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biochemi str y
sixth edition
Reginald H. Garrett | Charles M. Grisham

University of Virginia
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Dedication
To our grandchildren Jackson, Bella, Reggie, Ricky, Charlotte

Mayberry, and Ann Clara, and to the generations to follow...
About the Authors
Reginald H. Garrett was educated in the Baltimore city public Charles M. Grisham was born and raised in Minneapolis,
schools and at the Johns Hopkins University, where he received Minnesota, and educated at Benilde High School. He received his
his Ph.D. in biology in 1968. Since that time, he has been at the B.S. in chemistry from the Illinois Institute of Technology in 1969
University of Virginia, where he is currently Professor Emeritus and his Ph.D. in chemistry from the University of Minnesota in
of Biology. He is the author of previous editions of Biochemis- 1973. Following a postdoctoral appointment at the Institute for
try, as well as Principles of Biochemistry (Cengage, Brooks/Cole), Cancer Research in Philadelphia, he joined the faculty of the
and numerous papers and review articles on the biochemical, University of Virginia, where he is Professor of Chemistry. He is
genetic, and molecular biological aspects of inorganic nitrogen the author of previous editions of Biochemistry and Principles of
metabolism. His research interests focused on the pathway of Biochemistry (Cengage, Brooks/Cole), and numerous papers and
nitrate assimilation in filamentous fungi. His investigations con- review articles on active transport of sodium, potassium, and
tributed substantially to our understanding of the enzymology, calcium in mammalian systems, on protein kinase C, and on the
genetics, and regulation of this major pathway of biological applications of NMR and EPR spectroscopy to the study of
nitrogen acquisition. More recently, he has collaborated in biological systems. He has also authored Interactive Biochemistry
systems approaches to the metabolic basis of nutrition-related CD-ROM and Workbook, a tutorial CD for students. His work
diseases. His research has been supported by the National Insti- has been supported by the National Institutes of Health, the
tutes of Health, the National Science Foundation, and private National Science Foundation, the Muscular Dystrophy Associa-
industry. He is a former Fulbright Scholar at the Universität für tion of America, the Research Corporation, the American Heart
Bodenkultur in Vienna, Austria and served as Visiting Scholar at Association, and the American Chemical Society. He is a Research
the University of Cambridge on two separate occasions. During Career Development Awardee of the National Institutes of
the second, he was Thomas Jefferson Visiting Fellow in Downing Health, and in 1983 and 1984 he was a Visiting Scientist at the
College. In 2003, he was Professeur Invité at the Université Paul Aarhus University Institute of Physiology Denmark. In 1999, he
Sabatier/Toulouse III and the Centre National de la Recherche was Knapp Professor of Chemistry at the University of San
Scientifique, Institute for Pharmacology and Structural Biology Diego. He has taught biochemistry, introductory chemistry, and
in France. He taught biochemistry at the University of Virginia physical chemistry at the University of Virginia for more than
for 46 years. He is a member of the American Society for 40 years. He is a member of the American Society for Biochemis-
Biochemistry and Molecular Biology. try and Molecular Biology.
