enzymes Are Subject to Reversible or Irreversible Inhibition209

Box 6-2 Kinetic Tests for Determining Inhibition Mechanisms210

Enzyme Activity Depends on pH212

6.4 Examples of Enzymatic Reactions213

The Chymotrypsin Mechanism Involves Acylation and Deacylation of a Ser Residue213

Hexokinase Undergoes Induced Fit on Substrate Binding218

The Enolase Reaction Mechanism Requires Metal Ions219

Box 6-3 Evidence for Enzyme-Transition State Complementarity220

Lysozyme Uses Two Successive Nucleophilic Displacement Reactions222

6.5 Regulatory Enzymes225

Allosteric Enzymes Undergo Conformational Changes in Response to Modulator Binding225

In Many Pathways a Regulated Step Is Catalyzed by an Allosteric Enzyme226

The Kinetic Properties of Allosteric Enzymes Diverge from Michaelis-Menten Behavior227

Some Regulatory Enzymes Undergo Reversible Covalent Modification228

Phosphoryl Groups Affect the Structure and Catalytic Activity of Proteins228

Multiple Phosphorylations Allow Exquisite Regulatory Control230

Some Enzymes and Other Proteins Are Regulated by Proteolytic Cleavage of an Enzyme Precursor231

Some Regulatory Enzymes Use Several Regulatory Mechanisms232

7 Carbohydrates and Glycobiology238

7.1 Monosaccharides and Disaccharides239

The Two Families of Monosaccharides Are Aldoses and Ketoses239

Monosaccharides Have Asymmetric Centers239

The Common Monosaccharides Have Cyclic Structures240

Organisms Contain a Variety of Hexose Derivatives243

Monosaccharides Are Reducing Agents244

Disaccharides Contain a Glycosidic Bond245

7.2 Polysaccharides247

Some Homopolysaccharides Are Stored Forms of Fuel247

Some Homopolysaccharides Serve Structural Roles248

Steric Factors and Hydrogen Bonding Influence Homopolysaccharide Folding250

Bacterial and Algal Cell Walls Contain Structural Heteropolysaccharides252

Glycosaminoglycans Are Heteropolysaccharides of the Extracellular Matrix253

7.3 Glycoconjugates: Proteoglycans, Glycoproteins, and Glycolipids255

Proteoglycans Are Glycosaminoglycan-Containing Macromolecules of the Cell Surface and Extracellular Matrix256

Glycoproteins Have Covalently Attached Oligosaccharides258

Glycolipids and Lipopolysaccharides Are Membrane Components260

7.4 Carbohydrates as Informational Molecules: The Sugar Code261

Lectins Are Proteins That Read the Sugar Code and Mediate Many Biological Processes262

Lectin-Carbohydrate Interactions Are Very Strong and Highly Specific264

7.5 Working with Carbohydrates267

8 Nucleotides and Nucleic Acids273

8.1 Some Basics273

Nucleotides and Nucleic Acids Have Characteristic Bases and Pentoses273

Phosphodiester Bonds Link Successive Nucleotides in Nucleic Acids276

The Properties of Nucleotide Bases Affect the Three-Dimensional Structure of Nucleic Acids278

8.2 Nucleic Acid Structure279

DNA Stores Genetic Information280

DNA Molecules Have Distinctive Base Compositions281

DNA Is a Double Helix282

DNA Can Occur in Different Three-Dimensional Forms283

Certain DNA Sequences Adopt Unusual Structures285

Messenger RNAs Code for Polypeptide Chains287

Many RNAs Have More Complex Three-Dimensional Structures288

8.3 Nucleic Acid Chemistry291

Double-Helical DNA and RNA Can Be Denatured291

Nucleic Acids from Different Species Can Form Hybrids292

Nucleotides and Nucleic Acids Undergo Nonenzymatic Transformations293

Some Bases of DNA Are Methylated296

The Sequences of Long DNA Strands Can Be Determined296

The Chemical Synthesis of DNA Has Been Automated298

8.4 Other Functions of Nucleotides300

Nucleotides Carry Chemical Energy in Cells300

Adenine Nucleotides Are Components of Many Enzyme Cofactors301

Some Nucleotides Are Regulatory Molecules302

9 DNA-Based Information Technologies306

9.1 DNA Cloning: The Basics306

Restriction Endonucleases and DNA Ligase Yield Recombinant DNA307

Cloning Vectors Allow Amplification of Inserted DNA Segments311

Specific DNA Sequences Are Detectable by Hybridization314

Expression of Cloned Genes Produces Large Quantities of Protein315

Alterations in Cloned Genes Produce Modified Proteins316

9.2 From Genes to Genomes317

DNA Libraries Provide Specialized Catalogs of Genetic Information318

The Polymerase Chain Reaction Amplifies Specific DNA Sequences319

Genome Sequences Provide the Ultimate Genetic Libraries321

Box 9-1 A Potent Weapon In Forensic Medicine322

9.3 From Genomes to Proteomes325

Sequence or Structural Relationships Provide Information on Protein Function325

Cellular Expression Patterns Can Reveal the Cellular Function of a Gene326

Detection of Protein-Protein Interactions Helps to Define Cellular and Molecular Function327

9.4 Genome Alterations and New Products of Biotechnology330

A Bacterial Plant Parasite Aids Cloning in Plants330

Manipulation of Animal Cell Genomes Provides Information on Chromosome Structure and Gene Expression333

New Technologies Promise to Expedite the Discovery of New Pharmaceuticals335

Box 9-2 The Human Genome and Human Gene Therapy336

Recombinant DNA Technology Yields New Products and Challenges338

10Lipids343

10.1 Storage Lipids343

Fatty Acids Are Hydrocarbon Derivatives343

Triacylglycerols Are Fatty Acid Esters of Glycerol345

Triacylglycerols Provide Stored Energy and Insulation346

Many Foods Contain Triacylglycerols346

Box 10-1 Sperm Whales: Fatheads of the Deep347

Waxes Serve as Energy Stores and Water Repellents348

10.2 Structural Lipids in Membranes348

Glycerophospholipids Are Derivatives of Phosphatidic Acid349

Some Phospholipids Have Ether-Linked Fatty Acids349

Chloroplasts Contain Galactolipids and Sulfolipids351

Archaebacteria Contain Unique Membrane Lipids352

Sphingolipids Are Derivatives of Sphingosine352

Sphingolipids at Cell Surfaces Are Sites of Biological Recognition353

Phospholipids and Sphingolipids Are Degraded in Lysosomes354

Sterols Have Four Fused Carbon Rings354

Box 10-2 Inherited Human Diseases Resulting from Abnormal Accumulations of Membrane Lipids356

