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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 K_M Can Have Physiological Consequences	114
	K_M and V_max Values Can Be Determined by Several Means	115
	K_M and V_max Values Are Important Enzyme Characteristics	115
	k_cat/K_M 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

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