Georgia Cobb Garrett
Charles M. Grisham and Reginald H. Garrett
iv
Contents in Brief
Part I Molecular Components of Cells 1

1 The Facts of Life: Chemistry Is the Logic of Biological Phenomena 1
2 Water: The Medium of Life 31
3 Thermodynamics of Biological Systems 53
4 Amino Acids and the Peptide Bond 79
5 Proteins: Their Primary Structure and Biological Functions 105
6 Proteins: Secondary, Tertiary, and Quaternary Structure 147
7 Carbohydrates and the Glycoconjugates of Cell Surfaces 203
8 Lipids 245
9 Membranes and Membrane Transport 273
10 Nucleotides and Nucleic Acids 325
11 Structure of Nucleic Acids 353
12 Recombinant DNA, Cloning, Chimeric Genes, and Synthetic Biology 399
Part II Protein Dynamics 437

13 Enzymes—Kinetics and Specificity 437
14 Mechanisms of Enzyme Action 477
15 Enzyme Regulation 513
16 Molecular Motors 547
Part III Metabolism and Its Regulation 583

17 Metabolism: An Overview 583
18 Glycolysis 611
19 The Tricarboxylic Acid Cycle 643
20 Electron Transport and Oxidative Phosphorylation 679
21 Photosynthesis 719
22 Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway 755
23 Fatty Acid Catabolism 795
24 Lipid Biosynthesis 825
25 Nitrogen Acquisition and Amino Acid Metabolism 877
26 Synthesis and Degradation of Nucleotides 927
27 Metabolic Integration and Organ Specialization 957
Part IV Information Transfer 985

28 DNA Metabolism: Replication, Recombination, and Repair 985
29 Transcription and the Regulation of Gene Expression 1035
30 Protein Synthesis 1091
31 Completing the Protein Life Cycle: Folding, Processing, and Degradation 1131
32 The Reception and Transmission of Extracellular Information 1161
Abbreviated Answers to Problems A-1
Index I-1
Detailed Contents
Part I Molecular Components of Cells Critical Developments in Biochemistry: Synthetic

Life 18
How Many Genes Does a Cell Need? 19
1 The Facts of Life: Chemistry Is the Logic
Archaea and Bacteria Have a Relatively Simple Structural
of Biological Phenomena 1 Organization 20
1.1 What Are the Distinctive Properties of Living The Structural Organization of Eukaryotic Cells Is More
Systems? 1 Complex Than That of Prokaryotic Cells 20
1.2 What Kinds of Molecules Are Biomolecules? 4 1.6 What Are Viruses? 22
Biomolecules Are Carbon Compounds 5 SUMMARY 26
1.3 What Is the Structural Organization of Complex Foundational Biochemistry 27
Biomolecules? 7 PROBLEMS 27
Metabolites Are Used to Form the Building Blocks Further Reading 29
of Macromolecules 7
Organelles Represent a Higher Order in Biomolecular 2 Water: The Medium of Life 31
Organization 9
2.1 What Are the Properties of Water? 32
Membranes Are Supramolecular Assemblies That
Water Has Unusual Properties 32
Define the Boundaries of Cells 9
Hydrogen Bonding in Water Is Key to Its Properties 32
The Unit of Life Is the Cell 10
The Structure of Ice Is Based on H-Bond Formation 32
1.4 How Do the Properties of Biomolecules Reflect Their
Molecular Interactions in Liquid Water Are Based
Fitness to the Living Condition? 10 on H Bonds 33
Biological Macromolecules and Their Building Blocks The Solvent Properties of Water Derive from Its Polar
Have a “Sense” or Directionality 10 Nature 34
Biological Macromolecules Are Informational 10 Water Can Ionize to Form H1 and OH2 37
Biomolecules Have Characteristic Three-Dimensional
2.2 What Is pH? 38
Architecture 12
Strong Electrolytes Dissociate Completely in Water 39
Weak Forces Maintain Biological Structure
and Determine Biomolecular Interactions 12 Weak Electrolytes Are Substances That Dissociate Only
Slightly in Water 40
Van der Waals Attractive Forces Play an Important
Role in Biomolecular Interactions 12 The Henderson–Hasselbalch Equation Describes
the Dissociation of a Weak Acid in the Presence
Hydrogen Bonds Are Important in Biomolecular
of Its Conjugate Base 41
Interactions 13
Titration Curves Illustrate the Progressive Dissociation