10.3 Lipids as Signals, Cofactors, and Pigments357

Phosphatidylinositols and Sphingosine Derivatives Act as Intracellular Signals357

Eicosanoids Carry Messages to Nearby Cells358

Steroid Hormones Carry Messages between Tissues359

Plants Use Phosphatidylinositols, Steroids, and Eicosanoidlike Compounds in Signaling360

Vitamins A and D Are Hormone Precursors360

Vitamins E and K and the Lipid Quinones Are Oxidation-Reduction Cofactors362

Dolichols Activate Sugar Precursor for Biosynthesis363

10.4 Working with Lipids363

Lipid Extraction Requires Organic Solvents364

Adsorption Chromatography Separates Lipids of Different Polarity365

Gas-Liquid Chromatography Resolves Mixtures of Volatile Lipid Derivatives365

Specific Hydrolysis Aids in Determination of Lipid Structure365

Mass Spectrometry Reveals Complete Lipid Structure365

11 Biological Membranes and Transport369

11.1 The Composition and Architecture of Membranes370

Each Type of Membrane Has Characteristic Lipids and Proteins370

All Biological Membranes Share Some Fundamental Properties371

A Lipid Bilayer Is the Basic Structural Element of Membranes371

Peripheral Membrane Proteins Are Easily Solubilized373

Many Membrane Proteins Span the Lipid Bilayer373

Integral Proteins Are Held in the Membrane by Hydrophobic Interactions with Lipids375

The Topology of an Integral Membrane Protein Can Be Predicted from Its Sequence376

Covalently Attached Lipids Anchor Some Membrane Proteins378

11.2 Membrane Dynamics380

Acyl Groups in the Bilayer Interior Are Ordered to Varying Degrees380

Transbilayer Movement of Lipids Requires Catalysis381

Lipids and Proteins Diffuse Laterally in the Bilayer382

Box 11-1 Atomic Force Microscopy to Visualize Membrane Proteins384

Sphingolipids and Cholesterol Cluster Together in Membrane Rafts383

Caveolins Define a Special Class of Membrane Rafts385

Certain Integral Proteins Mediate Cell-Cell Interactions and Adhesion385

Membrane Fusion Is Central to Many Biological Processes387

11.3 Solute Transport across Membranes389

Passive Transport Is Facilitated by Membrane Proteins389

Transporters Can Be Grouped into Superfamilies Based onTheir Structures391

The Glucose Transporter of Erythrocytes Mediates Passive Transport393

The Chloride-Bicarbonate Exchanger Catalyzes Electroneutral Cotransport of Anions across the Plasma Membrane395

Box 11-2 Defective Glucose and Water Transport In Two Forms of Diabetes396

Active Transport Results in Solute Movement against a Concentration or Electrochemical Gradient397

P-Type ATPases Undergo Phosphorylation during Their Catalytic Cycles398

P-Type Ca 2+ Pumps Maintain a Low Concentration of Calcium in the Cytosol400

F-Type ATPases Are Reversible, ATP-Driven Proton Pumps401

ABC Transporters Use ATP to Drive the Active Transport of a Wide Variety of Substrates402

Ion Gradients Provide the Energy for Secondary Active Transport402

Box 11-3 A Defective Ion Channel in Cystic Fibrosis403

Aquaporins Form Hydrophilic Transmembrane Channels for the Passage of Water406

Ion-Selective Channels Allow Rapid Movement of Ions across Membranes408

Ion-Channel Function Is Measured Electrically408

The Structure of a K+ Channel Reveals the Basis for Its Specificity409

The Neuronal Na+ Channel Is a Voltage-Gated Ion Channel410

The Acetylcholine Receptor Is a Ligand-Gated Ion Channel411

Defective Ion Channels Can Have Adverse Physiological Consequences415

12 Biosignaling421

12.1 Molecular Mechanisms of Signal Transduction422

Box 12-1 Scatchard Analysis Quantifies the Receptor-Ligand Interaction423

12.2 Gated Ion Channels425

Ion Channels Underlie Electrical Signaling in Excitable Cells425

The Nicotinic Acetylcholine Receptor Is a Ligand-Gated Ion Channel426

Voltage-Gated Ion Channels Produce Neuronal Action Potentials427

Neurons Have Receptor Channels That Respond to Different Neurotransmitters428

12.3 Receptor Enzymes429

The Insulin Receptor Is a Tyrosine-Specific Protein Kinase429

Receptor Guanylyl Cyclases Generate the Second Messenger cGMP433

12.4 G Protein-Coupled Receptors and Second Messengers435

The β-Adrenergic Receptor System Acts through the Second Messenger cAMP435

The β-Adrenergic Receptor Is Desensitized by Phosphotylation439

Cyclic AMP Acts as a Second Messenger for a Number of Regulatory Molecules441

Two Second Messengers Are Derived from Phosphatidylinositols442

Calcium Is a Second Messenger in Many Signal Transductions442

Box 12-2 FRET: Biochemistry Vlsuallzed in a Living Cell446

12.5 Multivalent Scaffold Proteins and Membrane Rafts448

Protein Modules Bind Phosphorylated Tyr, Ser, or Thr Residues in Partner Proteins448

Membrane Rafts and Caveolae May Segregate Signaling Proteins451

12.6 Signaling in Microorganisms and Plants452

Bacterial Signaling Entails Phosphorylation in a Two-Component System452

Signaling Systems of Plants Have Some of the Same Components Used by Microbes and Mammals452

