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PART I The Molecular Design of Life

SECTION 1 Biochemistry Helps Us to Understand Our World

1

Chapter 1 Biochemistry and the Unity of Life

3

1.1

Living Systems Require a Limited Variety of Atoms and Molecules

4

1.2

There Are Four Major Classes of Biomolecules

5

 

Proteins Are Highly Versatile Biomolecules

5

 

Nucleic Acids Are the Information Molecules of the Cell

6

 

Lipids Are a Storage Form of Fuel and Serve as a Barrier

6

 

Carbohydrates Are Fuels and Informational Molecules

7

1.3

The Central Dogma Describes the Basic Principles of Biological Information Transfer

7

1.4

Membranes Define the Cell and Carry Out Cellular Functions

8

 

Biochemical Functions Are Sequestered in Cellular Compartments

11

 

Some Organelles Process and Sort Proteins and Exchange Material with the Environment

12

Clinical Insight Defects in Organelle Function May Lead to Disease

14

Chapter 2 Water, Weak Bonds, and the Generation of Order Out of Chaos

17

2.1

Thermal Motions Power Biological Interactions

18

2.2

Biochemical Interactions Take Place in an Aqueous Solution

18

2.3

Weak Interactions Are Important Biochemical Properties

20

 

Electrostatic Interactions Are Between Electrical Charges

20

 

Hydrogen Bonds Form Between an Electronegative Atom and Hydrogen

21

 

van der Waals Interactions Depend on Transient Asymmetry in Electrical Charge

21

 

Weak Bonds Permit Repeated Interactions

22

2.4

Hydrophobic Molecules Cluster Together

22

 

Membrane Formation Is Powered by the Hydrophobic Effect

23

 

Protein Folding Is Powered by the Hydrophobic Effect

24

 

Functional Groups Have Specific Chemical Properties

24

2.5

pH Is an Important Parameter of Biochemical Systems

26

 

Water Ionizes to a Small Extent

26

 

An Acid Is a Proton Donor, Whereas a Base Is a Proton Acceptor

27

 

Acids Have Differing Tendencies to Ionize

27

 

Buffers Resist Changes in pH

28

 

Buffers Are Crucial in Biological Systems

29

 

Making Buffers Is a Common Laboratory Practice

30

SECTION 2 Protein Composition and Structure

35

Chapter 3 Amino Acids

37

Two Different Ways of Depicting Biomolecules Will Be Used

38

3.1

Proteins Are Built from a Repertoire of 20 Amino Acids

38

 

Most Amino Acids Exist in Two Mirror-Image Forms

38

 

All Amino Acids Have at Least Two Charged Groups

38

3.2

Amino Acids Contain a Wide Array of Functional Groups

39

 

Hydrophobic Amino Acids Have Mainly Hydrocarbon Side Chains

39

 

Polar Amino Acids Have Side Chains That Contain an Electronegative Atom

41

 

Positively Charged Amino Acids Are Hydrophilic

42

 

Negatively Charged Amino Acids Have Acidic Side Chains

43

 

The Ionizable Side Chains Enhance Reactivity and Bonding

43

3.3

Essential Amino Acids Must Be Obtained from the Diet

44

Clinical Insight Pathological Conditions Result If Protein Intake Is Inadequate

44

Chapter 4 Protein Three-Dimensional Structure

47

4.1

Primary Structure: Amino Acids Are Linked by Peptide Bonds to Form Polypeptide Chains

48

 

Proteins Have Unique Amino Acid Sequences Specified by Genes

49

 

Polypeptide Chains Are Flexible Yet Conformationally Restricted

50

4.2

Secondary Structure: Polypeptide Chains Can Fold into Regular Structures

52

 

The Alpha Helix Is a Coiled Structure Stabilized by Intrachain Hydrogen Bonds

52

 

Beta Sheets Are Stabilized by Hydrogen Bonding Between Polypeptide Strands

53

 

Polypeptide Chains Can Change Direction by Making Reverse Turns and Loops

55

 

Fibrous Proteins Provide Structural Support for Cells and Tissues

55

Clinical Insight Defects in Collagen Structure Result in Pathological Conditions

57

4.3

Tertiary Structure: Water-Soluble Proteins Fold into Compact Structures

57

 

Myoglobin Illustrates the Principles of Tertiary Structure

57

 

The Tertiary Structure of Many Proteins Can Be Divided into Structural and Functional Units

59

4.4

Quaternary Structure: Multiple Polypeptide Chains Can Assemble into a Single Protein

59

4.5

The Amino Acid Sequence of a Protein Determines Its Three-Dimensional Structure

60

 

Proteins Fold by the Progressive Stabilization of Intermediates Rather Than by Random Search

61

 

Some Proteins Are Inherently Unstructured and Can Exist in Multiple Conformations

62

Clinical Insight Protein Misfolding and Aggregation Are Associated with Some Neurological Diseases

63

Chapter 5 Techniques in Protein Biochemistry

69

5.1

The Proteome Is the Functional Representation of the Genome

70

5.2

The Purification of a Protein Is the First Step in Understanding Its Function

70

 

Proteins Can Be Purified on the Basis of Differences in Their Chemical Properties

71

 

Proteins Must Be Removed from the Cell to Be Purified

71

 

Proteins Can Be Purified According to Solubility, Size, Charge, and Binding Affinity

72

 

Proteins Can Be Separated by Gel Electrophoresis and Displayed

74

 

A Purification Scheme Can Be Quantitatively Evaluated

77

5.3

Immunological Techniques Are Used to Purify and Characterize Proteins

78

 

Centrifugation Is a Means of Separating Proteins

78

 

Gradient Centrifugation Provides an Assay for the Estradiol–Receptor Complex

79

 

Antibodies to Specific Proteins Can Be Generated

80

 

Monoclonal Antibodies with Virtually Any Desired Specificity Can Be Readily Prepared

81

 

The Estrogen Receptor Can Be Purified by Immunoprecipitation

83

 

Proteins Can Be Detected and Quantified with the Use of an Enzyme-Linked Immunosorbent Assay

84

 

Western Blotting Permits the Detection of Proteins Separated by Gel Electrophoresis

84

5.4

Determination of Primary Structure Facilitates an Understanding of Protein Function

86

 

Mass Spectrometry Can Be Used to Determine a Protein’s Mass, Identity, and Sequence

88

 

Amino Acids Are Sources of Many Kinds of Insight

90

SECTION 3 Basic Concepts and Kinetics of Enzymes

95

Chapter 6 Basic Concepts of Enzyme Action

97

6.1

Enzymes Are Powerful and Highly Specific Catalysts

97

 

Proteolytic Enzymes Illustrate the Range of Enzyme Specificity

98

 

There Are Six Major Classes of Enzymes

98

6.2

Many Enzymes Require Cofactors for Activity

99

6.3

Gibbs Free Energy Is a Useful Thermodynamic Function for Understanding Enzymes

100

 

The Free-Energy Change Provides Information About the Spontaneity but Not the Rate of a Reaction

100

 

The Standard Free-Energy Change of a Reaction Is Related to the Equilibrium Constant

101

 

Enzymes Alter the Reaction Rate but Not the Reaction Equilibrium

102

6.4

Enzymes Facilitate the Formation of the Transition State

103

 

The Formation of an Enzyme–Substrate Complex Is the First Step in Enzymatic Catalysis

103

 

The Active Sites of Enzymes Have Some Common Features

104

 

The Binding Energy Between Enzyme and Substrate Is Important for Catalysis

105

 