The Defining Concept of Biochemistry Is
of a Weak Acid 42
“Molecular Recognition Through Structural
Complementarity” 14 Phosphoric Acid Has Three Dissociable H1 43
Biomolecular Recognition Is Mediated by Weak 2.3 What Are Buffers, and What Do They Do? 44
Chemical Forces 15 The Phosphate Buffer System Is a Major Intracellular
Weak Forces Restrict Organisms to a Narrow Range Buffering System 45
of Environmental Conditions 15 The Imidazole Group of Histidine Also Serves
Enzymes Catalyze Metabolic Reactions 16 as an Intracellular Buffering System 45
The Time Scale of Life 17 Human Biochemistry: The Bicarbonate Buffer System
of Blood Plasma 46
1.5 What Are the Organization and Structure of Cells? 18
“Good” Buffers Are Buffers Useful Within Physiological
The Eukaryotic Cell Likely Emerged from an Archaeal
pH Ranges 47
Lineage 18
vi
Detailed Contents vii
Human Biochemistry: Blood pH and Respiration 47 Standard Reduction Potentials Are Measured in Reaction
2.4 What Properties of Water Give It a Unique Role Half-Cells 71
in the Environment? 48 % o9 Values Can Be Used to Predict the Direction
of Redox Reactions 72
SUMMARY 48
% o9 Values Can Be Used to Analyze Energy Changes
Foundational Biochemistry 49 in Redox Reactions 72
PROBLEMS 50 The Reduction Potential Depends on Concentration 74
Further Reading 51 SUMMARY 74
Foundational Biochemistry 75
3 Thermodynamics of Biological Systems 53 PROBLEMS 76
3.1 What Are the Basic Concepts of Thermodynamics? 54 Further Reading 77
Three Quantities Describe the Energetics of Biochemical
Reactions 54 4 Amino Acids and the Peptide Bond 79
All Reactions and Processes Follow the Laws of 4.1 What Are the Structures and Properties of Amino
Thermodynamics 55
Acids? 79
A Deeper Look: Entropy, Information, and the
Typical Amino Acids Contain a Central Tetrahedral Carbon
Importance of “Negentropy” 56
Atom 79
Free Energy Provides a Simple Criterion for Equilibrium 56
Amino Acids Can Join via Peptide Bonds 80
3.2 What Is the Effect of Concentration on Net Free Energy There Are 20 Common Amino Acids 81
Changes? 57 Are There Other Ways to Classify Amino Acids? 84
3.3 What Is the Effect of pH on Standard-State Free Amino Acids 21 and 22—and More? 84
Energies? 58 A Deeper Look: Selenocysteine and Selenoproteins 84
A Deeper Look: Comparing Standard State, Equilibrium, Several Amino Acids Occur Only Rarely in Proteins 85
and Cellular Conditions 58
4.2 What Are the Acid–Base Properties of Amino
3.4 What Can Thermodynamic Parameters Tell Us About Acids? 85
Biochemical Events? 59
Amino Acids Are Weak Polyprotic Acids 85
3.5 What Are the Characteristics of High-Energy Critical Developments in Biochemistry: Adding
Biomolecules? 60 New Chemistry to Proteins with Unnatural Amino
ATP Is an Intermediate Energy-Shuttle Molecule 62 Acids 86
Group Transfer Potentials Quantify the Reactivity Side Chains of Amino Acids Undergo Characteristic
of Functional Groups 62 Ionizations 88
The Hydrolysis of Phosphoric Acid Anhydrides Is Highly 4.3 What Reactions Do Amino Acids Undergo? 89
Favorable 63
4.4 What Are the Optical and Stereochemical Properties
The Hydrolysis DG89 of ATP and ADP Is Greater Than That
of Amino Acids? 89
of AMP 66
Amino Acids Are Chiral Molecules 89
Acetyl Phosphate and 1,3-Bisphosphoglycerate Are
Phosphoric-Carboxylic Anhydrides 66 Chiral Molecules Are Described by the d,l and (R,S)
Naming Conventions 90
Enol Phosphates Are Potent Phosphorylating Agents 66
Critical Developments in Biochemistry: Green
3.6 What Are the Complex Equilibria Involved Fluorescent Protein—The “Light Fantastic” from
in ATP Hydrolysis? 67 Jellyfish to Gene Expression 91
The DG89 of Hydrolysis for ATP Is pH-Dependent 67 4.5 What Are the Spectroscopic Properties of Amino
Metal Ions Affect the Free Energy of Hydrolysis Acids? 91
of ATP 68
Critical Developments in Biochemistry: Discovery of