Plants Detect Ethylene through a Two-Component System and a MAPK Cascade454

Receptorlike Protein Kinases Transduce Signals from Peptides and Brassinosteroids455

12.7 Sensory Transduction in Vision, Olfaction, and Gustation456

Light Hyperpolarizes Rod and Cone Cells of the Vertebrate Eye456

Light Triggers Conformational Changes in the Receptor Rhodopsin457

Excited Rhodopsin Acts through the G Protein Transducin to Reduce the cGMP Concentration457

Amplification of the Visual Signal Occurs in the Rod and Cone Cells458

The Visual Signal Is Quickly Terminated458

Rhodopsin Is Desensitized by Phosphorylation459

Cone Cells Specialize in Color Vision460

Vertebrate Olfaction and Gustation Use Mechanisms Similar to the Visual System460

Box 12-3 Color Blindness: John Dalton's Experiment from the Grave461

G Protein-Coupled Serpentine Receptor Systems Share Several Features462

Disruption of G-Protein Signaling Causes Disease464

12.8 Regulation of Transcription by Steroid Hormones465

12.9 Regulation of the Cell Cycle by Protein Kinases466

The Cell Cycle Has Four Stages466

Levels of Cyclin-Dependent Protein Kinases Oscillate467

CDKs Regulate Cell Division by Phosphorylating Critical Proteins470

12.10 Oncogenes, Tumor Suppressor Genes, and Programmed Cell Death471

Oncogenes Are Mutant Forms of the Genes for Proteins That Regulate the Cell Cycle471

Defects in Tumor Suppressor Genes Remove Normal Restraints on Cell Division472

Apoptosis Is Programmed Cell Suicide473

Ⅱ BIOENERGETICS AND METABOLISM481

13 Principles of Bioenergetics489

13.1 Bioenergetics and Thermodynamics490

Biological Energy Transformations Obey the Laws of Thermodynamics490

Cells Require Sources of Free Energy491

The Standard Free-Energy Change Is Directly Related to the Equilibrium Constant491

Actual Free-Energy Changes Depend on Reactant and Product Concentrations493

Standard Free-Energy Changes Are Additive494

13.2 Phosphoryl Group Transfers and ATP496

The Free-Energy Change for ATP Hydrolysis Is Large and Negative496

Other Phosphorylated Compounds and Thioesters Also Have Large Free Energies of Hydrolysis497

Box 13-1 The Free Energy of Hydrolysis of ATP within Cells: The Real Cost of Doing Metabolic Business498

ATP Provides Energy by Group Transfers, Not by Simple Hydrolysis500

ATP Donates Phosphoryl, Pyrophosphoryl, and Adenylyl Groups502

Box 13-2 Firefly Flashes: Glowing Reports of ATP503

Assembly of Informational Macromolecules Requires Energy504

ATP Energizes Active Transport and Muscle Contraction504

Transphosphorylations between Nucleotides Occur in All Cell Types505

Inorganic Polyphosphate Is a Potential Phosphoryl Group Donor506

Biochemical and Chemical Equations Are Not Identical506

13.3 Biological Oxidation-Reduction Reactions507

The Flow of Electrons Can Do Biological Work507

Oxidation-Reduction Can Be Described as Half-Reactions508

Biological Oxidations Often Involve Dehydrogenation508

Reduction Potentials Measure Affinity for Electrons509

Standard Reduction Potentials Can Be Used to Calculate the Free-Energy Change510

Cellular Oxidation of Glucose to Carbon Dioxide Requires Specialized Electron Carriers512

A Few Types of Coenzymes and Proteins Serve as Universal Electron Carriers512

NADH and NADPH Act with Dehydrogenases as Soluble Electron Carriers512

Dietary Deficiency of Niacin, the Vitamin Form of NAD and NADP, Causes Pellagra514

Flavin Nucleotides Are Tightly Bound in Flavoproteins515

14 Glycolysis, Gluconeogenesis, and the Pentose Phosphate Pathway521

14.1 Glycolysis522

An Overview: Glycolysis Has Two Phases523

The Preparatory Phase of Glycolysis Requires ATP525

The Payoff Phase of Glycolysis Produces ATP and NADH529

The Overall Balance Sheet Shows a Net Gain of ATP533

Glycolysis Is under Tight Regulation533

Cancerous Tissue Has Deranged Glucose Catabolism533

14.2 Feeder Pathways for Glycolysis534

Glycogen and Starch Are Degraded by Phosphorolysis534

Dietary Polysaccharides and Disaccharides Undergo Hydrolysis to Monosaccharides535

Other Monosaccharides Enter the Glycolytic Pathway at Several Points536

14.3 Fates of Pyruvate under Anaerobic Conditions:Fermentation538

Pyruvate Is the Terminal Electron Acceptor in Lactic Acid Fermentation538

Ethanol Is the Reduced Product in Ethanol Fermentation538

Box 14-1 Athletes, Alligators, and Coelacanths: Glycolysis at Limiting Concentrations of Oxygen539

Thiamine Pyrophosphate Carries “Active Aldehyde” Groups540

Fermentations Yield a Variety of Common Foods and Industrial Chemicals541

Box 14-2 Brewing Beer542

14.4 Gluconeogenesis543

Conversion of Pyruvate to Phosphoenolpyruvate Requires Two Exergonic Reactions544

Conversion of Fructose 1,6-Bisphosphate to Fructose 6-Phosphate Is the Second Bypass547

Conversion of Glucose 6-Phosphate to Glucose Is the Third Bypass547

Gluconeogenesis Is Energetically Expensive, But Essential548

Citric Acid Cycle Intermediates and Many Amino Acids Are Glucogenic548

Glycolysis and Gluconeogenesis Are Regulated Reciprocally548

14.5 Pentose Phosphate Pathway of Glucose Oxidation549

The Oxidative Phase Produces Pentose Phosphates and NADPH550

Box 14-3 Why Pythagoras Wouldn't Eat Falafel: Glucose 6-Phosphate Dehydrogenase Deficiency551