Transition-State Analogs Are Potent Inhibitors of Enzyme

106

Chapter 7 Kinetics and Regulation

111

7.1

Kinetics Is the Study of Reaction Rates

112

7.2

The Michaelis–Menten Model Describes the Kinetics of Many Enzymes

113

Clinical Insight Variations in KM Can Have Physiological Consequences

114

 

KM and Vmax Values Can Be Determined by Several Means

115

 

KM and Vmax Values Are Important Enzyme Characteristics

115

 

kcat/KM Is a Measure of Catalytic Efficiency

116

 

Most Biochemical Reactions Include Multiple Substrates

117

7.3

Allosteric Enzymes Are Catalysts and Information Sensors

118

 

Allosteric Enzymes Are Regulated by Products of the Pathways Under Their Control

120

 

Allosterically Regulated Enzymes Do Not Conform to Michaelis–Menten Kinetics

121

 

Allosteric Enzymes Depend on Alterations in Quaternary Structure

121

 

Regulator Molecules Modulate the R ⇌ T Equilibrium

122

 

The Sequential Model Also Can Account for Allosteric Effects

123

Clinical Insight Loss of Allosteric Control May Result in Pathological Conditions

123

7.4

Enzymes Can Be Studied One Molecule at a Time

123

Chapter 8 Mechanisms and Inhibitors

131

8.1

A Few Basic Catalytic Strategies Are Used by Many Enzymes

131

8.2

Enzyme Activity Can Be Modulated by Temperature, pH, and Inhibitory Molecules

132

 

Temperature Enhances the Rate of Enzyme-Catalyzed Reactions

132

 

Most Enzymes Have an Optimal pH

133

 

Enzymes Can Be Inhibited by Specific Molecules

134

 

Reversible Inhibitors Are Kinetically Distinguishable

135

 

Irreversible Inhibitors Can Be Used to Map the Active Site

137

Clinical Insight Penicillin Irreversibly Inactivates a Key Enzyme in Bacterial Cell-Wall Synthesis

138

8.3

Chymotrypsin Illustrates Basic Principles of Catalysis and Inhibition

140

 

Serine 195 Is Required for Chymotrypsin Activity

140

 

Chymotrypsin Action Proceeds in Two Steps Linked by a Covalently Bound Intermediate

 

 

The Catalytic Role of Histidine 57 Was Demonstrated by Affinity Labeling

140

 

Serine Is Part of a Catalytic Triad That Includes Histidine and Aspartic Acid

142

Chapter 9 Hemoglobin, an Allosteric Protein

149

9.1

Hemoglobin Displays Cooperative Behavior

150

9.2

Myoglobin and Hemoglobin Bind Oxygen in Heme Groups

150

Clinical Insight Functional Magnetic Resonance Imaging Reveals Regions of the Brain Processing Sensory Information

152

9.3

Hemoglobin Binds Oxygen Cooperatively

152

9.4

An Allosteric Regulator Determines the Oxygen Affinity of Hemoglobin

154

Clinical Insight Hemoglobin’s Oxygen Affinity Is Adjusted to Meet Environmental Needs

154

Biological Insight Hemoglobin Adaptations Allow Oxygen Transport in Extreme Environments

155

9.5

Hydrogen Ions and Carbon Dioxide Promote the Release of Oxygen

155

9.6

Mutations in Genes Encoding Hemoglobin Subunits Can Result in Disease

156

Clinical Insight Sickle-Cell Anemia Is a Disease Caused by a Mutation in Hemoglobin

157

NEW Clinical Insight Thalassemia is Caused by an Imbalanced Production of Hemoglobin Chains

159

SECTION 4 Carbohydrates and Lipids

165

Chapter 10 Carbohydrates

167

10.1

Monosaccharides Are the Simplest Carbohydrates

168

 

Many Common Sugars Exist in Cyclic Forms

169

NEW

Pyranose and Furanose Rings Can Assume Different Conformations

171

NEW Clinical Insight Glucose Is a Reducing Sugar

171

 

Monosaccharides Are Joined to Alcohols and Amines Through Clycosidic Bonds

172

Biological Insight Glucosinolates Protect Plants and Add Flavor to Our Diets

173

10.2

Monosaccharides Are Linked to Form Complex Carbohydrates

173

 

Specific Enzymes Are Responsible for Oligosaccharide Assembly

173

 

Sucrose, Lactose, and Maltose Are the Common Disaccharides

174

 

Glycogen and Starch Are Storage Forms of Glucose

175

 

Cellulose, a Structural Component of Plants, Is Made of Chains of Glucose

175

10.3

Carbohydrates Are Attached to Proteins to Form Glycoproteins

177

 

Carbohydrates May Be Linked to Asparagine, Serine, or Threonine Residues of Proteins

177

Clinical Insight The Hormone Erythropoietin Is a Glycoprotein

178

 

Proteoglycans, Composed of Polysaccharides and Protein, Have Important Structural Roles

178

Clinical Insight Proteoglycans Are Important Components of Cartilage

179

Clinical Insight Mucins Are Glycoprotein Components of Mucus

180

Biological Insight Blood Groups Are Based on Protein Glycosylation Patterns

181

Clinical Insight Lack of Glycosylation Can Result in Pathological Conditions

182

10.4

Lectins Are Specific Carbohydrate-Binding Proteins

182

 

Lectins Promote Interactions Between Cells

183

Clinical Insight Lectins Facilitate Embryonic Development

183

Clinical Insight Influenza Virus Binds to Sialic Acid Residues

183

Chapter 11 Lipids

189

11.1

Fatty Acids Are a Main Source of Fuel

190

 

Fatty Acids Vary in Chain Length and Degree of Unsaturation

191

 

The Degree and Type of Unsaturation Are Important to Health

192

11.2

Triacylglycerols Are the Storage Form of Fatty Acids

193

11.3

There Are Three Common Types of Membrane Lipids

194

 

Phospholipids Are the Major Class of Membrane Lipids

194

 

Membrane Lipids Can Include Carbohydrates

196

 

Steroids Are Lipids That Have a Variety of Roles

196

Biological Insight Membranes of Extremophiles Are Built from Ether Lipids with Branched Chains

197

 

Membrane Lipids Contain a Hydrophilic and a Hydrophobic Moiety

197

 

Some Proteins Are Modified by the Covalent Attachment of Hydrophobic Groups

198

Clinical Insight Premature Aging Can Result from the Improper Attachment of a Hydrophobic Group to a Protein

199

SECTION 5 Cell Membranes, Channels, Pumps, and Receptors

203

Chapter 12 Membrane Structure and Function

205

12.1

Phospholipids and Glycolipids Form Bimolecular Sheets

206

Clinical Insight Lipid Vesicles Can Be Formed from Phospholipids

207

 

Lipid Bilayers Are Highly Impermeable to Ions and Most Polar Molecules

207

12.2

Membrane Fluidity Is Controlled by Fatty Acid Composition and Cholesterol Content

208

12.3

Proteins Carry Out Most Membrane Processes

209

 

Proteins Associate with the Lipid Bilayer in a Variety of Ways

209

Clinical Insight The Association of Prostaglandin H2 Synthase-I with the Membrane Accounts for the Action of Aspirin

211

12.4

Lipids and Many Membrane Proteins Diffuse Laterally in the Membrane

211

12.5

A Major Role of Membrane Proteins Is to Function As Transporters

212

 

The Na+–K+ ATPase Is an Important Pump in Many Cells

213

Clinical Insight Multidrug Resistance Highlights a Family of Membrane Pumps with ATP-Binding Domains

214

Clinical Insight Harlequin Ichthyosis Is a Dramatic Result of a Mutation in an ABC Transporter Protein

214

 