Concentration Affects the Free Energy of Hydrolysis Optically Active Molecules and Determination of
of ATP 68 Absolute Configuration 92
3.7 Why Are Coupled Processes Important to Living Phenylalanine, Tyrosine, and Tryptophan Absorb
Things? 69 Ultraviolet Light 92
3.8 What Is the Daily Human Requirement for ATP? 69 Amino Acids Can Be Characterized by Nuclear Magnetic
A Deeper Look: ATP Changes the Keq by a
Resonance 92
Factor of 108 70 A Deeper Look: The Murchison Meteorite—Discovery of
Extraterrestrial Handedness 93
3.9 What Are Reduction Potentials, and How Are
Critical Developments in Biochemistry: Rules for
They Used to Account for Free Energy Changes
Description of Chiral Centers in the (R,S) System 94
in Redox Reactions? 71
viii Detailed Contents
4.6 How Are Amino Acid Mixtures Separated Step 1. Separation of Polypeptide Chains 117
and Analyzed? 95 A Deeper Look: The Virtually Limitless Number
Amino Acids Can Be Separated by Chromatography 95 of Different Amino Acid Sequences 118
4.7 What Is the Fundamental Structural Pattern in Step 2. Cleavage of Disulfide Bridges 118
Proteins? 96 Step 3. N- and C-Terminal Analysis 118
The Peptide Bond Has Partial Double-Bond Character 97 Steps 4 and 5. Fragmentation of the Polypeptide
The Polypeptide Backbone Is Relatively Polar 99 Chain 120
Peptides Can Be Classified According to How Many Amino Step 6. Reconstruction of the Overall Amino Acid
Acids They Contain 99 Sequence 122
Proteins Are Composed of One or More Polypeptide The Amino Acid Sequence of a Protein Can Be
Chains 99 Determined by Mass Spectrometry 122
Sequence Databases Contain the Amino Acid Sequences
SUMMARY 101
of Millions of Different Proteins 126
5.5 What Is the Nature of Amino Acid Sequences? 127
PROBLEMS 102
Homologous Proteins from Different Organisms Have
Further Reading 103 Homologous Amino Acid Sequences 128
Computer Programs Can Align Sequences and Discover
5 Proteins: Their Primary Structure and Biological Homology between Proteins 128
Functions 105 Related Proteins Share a Common Evolutionary Origin 130
5.1 What Architectural Arrangements Characterize Protein Apparently Different Proteins May Share a Common
Structure? 105 Ancestry 130
Proteins Fall into Three Basic Classes According to Shape A Mutant Protein Is a Protein with a Slightly Different
and Solubility 105 Amino Acid Sequence 133
Protein Structure Is Described in Terms of Four Levels 5.6 Can Polypeptides Be Synthesized
of Organization 106 in the Laboratory? 134
Noncovalent Forces Drive Formation of the Higher Orders Solid-Phase Methods Are Very Useful in Peptide
of Protein Structure 107 Synthesis 135
A Protein’s Conformation Can Be Described as Its Overall 5.7 Do Proteins Have Chemical Groups Other Than
Three-Dimensional Structure 109 Amino Acids? 135
5.2 How Are Proteins Isolated and Purified 5.8 What Are the Many Biological Functions
from Cells? 109 of Proteins? 137
A Number of Protein Separation Methods Exploit
5.9 What Is the Proteome and What Does It Tell Us? 140
Differences in Size and Charge 110
The Proteome Is Dynamic 140
A Deeper Look: Estimation of Protein Concentrations
in Solutions of Biological Origin 110 Critical Developments in Biochemistry: Two New
Suffixes in Molecular Biology and Biochemistry: “-ome”
A Typical Protein Purification Scheme Uses a Series
and “-omics” 140
of Separation Methods 111
Determining the Proteome of a Cell 141
A Deeper Look: Techniques Used in Protein
Purification 111 SUMMARY 141
5.3 How Is the Amino Acid Analysis of Proteins Foundational Biochemistry 143
Performed? 115 PROBLEMS 143
Acid Hydrolysis Liberates the Amino Acids Further Reading 145
of a Protein 115
Chromatographic Methods Are Used to Separate 6 Proteins: Secondary, Tertiary, and Quaternary
the Amino Acids 116
Structure 147
The Amino Acid Compositions of Different Proteins
Are Different 116 6.1 What Noncovalent Interactions Stabilize the Higher