The Nonoxidative Phase Recycles Pentose Phosphates to Glucose 6-Phosphate552

Wernicke-Korsakoff Syndrome Is Exacerbated by a Defect in Transketolase554

Glucose 6-Phosphate Is Partitioned between Glycolysis and the Pentose Phosphate Pathway554

15 Principles of Metabolic Regulation:Glucose and Glycogen560

15.1 The Metabolism of Glycogen in Animals562

Glycogen Breakdown Is Catalyzed by Glycogen Phosphorylase562

Glucose 1-Phosphate Can Enter Glycolysis or, in Liver,Replenish Blood Glucose563

The Sugar Nucleotide UDP-Glucose Donates Glucose for Glycogen Synthesis565

Box 15-1 Carl and Gerty Cori: Pioneers in Glycogen Metabollsm and Disease566

Glycogenin Primes the Initial Sugar Residues in Glycogen569

15.2 Regulation of Metabolic Pathways571

Living Cells Maintain a Dynamic Steady State571

Regulatory Mechanisms Evolved under Strong Selective Pressures571

Regulatory Enzymes Respond to Changes in Metabolite Concentration572

Enzyme Activity Can Be Altered in Several Ways574

15.3 Coordinated Regulation of Glycolysis and Gluconeogenesis575

Hexokinase Isozymes of Muscle and Liver Are Affected Differently by Their Product, Glucose 6-Phosphate576

Box 15-2 Isozymes: Different Proteins That Catalyze the Same Reaction577

Phosphofructokinase-1 Is under Complex Allosteric Regulation578

Pyruvate Kinase Is Allosterically Inhibited by ATP579

Gluconeogenesis Is Regulated at Several Steps580

Fructose 2,6-Bisphosphate Is a Potent Regulator of Glycolysis and Gluconeogenesis581

Are Substrate Cycles Futile?583

Xylulose 5-Phosphate Is a Key Regulator of Carbohydrate and Fat Metabolism583

15.4 Coordinated Regulation of Glycogen Synthesis and Breakdown583

Glycogen Phosphorylase Is Regulated Allosterically and Hormonally583

Glycogen Synthase Is Also Regulated by Phosphorylation and Dephosphorylation586

Glycogen Synthase Kinase 3 Mediates the Actions of Insulin586

Phosphoprotein Phosphatase 1 Is Central to Glycogen Metabolism588

Transport into Cells Can Limit Glucose Utilization588

Allosteric and Hormonal Signals Coordinate Carbohydrate Metabolism588

Carbohydrate and Lipid Metabolism Are Integrated by Hormonal and Allosteric Mechanisms590

Insulin Changes the Expression of Many Genes Involved in Carbohydrate and Fat Metabolism590

15.5 Analysis of Metabolic Control591

The Contribution of Each Enzyme to Flux through a Pathway Is Experimentally Measurable592

The Control Coefficient Quantifies the Effect of a Change in Enzyme Activity on Metabolite Flux through a Pathway592

The Elasticity Coefficient Is Related to an Enzyme's Responsiveness to Changes in Metabolite or Regulator Concentrations593

The Response Coefficient Expresses the Effect of an Outside Controller on Flux through a Pathway593

Metabolic Control Analysis Has Been Applied to Carbohydrate Metabolism, with Surprising Results593

Box 15-3 Metabolic Control Analysis: Quantitative Aspects594

Metabolic Control Analysis Suggests a General Method for Increasing Flux through a Pathway596

16 The Citric Acid Cycle601

16.1 Production of Acetyl-CoA (Activated Acetate)602

Pyruvate Is Oxidized to Acetyl-CoA and CO2602

The Pyruvate Dehydrogenase Complex Requires Five Coenzymes603

The Pyruvate Dehydrogenase Complex Consists of Three Distinct Enzymes604

In Substrate Channeling, Intermediates Never Leave the Enzyme Surface605

16.2 Reactions of the Citric Acld Cycle606

The Citric Acid Cycle Has Eight Steps608

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 Conserved614

Box 16-2 Cltrate: A Symmetrlcal Molecule That Reacts Asymmetrlcally614

Why Is the Oxidation of Acetate So Complicated?615

Citric Acid Cycle Components Are Important Biosynthetic Intermediates616

Anaplerotic Reactions Replenish Citric Acid Cycle Intermediates616

Box 16-3 Citrate Synthase, Soda Pop, and the World Food Supply618

Biotin in Pyruvate Carboxylase Carries CO2 Groups618

16.3 Regulation of the Citric Acid Cycle621

Production of Acetyl-CoA by the Pyruvate Dehydrogenase Complex Is Regulated by Allosteric and Covalent Mechanisms621

The Citric Acid Cycle Is Regulated at Its Three Exergonic Steps622

Substrate Channeling through Multienzyme Complexes May Occur in the Citric Acid Cycle622

16.4 The Glyoxylate Cycle623

The Glyoxylate Cycle Produces Four-Carbon Compounds from Acetate623

The Citric Acid and Glyoxylate Cycles Are Coordinately Regulated624

17 Fatty Acid Catabolism631

17.1 Digestion, Mobilization, and Transport of Fats632

Dietary Fats Are Absorbed in the Small Intestine632

Hormones Trigger Mobilization of Stored Triacylglycerols634

Fatty Acids Are Activated and Transported into Mitochondria634

17.2 Oxidation of Fatty Acids637

The β Oxidation of Saturated Fatty Acids Has Four Basic Steps637

The Four β-Oxidation Steps Are Repeated to Yield Acetyl-CoA and ATP639

Acetyl-CoA Can Be Further Oxidized in the Citric Acid Cycle639

Oxidation of Unsaturated Fatty Acids Requires Two Additional Reactions639

Box 17-1 Fat Bears Carry Out β Oxldatlon In Thelr Sleep640

Complete Oxidation of Odd-Number Fatty Acids Requires Three Extra Reactions642

Fatty Acid Oxidation Is Tightly Regulated642

Genetic Defects in Fatty Acyl-CoA Dehydrogenases Cause Serious Disease643

Box 17-2 Coenzyme B12: A Radlcal Solutlon to a Perplexing Problem644

Peroxisomes Also Carry Out β Oxidation646

Plant Peroxisomes and Glyoxysomes Use Acetyl-CoA from β Oxidation as a Biosynthetic Precursor647