Secondary Transporters Use One Concentration Gradient to Power the Formation of Another

214

Clinical Insight Digitalis Inhibits the Na+-K+ Pump by Blocking Its Dephosphorylation

215

 

Specific Channels Can Rapidly Transport Ions Across Membranes

216

 

Biological Insight Venomous Pit Vipers Use Ion Channels to Generate a Thermal Image

216

 

The Structure of the Potassium Ion Channel Reveals the Basis of Ion Specificity

216

 

The Structure of the Potassium Ion Channel Explains Its Rapid Rate of Transport

218

Chapter 13 Signal-Transduction Pathways

225

13.1

Signal Transduction Depends on Molecular Circuits

225

13.2

Receptor Proteins Transmit Information into the Cell

227

 

Seven-Transmembrane-Helix Receptors Change Conformation in Response to Ligand Binding and Activate G Proteins

227

 

Ligand Binding to 7TM Receptors Leads to the Activation of G Proteins

228

 

Activated G Proteins Transmit Signals by Binding to Other Proteins

229

 

Cyclic AMP Stimulates the Phosphorylation of Many Target Proteins by Activating Protein Kinase A

229

NEW Clinical Insight Mutations in Protein Kinase A Can Cause Cushing’s Syndrome

230

 

G Proteins Spontaneously Reset Themselves Through GTP Hydrolysis

230

Clinical Insight Cholera and Whooping Cough Are Due to Altered G-Protein Activity

231

 

The Hydrolysis of Phosphatidylinositol Bisphosphate by Phospholipase C Generates Two Second Messengers

232

13.3

Some Receptors Dimerize in Response to Ligand Binding and Recruit Tyrosine Kinases

233

 

Receptor Dimerization May Result in Tyrosine Kinase Recruitment

233

Clinical Insight Some Receptors Contain Tyrosine Kinase Domains Within Their Covalent Structures

235

 

Ras Belongs to Another Class of Signaling G Proteins

236

13.4

Metabolism in Context: Insulin Signaling Regulates Metabolism

236

 

The Insulin Receptor Is a Dimer That Closes Around a Bound Insulin Molecule

236

 

The Activated Insulin-Receptor Kinase Initiates a Kinase Cascade

237

 

Insulin Signaling Is Terminated by the Action of Phosphatases

238

13.5

Calcium Ion Is a Ubiquitous Cytoplasmic Messenger

238

13.6

Defects in Signaling Pathways Can Lead to Diseases

239

Clinical Insight The Conversion of Proto-oncogenes into Oncogenes Disrupts the Regulation of Cell Growth

239

Clinical Insight Protein Kinase Inhibitors May Be Effective Anticancer Drugs

240

PART II Transducing and Storing Energy

 

SECTION 6 Basic Concepts and Design of Metabolism

245

Chapter 14 Digestion: Turning a Meal into Cellular Biochemicals

247

14.1

Digestion Prepares Large Biomolecules for Use in Metabolism

247

 

Most Digestive Enzymes Are Secreted as Inactive Precursors

248

14.2

Proteases Digest Proteins into Amino Acids and Peptides

248

NEW Clinical Insight Protein Digestion Begins in the Stomach

248

NEW

Protein Digestion Continues in the Intestine

249

NEW Clinical Insight Celiac Disease Results from the Inability to Properly Digest Certain Proteins

251

14.3

Dietary Carbohydrates Are Digested by Alpha-Amylase

251

14.4

The Digestion of Lipids Is Complicated by Their Hydrophobicity

252

Biological Insight Snake Venoms Digest from the Inside Out

254

Chapter 15 Metabolism: Basic Concepts and Design

257

15.1

Energy Is Required to Meet Three

 

NEW

Fundamental Needs

258

15.2

Metabolism Is Composed of Many Interconnecting Reactions

258

 

Metabolism Consists of Energy-Yielding Reactions and Energy-Requiring Reactions

259

 

A Thermodynamically Unfavorable Reaction Can Be Driven by a Favorable Reaction

260

15.3

ATP Is the Universal Currency of Free Energy

260

 

ATP Hydrolysis Is Exergonic

261

 

ATP Hydrolysis Drives Metabolism by Shifting the Equilibrium of Coupled Reactions

261

 

The High Phosphoryl-Transfer Potential of ATP Results from Structural Differences Between ATP and Its Hydrolysis Products

263

 

Phosphoryl-Transfer Potential Is an Important Form of Cellular Energy Transformation

264

Clinical Insight Exercise Depends on Various Means of Generating ATP

265

 

Phosphates Play a Prominent Role in Biochemical Processes

266

15.4

The Oxidation of Carbon Fuels Is an Important Source of Cellular Energy

266

 

Carbon Oxidation Is Paired with a Reduction

266

 

Compounds with High Phosphoryl-Transfer Potential Can Couple Carbon Oxidation to ATP Synthesis

267

15.5

Metabolic Pathways Contain Many Recurring Motifs

268

 

Activated Carriers Exemplify the Modular Design and Economy of Metabolism

268

Clinical Insight Lack of Activated Pantothenate Results in Neurological Problems

271

 

Many Activated Carriers Are Derived from Vitamins

271

15.6

Metabolic Processes Are Regulated in Three Principal Ways

273

 

The Amounts of Enzymes Are Controlled

274

 

Catalytic Activity Is Regulated

274

 

The Accessibility of Substrates Is Regulated

275

SECTION 7 Glycolysis and Gluconeogenesis

281

Chapter 16 Glycolysis

283

16.1

Glycolysis Is an Energy-Conversion Pathway

284

 

Hexokinase Traps Glucose in the Cell and Begins Glycolysis

284

 

Fructose 1,6-bisphosphate Is Generated from Glucose 6-phosphate

286

Clinical Insight The Six-Carbon Sugar Is Cleaved into Two Three-Carbon Fragments

287

 

The Oxidation of an Aldehyde Powers the Formation of a Compound Having High Phosphoryl-Transfer Potential

288

 

ATP Is Formed by Phosphoryl Transfer from 1,3-Bisphosphoglycerate

289

 

Additional ATP Is Generated with the Formation of Pyruvate

290

 

Two ATP Molecules Are Formed in the Conversion of Glucose into Pyruvate

291

16.2

NAD+ Is Regenerated from the Metabolism of Pyruvate

291

 

Fermentations Are a Means of Oxidizing NADH

292

Biological Insight Fermentations Provide Usable Energy in the Absence of Oxygen

294

16.3

Fructose and Galactose Are Converted into Glycolytic Intermediates

294

NEW

Fructose Is Converted into Glycolytic Intermediates by Fructokinase

295

NEW Clinical Insight Excessive Fructose Consumption Can Lead to Pathological Conditions

295

NEW

Galactose Is Converted into Glucose 6-phosphate

296

Clinical Insight Many Adults Are Intolerant of Milk Because They Are Deficient in Lactase

297

Clinical Insight Galactose Is Highly Toxic If the Transferase Is Missing

298

16.4

The Glycolytic Pathway Is Tightly Controlled

299

 

Glycolysis in Muscle Is Regulated by Feedback Inhibition to Meet the Need for ATP

299

 

The Regulation of Glycolysis in the Liver Corresponds to the Biochemical Versatility of the Liver

300

 

A Family of Transporters Enables Glucose to Enter and Leave Animal Cells

303

NEW Clinical Insight Aerobic Glycolysis Is a Property of Rapidly Growing Cells

304

Clinical Insight Cancer and Exercise Training Affect Glycolysis in a Similar Fashion