Levels of Protein Structure? 148
5.4 How Is the Primary Structure of a Protein
Hydrogen Bonds Are Formed Whenever Possible 148
Determined? 116
Hydrophobic Interactions Drive Protein Folding 148
The Sequence of Amino Acids in a Protein Is
Distinctive 116 Ionic Interactions Usually Occur on the Protein
Surface 149
Sanger Was the First to Determine the Sequence
of a Protein 117 Van der Waals Interactions Are Ubiquitous 149
Both Chemical and Enzymatic Methodologies Are Used in 6.2 What Role Does the Amino Acid Sequence Play
Protein Sequencing 117 in Protein Structure? 149
Detailed Contents ix
6.3 What Are the Elements of Secondary Structure Human Biochemistry: a1-Antitrypsin—A Tale
in Proteins, and How Are They Formed? 150 of Molecular Mousetraps and a Folding Disease 190
All Protein Structure Is Based on the Amide Plane 150 Human Biochemistry: Diseases of Protein Folding 191
The Alpha-Helix Is a Key Secondary Structure 151 Human Biochemistry: Structural Genomics 191
A Deeper Look: Knowing What the Right Hand and Left There Is Symmetry in Quaternary Structures 192
Hand Are Doing 152 Quaternary Association Is Driven by Weak Forces 192
The b-Pleated Sheet Is a Core Structure in Proteins 155 Open Quaternary Structures Can Polymerize 194
Critical Developments in Biochemistry: In Bed A Deeper Look: Immunoglobulins—All the Features
with a Cold, Pauling Stumbles onto the a-Helix of Protein Structure Brought Together 195
and a Nobel Prize 156 There Are Structural and Functional Advantages
Helix–Sheet Composites in Spider Silk 156 to Quaternary Association 195
b-Turns Allow the Protein Strand to Change Human Biochemistry: Faster-Acting Insulin: Genetic
Direction 158 Engineering Solves a Quaternary Structure Problem 195
6.4 How Do Polypeptides Fold into Three-Dimensional SUMMARY 197
Protein Structures? 159 Foundational Biochemistry 197
Fibrous Proteins Usually Play a Structural Role 160 PROBLEMS 198
A Deeper Look: The Coiled-Coil Motif in Proteins 161
Further Reading 199
Globular Proteins Mediate Cellular Function 164
Helices and Sheets Make up the Core of Most Globular 7 Carbohydrates and the Glycoconjugates
Proteins 165 of Cell Surfaces 203
Waters on the Protein Surface Stabilize the Structure 166
7.1 How Are Carbohydrates Named? 204
Packing Considerations 166
Human Biochemistry: Collagen-Related Diseases 168 7.2 What Are the Structure and Chemistry
of Monosaccharides? 204
Protein Domains Are Nature’s Modular Strategy
for Protein Design 168 Monosaccharides Are Classified as Aldoses
and Ketoses 204
Human Biochemistry: Domain-Based Engineering
of Proteins Forms the Basis of a Novel Cancer Stereochemistry Is a Prominent Feature
Treatment 169 of Monosaccharides 204
Classification Schemes for the Protein Universe Are Based Monosaccharides Exist in Cyclic and Anomeric Forms 206
on Domains 170 Haworth Projections Are a Convenient Device
A Deeper Look: Protein Sectors: Evolutionary Units for Drawing Sugars 207
of Three-Dimensional Structure 171 Monosaccharides Can Be Converted to Several
Denaturation Leads to Loss of Protein Structure Derivative Forms 210
and Function 174 A Deeper Look: Honey—An Ancestral Carbohydrate
Anfinsen’s Classic Experiment Proved That Sequence Treat 212
Determines Structure 176 7.3 What Are the Structure and Chemistry
Is There a Single Mechanism for Protein Folding? 177 of Oligosaccharides? 214
A Deeper Look: Measuring Friction in the Protein Disaccharides Are the Simplest Oligosaccharides 214
Folding Process 178 A Deeper Look: Trehalose—A Natural Protectant
What Is the Thermodynamic Driving Force for Folding for Bugs 215
of Globular Proteins? 180 Human Biochemistry: Alpha-Gal and Red Meat
Marginal Stability of the Tertiary Structure Makes Proteins Allergy 216
Flexible 180 A Variety of Higher Oligosaccharides Occur
Motion in Globular Proteins 180 in Nature 217