The β-Oxidation Enzymes of Different Organelles Have Diverged during Evolution647

The ω Oxidation of Fatty Acids Occurs in the Endoplasmic Reticulum647

Phytanic Acid Undergoes α Oxidation in Peroxisomes649

17.3 Ketone Bodies650

Ketone Bodies, Formed in the Liver, Are Exported to Other Organs as Fuel650

Ketone Bodies Are Overproduced in Diabetes and during Starvation652

18 Amino Acid Oxidation and the Production of Urea656

18.1 Metabolic Fates of Amino Groups657

Dietary Protein Is Enzymatically Degraded to Amino Acids658

Pyridoxal Phosphate Participates in the Transfer of α-Amino Groups to α-Ketoglutarate660

Glutamate Releases its Amino Group as Ammonia in the Liver661

Glutamine Transports Ammonia in the Bloodstream662

Box 18-1 Assays for Tissue Damage664

Alanine Transports Ammonia from Skeletal Muscles to the Liver664

Ammonia Is Toxic to Animals665

18.2 Nitrogen Excretion and the Urea Cycle665

Urea Is Produced from Ammonia in Five Enzymatic Steps667

The Citric Acid and Urea Cycles Can Be Linked668

The Activity of the Urea Cycle Is Regulated at Two Levels669

Pathway Interconnections Reduce the Energetic Cost of Urea Synthesis669

Genetic Defects in the Urea Cycle Can Be Life-Threatening669

18.3 Pathways of Amino Acid Degradation671

Some Amino Acids Are Converted to Glucose, Others to Ketone Bodies671

Several Enzyme Cofactors Play Important Roles in Amino Acid Catabolism672

Six Amino Acids Are Degraded to Pyruvate674

Seven Amino Acids Are Degraded to Acetyl-CoA677

Phenylalanine Catabolism Is Genetically Defective in Some People679

Five Amino Acids Are Converted to α-Ketoglutarate681

Four Amino Acids Are Converted to Succinyl-CoA682

Branched-Chain Amino Acids Are Not Degraded in the Liver683

Box 18-2 Sclentlflc Sleuths Solve a Murder Mystery684

Asparagine and Aspartate Are Degraded to Oxaloacetate685

19 Oxidative Phosphorylation and Photophosphorylation690

OXIDATIVE PHOSPHORYLATION691

19.1 Electron-Transfer Reactions in Mitochondria691

Electrons Are Funneled to Universal Electron Acceptors692

Electrons Pass through a Series of Membrane-Bound Carriers693

Electron Carriers Function in Multienzyme Complexes696

The Energy of Electron Transfer Is Efficiently Conserved in a Proton Gradient701

Plant Mitochondria Have Alternative Mechanisms for Oxidizing NADH704

19.2 ATP Synthesis704

Box 19-1 Hot, Stlnklng Plants and Alternatlve Resplratory Pathways706

ATP Synthase Has Two Functional Domains,Fo and F1708

ATP Is Stabilized Relative to ADP on the Surface of F1708

The Proton Gradient Drives the Release of ATP from the Enzyme Surface709

Each β Subunit of ATP Synthase Can Assume Three Different Conformations709

Rotational Catalysis Is Key to the Binding-Change Mechanism for ATP Synthesis711

Chemiosmotic Coupling Allows Nonintegral Stoichiometries of O2 Consumption and ATP Synthesis712

The Proton-Motive Force Energizes Active Transport713

Shuttle Systems Indirectly Convey Cytosolic NADH into Mitochondria for Oxidation714

19.3 Regulation of Oxidative Phosphorylation716

Oxidative Phosphorylation Is Regulated by Cellular Energy Needs716

An Inhibitory Protein Prevents ATP Hydrolysis during Ischemia717

Uncoupled Mitochondria in Brown Fat Produce Heat717

ATP-Producing Pathways Are Coordinately Regulated718

19.4 Mitochondrial Genes: Their Origin and the Effects of Mutations719

Mutations in Mitochondrial Genes Cause Human Disease719

Mitochondria Evolved from Endosymbiotic Bacteria 72119.5 The Role of Mitochondria in Apoptosis and OxidativeStress 721PHOTOSYNTHESIS: HARVESTING LIGHT ENERGY 72319.6 General Features of Photophosphorylation723

Photosynthesis in Plants Takes Place in Chloroplasts724

Light Drives Electron Flow in Chloroplasts724

19.7 Light Absorption725

Chlorophylls Absorb Light Energy for Photosynthesis725

Accessory Pigments Extend the Range of Light Absorption728

Chlorophyll Funnels the Absorbed Energy to Reaction Centers by Exciton Transfer728

19.8 The Central Photochemical Event: Light-Driven Electron Flow730

Bacteria Have One of Two Types of Single Photochemical Reaction Center730

Kinetic and Thermodynamic Factors Prevent the Dissipation of Energy by Internal Conversion732

In Plants, Two Reaction Centers Act in Tandem733

Antenna Chlorophylls Are Tightly Integrated with Electron Carriers734

Spatial Separation of Photosystems Ⅰ and Ⅱ Prevents Exciton Larceny736

The Cytochrome b6 f Complex Links Photosystems Ⅱ and I737

Cyanobacteria Use the Cytochrome b6 f Complex and Cytochrome c6 in Both Oxidative Phosphorylation and Photophosphorylation738

Water Is Split by the Oxygen-Evolving Complex738

19.9 ATP Synthesis by Photophosphorylation740

A Proton Gradient Couples Electron Flow and Photophosphorylation740

The Approximate Stoichiometry of Photophosphorylation Has Been Established741

Cyclic Electron Flow Produces ATP but Not NADPH or O2741

The ATP Synthase of Chloroplasts Is Like That of Mitochondria742

Chloroplasts Evolved from Endosymbiotic Bacteria742

Diverse Photosynthetic Organisms Use Hydrogen Donors Other Than Water743

In Halophilic Bacteria, a Single Protein Absorbs Light and Pumps Protons to Drive ATP Synthesis743