305

16.5

Metabolism in Context: Glycolysis Helps Pancreatic Beta Cells Sense Glucose

305

Chapter 17 Gluconeogenesis

313

17.1

Glucose Can Be Synthesized from Noncarbohydrate Precursors

314

 

Gluconeogenesis Is Not a Complete Reversal of Glycolysis

314

 

The Conversion of Pyruvate into Phosphoenolpyruvate Begins with the Formation of Oxaloacetate

316

 

Oxaloacetate Is Shuttled into the Cytoplasm and Converted into Phosphoenolpyruvate

317

 

The Conversion of Fructose 1,6-bisphosphate into Fructose 6-phosphate and Orthophosphate Is an Irreversible Step

318

 

The Generation of Free Glucose Is an Important Control Point

319

 

Six High-Transfer-Potential Phosphoryl Groups Are Spent in Synthesizing Glucose from Pyruvate

319

17.2

Gluconeogenesis and Glycolysis Are Reciprocally Regulated

320

 

Energy Charge Determines Whether Glycolysis or Gluconeogenesis Will Be More Active

320

 

The Balance Between Glycolysis and Gluconeogenesis in the Liver Is Sensitive to Blood-Glucose Concentration

321

Clinical Insight Insulin Fails to Inhibit Gluconeogenesis in Type 2 Diabetes

323

Clinical Insight Substrate Cycles Amplify Metabolic Signals

323

17.3

Metabolism in Context: Precursors Formed by Muscle Are Used by Other Organs

324

SECTION 8 The Citric Acid Cycle

329

Chapter 18 Preparation for the Cycle

331

18.1

Pyruvate Dehydrogenase Forms Acetyl Coenzyme A from Pyruvate

332

 

The Synthesis of Acetyl Coenzyme A from Pyruvate Requires Three Enzymes and Five Coenzymes

333

 

Flexible Linkages Allow Lipoamide to Move Between Different Active Sites

335

18.2

The Pyruvate Dehydrogenase Complex Is Regulated by Two Mechanisms

337

Clinical Insight Defective Regulation of Pyruvate Dehydrogenase Results in Lactic Acidosis

338

Clinical Insight Enhanced Pyruvate Dehydrogenase Kinase Activity Facilitates the Development of Cancer

339

Clinical Insight The Disruption of Pyruvate Metabolism Is the Cause of Beriberi

339

Chapter 19 Harvesting Electrons from the Cycle

343

19.1

The Citric Acid Cycle Consists of Two Stages

344

19.2

Stage One Oxidizes Two Carbon Atoms to Gather Energy-Rich Electrons

344

 

Citrate Synthase Forms Citrate from Oxaloacetate and Acetyl Coenzyme A

344

 

The Mechanism of Citrate Synthase Prevents Undesirable Reactions

345

 

Citrate Is Isomerized into Isocitrate

346

 

Isocitrate Is Oxidized and Decarboxylated to Alpha-Ketoglutarate

346

 

Succinyl Coenzyme A Is Formed by the Oxidative Decarboxylation of Alpha-Ketoglutarate

347

19.3

Stage Two Regenerates Oxaloacetate and Harvests Energy-Rich Electrons

347

 

A Compound with High Phosphoryl-Transfer Potential Is Generated from Succinyl Coenzyme A

347

 

Succinyl Coenzyme A Synthetase Transforms Types of Biochemical Energy

348

 

Oxaloacetate Is Regenerated by the Oxidation of Succinate

349

 

The Citric Acid Cycle Produces High-Transfer-Potential Electrons, an ATP, and Carbon Dioxide

349

19.4

The Citric Acid Cycle Is Regulated

352

 

The Citric Acid Cycle Is Controlled at Several Points

352

 

The Citric Acid Cycle Is a Source of Biosynthetic Precursors

353

 

The Citric Acid Cycle Must Be Capable of Being Rapidly Replenished

353

Clinical Insight Defects in the Citric Acid Cycle Contribute to the Development of Cancer

354

19.5

The Glyoxylate Cycle Enables Plants and Bacteria to Convert Fats into Carbohydrates

355

SECTION 9 Oxidative Phosphorylation

361

Chapter 20 The Electron-Transport Chain

363

20.1

Oxidative Phosphorylation in Eukaryotes Takes Place in Mitochondria

364

 

Mitochondria Are Bounded by a Double Membrane

364

Biological Insight Mitochondria Are the Result of an Endosymbiotic Event

365

20.2

Oxidative Phosphorylation Depends on Electron Transfer

366

 

The Electron-Transfer Potential of an Electron Is Measured as Redox Potential

366

 

Electron Flow Through the Electron-Transport Chain Creates a Proton Gradient

367

 

The Electron-Transport Chain Is a Series of Coupled Oxidation–Reduction Reactions

368

NEW Clinical Insight Loss of Iron-Sulfur Cluster Results in Friedreich’s Ataxia

371

20.3

The Respiratory Chain Consists of Proton Pumps and a Physical Link to the Citric Acid Cycle

371

 

The High-Potential Electrons of NADH Enter the Respiratory Chain at NADH-Q Oxidoreductase

371

 

Ubiquinol Is the Entry Point for Electrons from FADH2 of Flavoproteins

373

 

Electrons Flow from Ubiquinol to Cytochrome c Through Q-Cytochrome c Oxidoreductase

373

 

The Q Cycle Funnels Electrons from a Two-Electron Carrier to a One-Electron Carrier and Pumps Protons

374

 

Cytochrome c Oxidase Catalyzes the Reduction of Molecular Oxygen to Water

375

Biological Insight The Dead Zone: Too Much Respiration

377

 

Toxic Derivatives of Molecular Oxygen Such As Superoxide Radical Are Scavenged by Protective Enzymes

377

Chapter 21 The Proton-Motive Force

383

21.1

A Proton Gradient Powers the Synthesis of ATP

384

 

ATP Synthase Is Composed of a Proton-Conducting Unit and a Catalytic Unit

385

 

Proton Flow Through ATP Synthase Leads to the Release of Tightly Bound ATP

386

 

Rotational Catalysis Is the World’s Smallest Molecular Motor

387

 

Proton Flow Around the c Ring Powers ATP Synthesis

388

21.2

Shuttles Allow Movement Across Mitochondrial Membranes

390

 

Electrons from Cytoplasmic NADH Enter Mitochondria by Shuttles

390

 

The Entry of ADP into Mitochondria Is Coupled to the Exit of ATP

392

 

Mitochondrial Transporters Allow Metabolite Exchange Between the Cytoplasm and Mitochondria

393

21.3

Cellular Respiration Is Regulated by the Need for ATP

393

 

The Complete Oxidation of Glucose Yields About 30 Molecules of ATP

393

 

The Rate of Oxidative Phosphorylation Is Determined by the Need for ATP

395

NEW Clinical Insight ATP Synthase Can Be Regulated

395

Biological Insight Regulated Uncoupling Leads to the Generation of Heat

396

Clinical Insight Oxidative Phosphorylation Can Be Inhibited at Many Stages

398

Clinical Insight Mitochondrial Diseases Are Being Discovered in Increasing Numbers

399

 

Power Transmission by Proton Gradients Is a Central Motif of Bioenergetics

400

SECTION 10 The Light Reactions of Photosynthesis and the Calvin Cycle

405

Chapter 22 The Light Reactions

407

22.1

Photosynthesis Takes Place in Chloroplasts

408

Biological Insight Chloroplasts, Like Mitochondria, Arose from an Endosymbiotic Event

409

22.2

Photosynthesis Transforms Light Energy into Chemical Energy

409

 

Chlorophyll Is the Primary Receptor in Most Photosynthetic Systems

410

 