The Folding Tendencies and Patterns of Globular 7.4 What Are the Structure and Chemistry
Proteins 181 of Polysaccharides? 217
A Deeper Look: Metamorphic Proteins—A Consequence Nomenclature for Polysaccharides Is Based on Their
of Dynamism and Marginal Stability 182 Composition and Structure 217
Most Globular Proteins Belong to One of Four Structural Polysaccharides Serve Energy Storage, Structure,
Classes 184 and Protection Functions 218
Molecular Chaperones Are Proteins That Help Other Polysaccharides Provide Stores of Energy 218
Proteins to Fold 186
Polysaccharides Provide Physical Structure and Strength
Some Proteins Are Intrinsically Unstructured 186 to Organisms 219
6.5 How Do Protein Subunits Interact at the Quaternary A Deeper Look: Billiard Balls, Exploding Teeth,
Level of Protein Structure? 189 and Dynamite—The Colorful History of Cellulose 220
x Detailed Contents
A Deeper Look: Ruth Benerito and Wrinkle-Free Cotton 8.3 What Are the Structures and Chemistry
Fabrics 222 of Glycerophospholipids? 250
A Deeper Look: A Complex Polysaccharide in Red Glycerophospholipids Are the Most Common
Wine—The Strange Story of Rhamnogalacturonan II 224 Phospholipids 250
Polysaccharides Provide Strength and Rigidity to Bacterial A Deeper Look: Will the Real Glycophospholipid
Cell Walls 225 Come Forward? 251
A Deeper Look: The Secrets of Phloem and the Large Ether Glycerophospholipids Include PAF
Fruits of Cucurbitaceae 225 and Plasmalogens 253
Peptidoglycan Is the Polysaccharide of Bacterial Cell Human Biochemistry: Platelet-Activating Factor:
Walls 226 A Potent Glyceroether Mediator 254
Animals Display a Variety of Cell Surface Polysaccharides 228 8.4 What Are Sphingolipids, and How Are They Important
7.5 What Are Glycoproteins, and How Do They Function for Higher Animals? 254
in Cells? 228 8.5 What Are Waxes, and How Are They Used? 254
Carbohydrates on Proteins Can Be O-Linked A Deeper Look: Novel Lipids with Valuable Properties 256
or N-Linked 228
8.6 What Are Terpenes, and What Is Their Relevance
O-GlcNAc Signaling Is Altered in Diabetes and Cancer 230
to Biological Systems? 257
O-Linked Saccharides Form Rigid Extended Extracellular
A Deeper Look: Why Do Plants Emit Isoprene? 259
Structures 230
Human Biochemistry: Coumadin or Warfarin—Agent
Polar Fish Depend on Antifreeze Glycoproteins 230
of Life or Death 259
N-Linked Oligosaccharides Can Affect the Physical
Properties and Functions of a Protein 231 8.7 What Are Steroids, and What Are Their Cellular
A Deeper Look: Drug Research Finds a Sweet Spot 232 Functions? 260
Sialic Acid Terminates the Oligosaccharides Cholesterol 260
of Glycoproteins and Glycolipids 232 Steroid Hormones Are Derived from Cholesterol 261
A Deeper Look: N-Linked Oligosaccharides Help Human Biochemistry: Plant Sterols and Stanols—
Proteins Fold by Both Intrinsic and Extrinsic Natural Cholesterol Fighters 261
Effects 233 Human Biochemistry: 17b-Hydroxysteroid
Sialic Acid Cleavage Can Serve as a Timing Device Dehydrogenase 3 Deficiency 262
for Protein Degradation 233 8.8 How Do Lipids and Their Metabolites Act
7.6 How Do Proteoglycans Modulate Processes as Biological Signals? 263
in Cells and Organisms? 234 A Deeper Look: Glycerophospholipid Degradation:
Functions of Proteoglycans Involve Binding to Other One of the Effects of Snake Venom 264
Proteins 234 Human Biochemistry: The Endocannabinoid Signaling
Proteoglycans May Modulate Cell Growth Processes 236 System: A Target for Next-Generation Therapeutics 264
Proteoglycans Make Cartilage Flexible and Resilient 237 Human Biochemistry: Fingolimod—a Sphingosine-1-P
Mimic Is an Oral Drug for Multiple Sclerosis 266
7.7 Do Carbohydrates Provide a Structural Code? 237
Lectins Translate the Sugar Code 238 8.9 What Can Lipidomics Tell Us about Cell, Tissue, and
Selectins, Rolling Leukocytes, and the Inflammatory