20 Carbohydrate Biosynthesis in Plants and Bacteria751

20.1 Photosynthetic Carbohydrate Synthesis751

Plastids Are Organelles Unique to Plant Cells and Algae752

Carbon Dioxide Assimilation Occurs in Three Stages753

Synthesis of Each Triose Phosphate from CO2 Requires Six NADPH and Nine ATP762

A Transport System Exports Triose Phosphates from the Chloroplast and Imports Phosphate763

Four Enzymes of the Calvin Cycle Are Indirectly Activated by Light764

20.2 Photorespiration and the C4 and CAM Pathways766

Photorespiration Results from Rubisco's Oxygenase Activity766

The Salvage of Phosphoglycolate Is Costly767

In C4 Plants, CO2 Fixation and Rubisco Activity Are Spatially Separated769

In CAM Plants, CO2 Capture and Rubisco Action Are Temporally Separated770

20.3 Biosynthesis of Starch and Sucrose771

ADP-Glucose Is the Substrate for Starch Synthesis in Plant Plastids and for Glycogen Synthesis in Bacteria771

UDP-Glucose Is the Substrate for Sucrose Synthesis in the Cytosol of Leaf Cells771

Conversion of Triose Phosphates to Sucrose and Starch Is Tightly Regulated772

20.4 Synthesis of Cell Wall Polysaccharides: Plant Cellulose and Bacterial Peptidoglycan775

Cellulose Is Synthesized by Supramolecular Structures in the Plasma Membrane775

Lipid-Linked Oligosaccharides Are Precursors for Bacterial Cell Wall Synthesis777

Box 20-1 The Magic Bullet versus the Bulletproof Vest: Penicillin and β-Lactamase779

20.5 Integration of Carbohydrate Metabolism in the Plant Cell780

Gluconeogenesis Converts Fats and Proteins to Glucose in Germinating Seeds780

Pools of Common Intermediates Link Pathways in Different Organelles781

21 Lipid Biosynthesis787

21.1 Biosynthesis of Fatty Acids and Eicosanoids787

Malonyl-CoA Is Formed from Acetyl-CoA and Bicarbonate787

Fatty Acid Synthesis Proceeds in a Repeating Reaction Sequence788

The Fatty Acid Synthase Complex Has Seven Different Active Sites789

Fatty Acid Synthase Receives the Acetyl and Malonyl Groups790

The Fatty Acid Synthase Reactions Are Repeated to Form Palmitate791

The Fatty Acid Synthase of Some Organisms Consists of Multifunctional Proteins794

Fatty Acid Synthesis Occurs in the Cytosol of Many Organisms but in the Chloroplasts of Plants794

Acetate Is Shuttled out of Mitochondria as Citrate794

Fatty Acid Biosynthesis Is Tightly Regulated795

Long-Chain Saturated Fatty Acids Are Synthesized from Palmitate797

Desaturation of Fatty Acids Requires a Mixed-Function Oxidase798

Box 21-1 Mixed-Function Oxidases, Oxygenases, and Cytochrome P-450798

Eicosanoids Are Formed from 20-Carbon Polyunsaturated Fatty Acids800

Box 21-2 Relief Is in (the Active) Site: Cyclooxygenase Isozymes and the Search for a Better Aspirin802

21.2 Biosynthesis of Triacylglycerols804

Triacylglycerols and Glycerophospholipids Are Synthesized from the Same Precursors804

Triacylglycerol Biosynthesis in Animals Is Regulated by Hormones804

Adipose Tissue Generates Glycerol 3-phosphate by Glyceroneogenesis806

21.3 Biosynthesis of Membrane Phospholipids808

Cells Have Two Strategies for Attaching Phospholipid Head Groups809

Phospholipid Synthesis in E.coli Employs CDP-Diacylglycerol811

Eukaryotes Synthesize Anionic Phospholipids from CDP-Diacylglycerol811

Eukaryotic Pathways to Phosphatidylserine,Phosphatidylethanolamine, and Phosphatidylcholine Are Interrelated812

Plasmalogen Synthesis Requires Formation of an Ether-Linked Fatty Alcohol813

Sphingolipid and Glycerophospholipid Synthesis Share Precursors and Some Mechanisms813

Polar Lipids Are Targeted to Specific Cellular Membranes814

21.4 Biosynthesis of Cholesterol, Steroids, and Isoprenoids816

Cholesterol Is Made from Acetyl-CoA in Four Stages816

Cholesterol Has Several Fates820

Cholesterol and Other Lipids Are Carried on Plasma Lipoproteins820

Box 21-3 ApoE Alleles Predict Incidence of Alzheimer's Disease824

Cholesteryl Esters Enter Cells by Receptor-Mediated Endocytosis824

Cholesterol Biosynthesis Is Regulated at Several Levels825

Steroid Hormones Are Formed by Side-Chain Cleavage and Oxidation of Cholesterol827

Intermediates in Cholesterol Biosynthesis Have Many Alternative Fates828

22 Biosynthesis of Amino Acids, Nucleotides,and Related Molecules833

22.1 Overview of Nitrogen Metabolism834

The Nitrogen Cycle Maintains a Pool of Biologically Available Nitrogen834

Nitrogen Is Fixed by Enzymes of the Nitrogenase Complex834

Ammonia Is Incorporated into Biomolecules through Glutamate and Glutamine837

Glutamine Synthetase Is a Primary Regulatory Point in Nitrogen Metabolism838

Several Classes of Reactions Play Special Roles in the Biosynthesis of Amino Acids and Nucleotides840

22.2 Biosynthesis of Amino Acids841

α-Ketoglutarate Gives Rise to Glutamate, Glutamine, Proline,and Arginine842

Serine, Glycine, and Cysteine Are Derived from 3-Phospho-glycerate842

Three Nonessential and Six Essential Amino Acids Are Synthesized from Oxaloacetate and Pyruvate845