Light-Harvesting Complexes Enhance the Efficiency of Photosynthesis

411

Biological Insight Chlorophyll in Potatoes Suggests the Presence of a Toxin

413

22.3

Two Photosystems Generate a Proton Gradient and NADPH

413

 

Photosystem I Uses Light Energy to Generate Reduced Ferredoxin, a Powerful Reductant

414

 

Photosystem II Transfers Electrons to Photosystem I and Generates a Proton Gradient

415

 

Cytochrome b6f Links Photosystem II to Photosystem I

416

 

The Oxidation of Water Achieves Oxidation–Reduction Balance and Contributes Protons to the Proton Gradient

416

22.4

A Proton Gradient Drives ATP Synthesis

418

 

The ATP Synthase of Chloroplasts Closely Resembles That of Mitochondria

418

NEW

The Activity of Chloroplast ATP Synthase Is Regulated

419

 

Cyclic Electron Flow Through Photosystem I Leads to the Production of ATP Instead of NADPH

419

 

The Absorption of Eight Photons Yields One O2, Two NADPH, and Three ATP Molecules

420

 

The Components of Photosynthesis Are Highly Organized

421

Biological Insight Many Herbicides Inhibit the Light Reactions of Photosynthesis

421

Chapter 23 The Calvin Cycle

427

23.1

The Calvin Cycle Synthesizes Hexoses from Carbon Dioxide and Water

428

 

Carbon Dioxide Reacts with Ribulose 1,5-bisphosphate to Form Two Molecules of 3-Phosphoglycerate

429

 

Hexose Phosphates Are Made from Phosphoglycerate, and Ribulose 1,5-bisphosphate Is Regenerated

430

 

Three Molecules of ATP and Two Molecules of NADPH Are Used to Bring Carbon Dioxide to the Level of a Hexose

430

Biological Insight A Volcanic Eruption Can Affect Photosynthesis Worldwide

432

 

Starch and Sucrose Are the Major Carbohydrate Stores in Plants

433

Biological Insight Why Bread Becomes Stale: The Role of Starch

434

23.2

The Calvin Cycle Is Regulated by the Environment

434

 

Thioredoxin Plays a Key Role in Regulating the Calvin Cycle

435

 

Rubisco Also Catalyzes a Wasteful Oxygenase Reaction

436

 

The C4 Pathway of Tropical Plants Accelerates Photosynthesis by Concentrating Carbon Dioxide

436

 

Crassulacean Acid Metabolism Permits Growth in Arid Ecosystems

438

SECTION 11 Glycogen Metabolism and the Pentose Phosphate Pathway

443

Chapter 24 Glycogen Degradation

445

24.1

Glycogen Breakdown Requires Several Enzymes

446

 

Phosphorylase Cleaves Glycogen to Release Glucose 1-phosphate

446

 

A Debranching Enzyme Also Is Needed for the Breakdown of Glycogen

447

 

Phosphoglucomutase Converts Glucose 1-phosphate into Glucose 6-phosphate

448

 

Liver Contains Glucose 6-phosphatase, a Hydrolytic Enzyme Absent from Muscle

448

24.2

Phosphorylase Is Regulated by Allosteric Interactions and Reversible Phosphorylation

449

 

Liver Phosphorylase Produces Glucose for Use by Other Tissues

449

 

Muscle Phosphorylase Is Regulated by the Intracellular Energy Charge

450

 

Biochemical Characteristics of Muscle Fiber Types Differ

451

NEW

Phosphorylation Promotes the Conversion of Phosphorylase b to Phosphorylase a

451

 

Phosphorylase Kinase Is Activated by Phosphorylation and Calcium Ions

452

Clinical Insight Hers Disease Is Due to a Phosphorylase Deficiency

453

24.3

Epinephrine and Glucagon Signal the Need for Glycogen Breakdown

453

 

G Proteins Transmit the Signal for the Initiation of Glycogen Breakdown

453

 

Glycogen Breakdown Must Be Rapidly Turned Off When Necessary

455

Biological Insight Glycogen Depletion Coincides with the Onset of Fatigue

455

Chapter 25 Glycogen Synthesis

459

25.1

Glycogen Is Synthesized and Degraded by Different Pathways

459

 

UDP-Glucose Is an Activated Form of Glucose

460

 

Glycogen Synthase Catalyzes the Transfer of Glucose from UDP-Glucose to a Growing Chain

460

 

A Branching Enzyme Forms Alpha-1,6 Linkages

461

 

Glycogen Synthase Is the Key Regulatory Enzyme in Glycogen Synthesis

461

 

Glycogen Is an Efficient Storage Form of Glucose

462

25.2

Metabolism in Context: Glycogen Breakdown and Synthesis Are Reciprocally Regulated

462

 

Protein Phosphatase 1 Reverses the Regulatory Effects of Kinases on Glycogen Metabolism

462

 

Insulin Stimulates Glycogen Synthesis by Inactivating Glycogen Synthase Kinase

464

 

Glycogen Metabolism in the Liver Regulates the Blood-Glucose Concentration

465

Clinical Insight Diabetes Mellitus Results from Insulin Insufficiency and Glucagon Excess

466

Clinical Insight A Biochemical Understanding of Glycogen-Storage Diseases Is Possible

467

Chapter 26 The Pentose Phosphate Pathway

473

26.1

The Pentose Phosphate Pathway Yields NADPH and Five-Carbon Sugars

474

 

Two Molecules of NADPH Are Generated in the Conversion of Glucose 6-phosphate into Ribulose 5-phosphate

474

 

The Pentose Phosphate Pathway and Glycolysis Are Linked by Transketolase and Transaldolase

474

26.2

Metabolism in Context: Glycolysis and the Pentose Phosphate Pathway Are Coordinately Controlled

478

 

The Rate of the Pentose Phosphate Pathway Is Controlled by the Level of NADP+

478

 

The Fate of Glucose 6-phosphate Depends on the Need for NADPH, Ribose 5-phosphate, and ATP

478

NEW Clinical Insight The Pentose Phosphate Pathway Is Required For Rapid Cell Growth

481

26.3

Glucose 6-phosphate Dehydrogenase Lessens Oxidative Stress

481

Clinical Insight Glucose 6-phosphate Dehydrogenase Deficiency Causes a Drug-Induced Hemolytic Anemia

481

Biological Insight A Deficiency of Glucose 6-phosphate Dehydrogenase Confers an Evolutionary Advantage in Some Circumstances

483

SECTION 12 Fatty Acid and Lipid Metabolism

487

Chapter 27 Fatty Acid Degradation

489

27.1

Fatty Acids Are Processed in Three Stages

489

Clinical Insight Triacylglycerols Are Hydrolyzed by Hormone-Stimulated Lipases

490

NEW

Free Fatty Acids and Glycerol Are Released into the Blood

491

 

Fatty Acids Are Linked to Coenzyme A Before They Are Oxidized

491

Clinical Insight Pathological Conditions Result if Fatty Acids Cannot Enter the Mitochondria

493

 

Acetyl CoA, NADH, and FADH2 Are Generated by Fatty Acid Oxidation

493

 

The Complete Oxidation of Palmitate Yields 106 Molecules of ATP

495

27.2

The Degradation of Unsaturated and Odd-Chain Fatty Acids Requires Additional Steps

495

 

An Isomerase and a Reductase Are Required for the Oxidation of Unsaturated Fatty Acids

495

 

Odd-Chain Fatty Acids Yield Propionyl CoA in the Final Thiolysis Step

497

27.3

Ketone Bodies Are Another Fuel Source Derived from Fats

497

 