Chorismate Is a Key Intermediate in the Synthesis of Tryptophan, Phenylalanine, and Tyrosine849

Histidine Biosynthesis Uses Precursors of Purine Biosynthesis851

Amino Acid Biosynthesis Is under Allosteric Regulation851

22.3 Molecules Derived from Amino Acids854

Glycine Is a Precursor of Porphyrins854

Heme Is the Source of Bile Pigments854

Box 22-1 Blochemistry of Kings and Vampires857

Amino Acids Are Precursors of Creatine and Glutathione857

D-Amino Acids Are Found Primarily in Bacteria858

Aromatic Amino Acids Are Precursors of Many Plant Substances859

Biological Amines Are Products of Amino Acid Decarboxylation859

Arginine Is the Precursor for Biological Synthesis of Nitric Oxide860

Box 22-2 Curing African Sleeping Sickness wlth a Biochemical Trojan Horse862

22.4 Biosynthesis and Degradation of Nucleotides862

De Novo Purine Nucleotide Synthesis Begins with PRPP864

Purine Nucleotide Biosynthesis Is Regulated by Feedback Inhibition866

Pyrimidine Nucleotides Are Made from Aspartate, PRPP, and Carbamoyl Phosphate867

Pyrimidine Nucleotide Biosynthesis Is Regulated by Feedback Inhibition868

Nucleoside Monophosphates Are Converted to Nucleoside Triphosphates868

Ribonucleotides Are the Precursors of Deoxyribonucleotides869

Thymidylate Is Derived from dCDP and dUMP872

Degradation of Purines and Pyrimidines Produces Uric Acid and Urea, Respectively873

Purine and Pyrimidine Bases Are Recycled by Salvage Pathways875

Excess Uric Acid Causes Gout875

Many Chemotherapeutic Agents Target Enzymes in the Nucleotide Biosynthetic Pathways876

23 Hormonal Regulation and Integration of Mammalian Metabolism881

23.1 Hormones: Diverse Structures for Diverse Functions881

The Discovery and Purification of Hormones Require a Bioassay882

Box 23-1 How Is a Hormone Dlscovered? The Arduous Path to Purlfied Insulin883

Hormones Act through Specific High-Affinity Cellular Receptors884

Hormones Are Chemically Diverse886

Hormone Release Is Regulated by a Hierarchy of Neuronal and Hormonal Signals889

23.2 Tissue-Specific Metabolism: The Dlvision of Labor892

The Liver Processes and Distributes Nutrients893

Adipose Tissue Stores and Supplies Fatty Acids897

Muscles Use ATP for Mechanical Work898

The Brain Uses Energy for Transmission of Electrical Impulses900

Blood Carries Oxygen, Metabolites, and Hormones900

23.3 Hormonal Regulatlon of Fuel Metabollsm902

The Pancreas Secretes Insulin or Glucagonin Response to Changes in Blood Glucose902

Insulin Counters High Blood Glucose904

Glucagon Counters Low Blood Glucose904

During Fasting and Starvation, Metabolism Shifts to Provide Fuel for the Brain906

Epinephrine Signals Impending Activity908

Cortisol Signals Stress, Including Low Blood Glucose909

Diabetes Mellitus Arises from Defects in Insulin Production or Action909

23.4 Obesity and the Regulation of Body Mass910

The Lipostat Theory Predicts the Feedback Regulation of Adipose Tissue910

Leptin Stimulates Production of Anorexigenic Peptide Hormones912

Leptin Triggers a Signaling Cascade That Regulates Gene Expression913

The Leptin System May Have Evolved to Regulate the Starvation Response913

Insulin Acts in the Arcuate Nucleus to Regulate Eating and Energy Conservation914

Adiponectin Acts through AMPK914

Diet Regulates the Expression of Genes Central to Maintaining Body Mass915

Short-Term Eating Behavior Is Set by Ghrelin and PYY3-36916

Ⅲ INFORMATION PATHWAYS921

24 Genes and Chromosomes923

24.1 Chromosomal Elements924

Genes Are Segments of DNA That Code for Polypeptide Chains and RNAs924

DNA Molecules Are Much Longer Than the Cellular Packages That Contain Them925

Eukaryotic Genes and Chromosomes Are Very Complex928

24.2 DNA Supercoiling930

Most Cellular DNA Is Underwound932

DNA Underwinding Is Defined by Topological Linking Number933

Topoisomerases Catalyze Changes in the Linking Number of DNA935

DNA Compaction Requires a Special Form of Supercoiling937

24.3 The Structure of Chromosomes938

Chromatin Consists of DNA and Proteins938

Histones Are Small, Basic Proteins939

Nucleosomes Are the Fundamental Organizational Units of Chromatin940

Nucleosomes Are Packed into Successively Higher Order Structures942

Condensed Chromosome Structures Are Maintained by SMC Proteins943

Bacterial DNA Is Also Highly Organized943

25 DNA Metabolism948

25.1 DNA Replication950

DNA Replication Follows a Set of Fundamental Rules950

DNA Is Degraded by Nucleases952

DNA Is Synthesized by DNA Polymerases952

Replication Is Very Accurate954

E.coli Has at Least Five DNA Polymerases955

DNA Replication Requires Many Enzymes and Protein Factors957

Replication of the E.coli Chromosome Proceeds in Stages958

Bacterial Replication Is Organized in Membrane-Bound Replication Factories963

Replication in Eukaryotic Cells Is More Complex964

25.2 DNA Repair966

Mutations Are Linked to Cancer966

All Cells Have Multiple DNA Repair Systems967

Box 25-1 DNA Repair and Cancer970

The Interaction of Replication Forks with DNA Damage Can Lead to Error-Prone Translesion DNA Synthesis976

25.3 DNA Recombination978

Homologous Genetic Recombination Has Several Functions979

Recombination during Meiosis Is Initiated with Double-Strand Breaks980

Recombination Requires a Host of Enzymes and Other Proteins982

All Aspects of DNA Metabolism Come Together to Repair Stalled Replication Forks984

Site-Specific Recombination Results in Precise DNA Rearrangements984

Complete Chromosome Replication Can Require Site-Specific Recombination988

Transposable Genetic Elements Move from One Location to Another988

Immunoglobulin Genes Assemble by Recombination990

26 RNA Metabolism995

26.1 DNA-Dependent Synthesis of RNA996

RNA Is Synthesized by RNA Polymerases996

RNA Synthesis Begins at Promoters998

Transcription Is Regulated at Several Levels1001

Specific Sequences Signal Termination of RNA Synthesis1001

Box 26-1 RNA Polymerase Leaves Its Footprint on a Promoter1002

Eukaryotic Cells Have Three Kinds of Nuclear RNA Polymerases1003

RNA Polymerase Ⅱ Requires Many Other Protein Factors for Its Activity1003

DNA-Dependent RNA Polymerase Undergoes Selective Inhibition1006

26.2 RNA Processing1007

Eukaryotic mRNAs Are Capped at the 5' End1008

Both Introns and Exons Are Transcribed from DNA into RNA1008

RNA Catalyzes the Splicing of Introns1009

Eukaryotic mRNAs Have a Distinctive 3' End Structure1011

A Gene Can Give Rise to Multiple Products by Differential RNA Processing1014

Ribosomal RNAs and tRNAs Also Undergo Processing1014

RNA Enzymes Are the Catalysts of Some Events in RNA Metabolism1017

Cellular mRNAs Are Degraded at Different Rates1020

Polynucleotide Phosphorylase Makes Random RNA-like Polymers1020

26.3 RNA-Dependent Synthesis of RNA and DNA1021

Reverse Transcriptase Produces DNA from Viral RNA1021

Some Retroviruses Cause Cancer and AIDS1023

Many Transposons, Retroviruses, and Introns May Have a Common Evolutionary Origin1023

Box 26-2 Fighting AIDS with Inhibitors of HIV Reverse Transcriptase1024

Telomerase Is a Specialized Reverse Transcriptase1025

Some Viral RNAs Are Replicated by RNA-Dependent RNA Polymerase1027

RNA Synthesis Offers Important Clues to Biochemical Evolution1027

Box 26-3 The SELEX Method for Generating RNA Polymers with New Functlons1030

27 Protein Metabolism1034

27.1 The Genetic Code1034

The Genetic Code Was Cracked Using Artificial mRNA Templates1035

Wobble Allows Some tRNAs to Recognize More than One Codon1039

Box 27-1 Changing Horses in Midstream: Translational Frameshiftlng and mRNA Editing1040

Box 27-2 Exceptions That Prove the Rule: Natural Variations In the Genetic Code1042

27.2 Protein Synthesis1044

Protein Biosynthesis Takes Place in Five Stages1044

The Ribosome Is a Complex Supramolecular Machine1045

Box 27-3 From an RNA World to a Protein World1048

Transfer RNAs Have Characteristic Structural Features1049

Stage 1: Aminoacyl-tRNA Synthetases Attach the Correct Amino Acids to Their tRNAs1051

Stage 2: A Specific Amino Acid Initiates Protein Synthesis1054

Stage 3: Peptide Bonds Are Formed in the Elongation Stage1058

Stage 4: Termination of Polypeptide Synthesis Requires a Special Signal1061

Stage 5: Newly Synthesized Polypeptide Chains Undergo Folding and Processing1062

Box 27-4 Induced Varlatlon in the Genetlc Code: Nonsense Suppresslon1065

Protein Synthesis Is Inhibited by Many Antibiotics and Toxins1065

27.3 Protein Targeting and Degradation1068

Post translational Modification of Many Eukaryotic Proteins Begins in the Endoplasmic Reticulum1068

Glycosylation Plays a Key Role in Protein Targeting1069

Signal Sequences for Nuclear Transport Are Not Cleaved1071

Bacteria Also Use Signal Sequences for Protein Targeting1072

Cells Import Proteins by Receptor-Mediated Endocytosis1074

Protein Degradation Is Mediated by Specialized Systems in All Cells1075

28 Regulation of Gene Expression1081

28.1 Principles of Gene Regulation1082

RNA Polymerase Binds to DNA at Promoters1082

Transcription Initiation Is Regulated by Proteins That Bind to or Near Promoters1083

Many Prokaryotic Genes Are Clustered and Regulated in Operons1085

The lac Operon Is Subject to Negative Regulation1085

Regulatory Proteins Have Discrete DNA-Binding Domains1087

Regulatory Proteins Also Have Protein-Protein Interaction Domains1090

28.2 Regulation of Gene Expression in Prokaryotes1092

The lac Operon Undergoes Positive Regulation1093

Many Genes for Amino Acid Biosynthetic Enzymes Are Regulated by Transcription Attenuation1094

Induction of the SOS Response Requires Destruction of Repressor Proteins1097

Synthesis of Ribosomal Proteins Is Coordinated with rRNA Synthesis1098

Some Genes Are Regulated by Genetic Recombination1100

28.3 Regulation of Gene Expression in Eukaryotes1102

Transcriptionally Active Chromatin Is Structurally Distinct from Inactive Chromatin1102

Chromatin Is Remodeled by Acetylation and Nucleosomal Displacements1103

Many Eukaryotic Promoters Are Positively Regulated1103

DNA-Binding Transactivators and Coactivators Facilitate Assembly of the General Transcription Factors1104

The Genes of Galactose Metabolism in Yeast Are Subject to Both Positive and Negative Regulation1106

DNA-Binding Transactivators Have a Modular Structure1106

Eukaryotic Gene Expression Can Be Regulated by Intercellular and Intracellular Signals1108

Regulation Can Result from Phosphorylation of Nuclear Transcription Factors1109

Many Eukaryotic mRNAs Are Subject to Translational Repression1109

Posttranscriptional Gene Silencing Is Mediated by RNA Interference1110

Development Is Controlled by Cascades of Regulatory Proteins1111

Appendix A Common Abbreviations in the Biochemical Research Literature A-11148

Appendix B Abbreviated Solutions to Problems AS-11152

Glossary G-11121

Credits C-11139

Index I-11174

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