Ketone-Body Synthesis Takes Place in the Liver

497

NEW Clinical Insight Ketogenic Diets May Have Therapeutic Properties

498

 

Animals Cannot Convert Fatty Acids into Glucose

498

27.4

Metabolism in Context: Fatty Acid Metabolism Is a Source of Insight into Various Physiological States

499

Clinical Insight Diabetes Can Lead to a Life-Threatening Excess of Ketone-Body Production

499

Clinical Insight Ketone Bodies Are a Crucial Fuel Source During Starvation

500

NEW Clinical Insight Some Fatty Acids May Contribute to the Development of Pathological Conditions

501

Chapter 28 Fatty Acid Synthesis

507

28.1

Fatty Acid Synthesis Takes Place in Three Stages

507

 

Citrate Carries Acetyl Groups from Mitochondria to the Cytoplasm

508

 

Several Sources Supply NADPH for Fatty Acid Synthesis

508

 

The Formation of Malonyl CoA Is the Committed Step in Fatty Acid Synthesis

509

 

Fatty Acid Synthesis Consists of a Series of Condensation, Reduction, Dehydration, and Reduction Reactions

510

 

The Synthesis of Palmitate Requires 8 Molecules of Acetyl CoA, 14 Molecules of NADPH, and 7 Molecules of ATP

512

 

Fatty Acids Are Synthesized by a Multifunctional Enzyme Complex in Animals

512

Clinical Insight Fatty Acid Metabolism Is Altered in Tumor Cells

513

Clinical Insight A Small Fatty Acid That Causes Big Problems

513

28.2

Additional Enzymes Elongate and Desaturate Fatty Acids

514

 

Membrane-Bound Enzymes Generate Unsaturated Fatty Acids

514

 

Eicosanoid Hormones Are Derived from Polyunsaturated Fatty Acids

514

Clinical Insight Aspirin Exerts Its Effects by Covalently Modifying a Key Enzyme

515

28.3

Acetyl CoA Carboxylase Is a Key Regulator of Fatty Acid Metabolism

516

 

Acetyl CoA Carboxylase Is Regulated by Conditions in the Cell

516

 

Acetyl CoA Carboxylase Is Regulated by a Variety of Hormones

516

28.4

Metabolism in Context: Ethanol Alters Energy Metabolism in the Liver

517

Chapter 29 Lipid Synthesis: Storage Lipids, Phospholipids, and Cholesterol

523

29.1

Phosphatidate Is a Precursor of Storage Lipids and Many Membrane Lipids

523

 

Triacylglycerol Is Synthesized from Phosphatidate in Two Steps

524

 

Phospholipid Synthesis Requires Activated Precursors

524

NEW Clinical Insight Phosphatidylcholine Is an Abundant Phospholipid

526

 

Sphingolipids Are Synthesized from Ceramide

526

Clinical Insight Gangliosides Serve as Binding Sites for Pathogens

527

Clinical Insight Disrupted Lipid Metabolism Results in Respiratory Distress Syndrome and Tay–Sachs Disease

528

 

Phosphatidic Acid Phosphatase Is a Key Regulatory Enzyme in Lipid Metabolism

529

29.2

Cholesterol Is Synthesized from Acetyl Coenzyme A in Three Stages

529

 

The Synthesis of Mevalonate Initiates the Synthesis of Cholesterol

530

 

Squalene (C30) Is Synthesized from Six Molecules of Isopentenyl Pyrophosphate (C5)

530

 

Squalene Cyclizes to Form Cholesterol

532

29.3

The Regulation of Cholesterol Synthesis Takes Place at Several Levels

532

29.4

Lipoproteins Transport Cholesterol and Triacylglycerols Throughout the Organism

534

 

Low-Density Lipoproteins Play a Central Role in Cholesterol Metabolism

535

Clinical Insight The Absence of the LDL Receptor Leads to Familial Hypercholesterolemia and Atherosclerosis

536

NEW Clinical Insight Cycling of the LDL Receptor Is Regulated

537

Clinical Insight HDL Seems to Protect Against Atherosclerosis

537

NEW Clinical Insight The Clinical Management of Cholesterol Levels Can Be Understood at a Biochemical Level

538

29.5

Cholesterol Is the Precursor of Steroid Hormones

539

NEW Clinical Insight Bile Salts Facilitate Lipid Absorption

539

 

Steroid Hormones Are Crucial Signal Molecules

539

 

Vitamin D Is Derived from Cholesterol by the Energy of Sunlight

540

Clinical Insight Vitamin D Is Necessary for Bone Development

541

Clinical Insight Androgens Can Be Used to Artificially Enhance Athletic Performance

542

 

Oxygen Atoms Are Added to Steroids by Cytochrome P450 Monooxygenases

542

 

Metabolism in Context: Ethanol Also Is Processed by the Cytochrome P450 System

543

SECTION 13 The Metabolism of Nitrogen-Containing Molecules

549

Chapter 30 Amino Acid Degradation and the Urea Cycle

551

30.1

Nitrogen Removal Is the First Step in the Degradation of Amino Acids

552

 

Alpha-Amino Groups Are Converted into Ammonium Ions by the Oxidative Deamination of Glutamate

552

NEW Clinical Insight Blood Levels of Amonitransferases Serve a Diagnostic Function

553

NEW

Serine and Threonine Can Be Directly Deaminated

553

 

Peripheral Tissues Transport Nitrogen to the Liver

554

30.2

Ammonium Ion Is Converted into Urea in Most Terrestrial Vertebrates

555

NEW

Carbamoyl Phosphate Synthetase Is the Key Regulatory Enzyme for Urea Synthesis

556

NEW

Carbamoyl Phosphate Reacts with Ornithine to Begin the Urea Cycle

556

 

The Urea Cycle Is Linked to Gluconeogenesis

557

Clinical Insight Metabolism in Context: Inherited Defects of the Urea Cycle Cause Hyperammonemia

558

Biological Insight Hibernation Presents Nitrogen Disposal Problems

558

Biological Insight Urea Is Not the Only Means of Disposing of Excess Nitrogen

559

30.3

Carbon Atoms of Degraded Amino Acids Emerge as Major Metabolic Intermediates

559

 

Pyruvate Is a Point of Entry into Metabolism

560

 

Oxaloacetate Is Another Point of Entry into Metabolism

561

 

Alpha-Ketoglutarate Is Yet Another Point of Entry into Metabolism

561

 

Succinyl Coenzyme A Is a Point of Entry for Several Nonpolar Amino Acids

562

 

The Branched-Chain Amino Acids Yield Acetyl Coenzyme A, Acetoacetate, or Succinyl Coenzyme A

562

 

Oxygenases Are Required for the Degradation of Aromatic Amino Acids

563

 

Methionine Is Degraded into Succinyl Coenzyme A

565

Clinical Insight Inborn Errors of Metabolism Can Disrupt Amino Acid Degradation

565

NEW Clinical Insight Determining the Basis of the Neurological Symptoms of Phenylketonuria Is an Active Area of Research

566

Chapter 31 Amino Acid Synthesis J

571

31.1

The Nitrogenase Complex Fixes Nitrogen

572

 

The Molybdenum–Iron Cofactor of Nitrogenase Binds and Reduces Atmospheric Nitrogen

573

 

Ammonium Ion Is Incorporated into an Amino Acid Through Glutamate and Glutamine

573

31.2

Amino Acids Are Made from Intermediates of Major Pathways

574

 

Human Beings Can Synthesize Some Amino Acids but Must Obtain Others from the Diet

574

 

Some Amino Acids Can Be Made by Simple Transamination Reactions

575

 

Serine, Cysteine, and Glycine Are Formed from 3-Phosphoglycerate

576

Clinical Insight Tetrahydrofolate Carries Activated One-Carbon Units

576

 

S-Adenosylmethionine Is the Major Donor of Methyl Groups

578

Clinical Insight High Homocysteine Levels Correlate with Vascular Disease

578

31.3

Feedback Inhibition Regulates Amino Acid Biosynthesis

579

 

The Committed Step Is the Common Site of Regulation

579

 

Branched Pathways Require Sophisticated Regulation

579

Chapter 32 Nucleotide Metabolism

585

32.1

An Overview of Nucleotide Biosynthesis and Nomenclature

586

32.2

The Pyrimidine Ring Is Assembled and Then Attached to a Ribose Sugar

587

 

CTP Is Formed by the Amination of UTP

589

 

Kinases Convert Nucleoside Monophosphates into Nucleoside Triphosphates

589

NEW Clinical Insight Salvage Pathways Recycle Pyrimidine Bases

589

32.3

The Purine Ring Is Assembled on Ribose Phosphate

590

 

AMP and GMP Are Formed from IMP

590

Clinical Insight Enzymes of the Purine-Synthesis Pathway Are Associated with One Another in Vivo

592

 

Bases Can Be Recycled by Salvage Pathways

593

32.4

Ribonucleotides Are Reduced to Deoxyribonucleotides

593

 

Thymidylate Is Formed by the Methylation of Deoxyuridylate

594

Clinical Insight Several Valuable Anticancer Drugs Block the Synthesis of Thymidylate

595

32.5

Nucleotide Biosynthesis Is Regulated by Feedback Inhibition

596

 

Pyrimidine Biosynthesis Is Regulated by Aspartate Transcarbamoylase

596

 

The Synthesis of Purine Nucleotides Is Controlled by Feedback Inhibition at Several Sites

596

NEW Clinical Insight The Synthesis of Deoxyribonucleotides Is Controlled by the Regulation of Ribonucleotide Reductase

597

32.6

Disruptions in Nucleotide Metabolism Can Cause Pathological Conditions

598

Clinical Insight The Loss of Adenosine Deaminase Activity Results in Severe Combined Immunodeficiency

598

Clinical Insight Gout Is Induced by High Serum Levels of Urate

599

Clinical Insight Lesch–Nyhan Syndrome Is a Dramatic Consequence of Mutations in a Salvage-Pathway Enzyme

600

Clinical Insight Folic Acid Deficiency Promotes Birth Defects Such As Spina Bifida

600

PART III Synthesizing the Molecules of Life

Section 14 Nucleic Acid Structure and DNA Replication

605

Chapter 33 The Structure of Informational Macromolecules: DNA and RNA

607

33.1

A Nucleic Acid Consists of Bases Linked to a Sugar–Phosphate Backbone

608

 

DNA and RNA Differ in the Sugar Component and One of the Bases

608

 

Nucleotides Are the Monomeric Units of Nucleic Acids

609

 

DNA Molecules Are Very Long and Have Directionality

610

33.2

Nucleic Acid Strands Can Form a Double-Helical Structure

611

 

The Double Helix Is Stabilized by Hydrogen Bonds and the Hydrophobic Effect

611

 

The Double Helix Facilitates the Accurate Transmission of Hereditary Information

613

 

Meselson and Stahl Demonstrated That Replication Is Semiconservative

614

 

The Strands of the Double Helix Can Be Reversibly Separated

615

33.3

DNA Double Helices Can Adopt Multiple Forms

615

 

Z-DNA Is a Left-Handed Double Helix in Which Backbone Phosphoryl Groups Zigzag

616

 

The Major and Minor Grooves Are Lined by Sequence-Specific Hydrogen-Bonding Groups

616

 

Double-Stranded DNA Can Wrap Around Itself to Form Supercoiled Structures

617

33.4

Eukaryotic DNA Is Associated with Specific Proteins

619

 

Nucleosomes Are Complexes of DNA and Histones

619

 

Eukaryotic DNA Is Wrapped Around Histones to Form Nucleosomes

620

Clinical Insight Damaging DNA Can Inhibit Cancer-Cell Growth

622

33.5

RNA Can Adopt Elaborate Structures

622

Chapter 34 DNA Replication

627

34.1

DNA Is Replicated by Polymerases

628

 

DNA Polymerase Catalyzes Phosphodiester-Linkage Formation

628

 

The Specificity of Replication Is Dictated by the Complementarity of Bases

630

Clinical Insight The Separation of DNA Strands Requires Specific Helicases and ATP Hydrolysis

630

 

Topoisomerases Prepare the Double Helix for Unwinding

632

Clinical Insight Bacterial Topoisomerase Is a Therapeutic Target

632

 

Many Polymerases Proofread the Newly Added Bases and Excise Errors

633

34.2

DNA Replication Is Highly Coordinated

633

 

DNA Replication in E. coli Begins at a Unique Site

634

 

An RNA Primer Synthesized by Primase Enables DNA Synthesis to Begin

634

 

One Strand of DNA Is Made Continuously and the Other Strand Is Synthesized in Fragments

635

 

DNA Replication Requires Highly Processive Polymerases

635

 

The Leading and Lagging Strands Are Synthesized in a Coordinated Fashion

636

 

DNA Synthesis Is More Complex in Eukaryotes Than in Bacteria

638

 

Telomeres Are Unique Structures at the Ends of Linear Chromosomes

638

Clinical Insight Telomeres Are Replicated by Telomerase, a Specialized Polymerase That Carries Its Own RNA Template

639

Chapter 35 DNA Repair and Recombination

643

35.1

Errors Can Arise in DNA Replication

644

Clinical Insight Some Genetic Diseases Are Caused by the Expansion of Repeats of Three Nucleotides

644

 

Bases Can Be Damaged by Oxidizing Agents, Alkylating Agents, and Light

645

35.2

DNA Damage Can Be Detected and Repaired

647

 

The Presence of Thymine Instead of Uracil in DNA Permits the Repair of Deaminated Cytosine

649

Clinical Insight Many Cancers Are Caused by the Defective Repair of DNA

650

Clinical Insight Many Potential Carcinogens Can Be Detected by Their Mutagenic Action on Bacteria

650

35.3

DNA Recombination Plays Important Roles in Replication and Repair

651

 

Double Strand Breaks Can Be Repaired by Recombination

652

 

DNA Recombination Is Important in a Variety of Biological Processes

652

SECTION 15 RNA Synthesis, Processing, and Regulation

657

Chapter 36 RNA Synthesis and Regulation in Bacteria

659

36.1

Cellular RNA Is Synthesized by RNA Polymerases

659

 

Genes Are the Transcriptional Units

660

 

RNA Polymerase Is Composed of Multiple Subunits

661

36.2

RNA Synthesis Comprises Three Stages

661

 

Transcription Is Initiated at Promoter Sites on the DNA Template

661

 

Sigma Subunits of RNA Polymerase Recognize Promoter Sites

662

 

RNA Strands Grow in the 5′-to-3′ Direction

663

 

Elongation Takes Place at Transcription Bubbles That Move Along the DNA Template

664

 

An RNA Hairpin Followed by Several Uracil Residues Terminates the Transcription of Some Genes

664

 

The Rho Protein Helps Terminate the Transcription of Some Genes

665

 

Precursors of Transfer and Ribosomal RNA Are Cleaved and Chemically Modified After Transcription

666

Clinical Insight Some Antibiotics Inhibit Transcription

667

36.3

The lac Operon Illustrates the Control of Bacterial Gene Expression

668

 

An Operon Consists of Regulatory Elements and Protein-Encoding Genes

668

 

Ligand Binding Can Induce Structural Changes in Regulatory Proteins

669

 

Transcription Can Be Stimulated by Proteins That Contact RNA Polymerase

669

Clinical and Biological Insight Many Bacterial Cells Release Chemical Signals That Regulate Gene Expression in Other Cells

670

 

Some Messenger RNAs Directly Sense Metabolite Concentrations

670

Chapter 37 Gene Expression in Eukaryotes

675

37.1

Eukaryotic Cells Have Three Types of RNA Polymerases

676

37.2

RNA Polymerase II Requires Complex Regulation

678

 

The Transcription Factor IID Protein Complex Initiates the Assembly of the Active Transcription Complex

679

 

Enhancer Sequences Can Stimulate Transcription at Start Sites Thousands of Bases Away

679

Clinical Insight Inappropriate Enhancer Use May Cause Cancer

680

 

Multiple Transcription Factors Interact with Eukaryotic Promoters and Enhancers

680

Clinical Insight Induced Pluripotent Stem Cells Can Be Generated by Introducing Four Transcription Factors into Differentiated Cells

680

37.3

Gene Expression Is Regulated by Hormones

681

 

Nuclear Hormone Receptors Have Similar Domain Structures

681

 

Nuclear Hormone Receptors Recruit Coactivators and Corepressors

682

Clinical Insight Steroid-Hormone Receptors Are Targets for Drugs

683

37.4

Histone Acetylation Results in Chromatin Remodeling

684

 

Metabolism in Context: Acetyl CoA Plays a Key Role in the Regulation of Transcription

684

 

Histone Deacetylases Contribute to Transcriptional Repression

686

Chapter 38 RNA Processing in Eukaryotes

691

38.1

Mature Ribosomal RNA Is Generated by the Cleavage of a Precursor Molecule

692

38.2

Transfer RNA Is Extensively Processed

692

38.3

Messenger RNA Is Modified and Spliced

693

 

Sequences at the Ends of Introns Specify Splice Sites in mRNA Precursors

694

 

Small Nuclear RNAs in Spliceosomes Catalyze the Splicing of mRNA Precursors

695

Clinical Insight Mutations That Affect Pre-mRNA Splicing Cause Disease

696

Clinical Insight Most Human Pre-mRNAs Can Be Spliced in Alternative Ways to Yield Different Proteins

697

 

The Transcription and Processing of mRNA Are Coupled

698

Biological Insight RNA Editing Changes the Proteins Encoded by mRNA

698

38.4

RNA Can Function as a Catalyst

699

SECTION 16 Protein Synthesis and Recombinant DNA Techniques

705

Chapter 39 The Genetic Code

707

39.1

The Genetic Code Links Nucleic Acid and Protein Information

708

 

The Genetic Code Is Nearly Universal

708

 

Transfer RNA Molecules Have a Common Design

709

 

Some Transfer RNA Molecules Recognize More Than One Codon Because of Wobble in Base-Pairing

711

 

The Synthesis of Long Proteins Requires a Low Error Frequency

712

39.2

Amino Acids Are Activated by Attachment to Transfer RNA

712

 

Amino Acids Are First Activated by Adenylation

713

 

Aminoacyl-tRNA Synthetases Have Highly Discriminating Amino Acid Activation Sites

714

 

Proofreading by Aminoacyl-tRNA Synthetases Increases the Fidelity of Protein Synthesis

714

 

Synthetases Recognize the Anticodon Loops and Acceptor Stems of Transfer RNA Molecules

714

39.3

A Ribosome Is a Ribonucleoprotein Particle Made of Two Subunits

715

 

Ribosomal RNAs Play a Central Role in Protein Synthesis

715

 

Messenger RNA Is Translated in the 5′-to-3′ Direction

716

Chapter 40 The Mechanism of Protein Synthesis

721

40.1

Protein Synthesis Decodes the Information in Messenger RNA

722

 

Ribosomes Have Three tRNA-Binding Sites That Bridge the 30S and 50S Subunits

722

 

The Start Signal Is AUG Preceded by Several Bases That Pair with 16S Ribosomal RNA

722

 

Bacterial Protein Synthesis Is Initiated by Formylmethionyl Transfer RNA

723

 

Formylmethionyl-tRNAf Is Placed in the P Site of the Ribosome in the Formation of the 70S Initiation Complex

724

 

Elongation Factors Deliver Aminoacyl-tRNA to the Ribosome

724

40.2

Peptidyl Transferase Catalyzes Peptide-Bond Synthesis

725

 

The Formation of a Peptide Bond Is Followed by the GTP-Driven Translocation of tRNAs and mRNA

725

 

Protein Synthesis Is Terminated by Release Factors That Read Stop Codons

728

40.3

Bacteria and Eukaryotes Differ in the Initiation of Protein Synthesis

728

Clinical Insight Mutations in Initiation Factor 2 Cause a Curious Pathological Condition

730

40.4

A Variety of Biomolecules Can Inhibit Protein Synthesis

730

Clinical Insight Some Antibiotics Inhibit Protein Synthesis

730

Clinical Insight Diphtheria Toxin Blocks Protein Synthesis in Eukaryotes by Inhibiting Translocation

731

Clinical Insight Ricin Fatally Modifies 28S Ribosomal RNA

732

40.5

Ribosomes Bound to the Endoplasmic Reticulum Manufacture Secretory and Membrane Proteins

733

 

Protein Synthesis Begins on Ribosomes That Are Free in the Cytoplasm

733

 

Signal Sequences Mark Proteins for Translocation Across the Endoplasmic Reticulum Membrane

733

40.6

Protein Synthesis Is Regulated by a Number of Mechanisms

735

 

Messenger RNA Use Is Subject to Regulation

735

 

The Stability of Messenger RNA Also Can Be Regulated

736

 

Small RNAs Can Regulate mRNA Stability and Use

736

Chapter 41 Recombinant DNA Techniques

743

41.1

Nucleic Acids Can Be Synthesized from Protein-Sequence Data

744

 

Protein Sequence Is a Guide to Nucleic Acid Information

744

 

DNA Probes Can Be Synthesized by Automated Methods

744

41.2

Recombinant DNA Technology Has Revolutionized All Aspects of Biology

745

 

Restriction Enzymes Split DNA into Specific Fragments

745

 

Restriction Fragments Can Be Separated by Gel Electrophoresis and Visualized

746

 

Restriction Enzymes and DNA Ligase Are Key Tools for Forming Recombinant DNA Molecules

747

41.3

Eukaryotic Genes Can Be Manipulated with Considerable Precision

748

 

Complementary DNA Prepared from mRNA Can Be Expressed in Host Cells

748

 

Estrogen-Receptor cDNA Can Be Identified by Screening a cDNA Library

749

 

Complementary DNA Libraries Can Be Screened for Synthesized Protein

750

 

Specific Genes Can Be Cloned from Digests of Genomic DNA

750

 

DNA Can Be Sequenced by the Controlled Termination of Replication

751

Clinical and Biological Insight Next-Generation Sequencing Methods Enable the Rapid Determination of a Complete Genome Sequence

753

 

Selected DNA Sequences Can Be Greatly Amplified by the Polymerase Chain Reaction

754

Clinical and Biological Insight PCR Is a Powerful Technique in Medical Diagnostics, Forensics, and Studies of Molecular Evolution

756

 

Gene-Expression Levels Can Be Comprehensively Examined

756

Appendices

A1

Glossary

B1

Answers to Problems

C1

Index

D1

Selected Readings (online at www.whfreeman.com/tymoczko3e)

E1

xxviii