Organ Physiology? 267
Response 239 SUMMARY 269
Galectins—Mediators of Inflammation, Immunity, Foundational Biochemistry 270
and Cancer 240 PROBLEMS 270
C-Reactive Protein—A Lectin That Limits Inflammation Further Reading 271
Damage 240
SUMMARY 241 9 Membranes and Membrane Transport 273
Foundational Biochemistry 242 9.1 What Are the Chemical and Physical Properties
PROBLEMS 242 of Membranes? 274
Further Reading 243 The Composition of Membranes Suits Their Functions 274
Lipids Form Ordered Structures Spontaneously in Water 275
8 Lipids 245
The Fluid Mosaic Model Describes Membrane
8.1 What Are the Structures and Chemistry of Fatty Dynamics 277
Acids? 245 9.2 What Are the Structure and Chemistry
8.2 What Are the Structures and Chemistry of Membrane Proteins? 279
of Triacylglycerols? 248 Peripheral Membrane Proteins Associate Loosely
A Deeper Look: Polar Bears Prefer Nonpolar Food 249 with the Membrane 279
Detailed Contents xi
Integral Membrane Proteins Are Firmly Anchored The Properties of Pyrimidines and Purines Can Be Traced
in the Membrane 280 to Their Electron-Rich Nature 327
Lipid-Anchored Membrane Proteins Are Switching 10.2 What Are Nucleosides? 328
Devices 287 Human Biochemistry: Adenosine: A Nucleoside
Human Biochemistry: “Fat-Free Proteins” May Point with Physiological Activity 328
the Way to Drugs for Sleeping Sickness 289
10.3 What Are the Structure and Chemistry
9.3 How Are Biological Membranes Organized? 290 of Nucleotides? 329
Membranes Are Asymmetric and Heterogeneous Cyclic Nucleotides Are Cyclic Phosphodiesters 330
Structures 290
Nucleoside Diphosphates and Triphosphates Are
9.4 What Are the Dynamic Processes That Modulate Nucleotides with Two or Three Phosphate Groups 330
Membrane Function? 291 Human Biochemistry: cGAMP, A Cyclic Dinucleotide
Lipids and Proteins Undergo a Variety of Movements That Triggers a Response to Infection 331
in Membranes 291 NDPs and NTPs Are Polyprotic Acids 332
Membrane Lipids Can Be Ordered to Different Extents 292 Nucleoside 59-Triphosphates Are Carriers of Chemical
9.5 How Does Transport Occur Across Biological Energy 332
Membranes? 300 10.4 What Are Nucleic Acids? 333
9.6 What Is Passive Diffusion? 301 The Base Sequence of a Nucleic Acid Is Its Defining
Charged Species May Cross Membranes by Passive Characteristic 333
Diffusion 301 10.5 What Are the Different Classes of Nucleic Acids? 334
9.7 How Does Facilitated Diffusion Occur? 301 The Fundamental Structure of DNA Is a Double Helix 334
Membrane Channel Proteins Facilitate Diffusion 302 Various Forms of RNA Serve Different Roles in Cells 337
The B. cereus NaK Channel Uses a Variation A Deeper Look: Do the Properties of DNA Invite
on the K1 Selectivity Filter 304 Practical Applications? 339
CorA Is a Pentameric Mg21 Channel 305 A Deeper Look: The RNA World and Early Evolution 342
Chloride, Water, Glycerol, and Ammonia Flow Through The Chemical Differences Between DNA and RNA Have
Single-Subunit Pores 306 Biological Significance 342
9.8 How Does Energy Input Drive Active Transport 10.6 Are Nucleic Acids Susceptible to Hydrolysis? 343
Processes? 307 RNA Is Susceptible to Hydrolysis by Base, but DNA
All Active Transport Systems Are Energy-Coupling Is Not 343
Devices 307 The Enzymes That Hydrolyze Nucleic Acids Are
Many Active Transport Processes Are Driven by ATP 308 Phosphodiesterases 343
A Deeper Look: Cardiac Glycosides: Potent Drugs Nucleases Differ in Their Specificity for Different Forms of
from Ancient Times 312 Nucleic Acid 345
ABC Transporters Use ATP to Drive Import and Export Restriction Enzymes Are Nucleases That Cleave
Functions and Provide Multidrug Resistance 313 Double-Stranded DNA Molecules 345
9.9 How Are Certain Transport Processes Driven Type II Restriction Endonucleases Are Useful
for Manipulating DNA in the Lab 346
by Light Energy? 315
Restriction Endonucleases Can Be Used to Map
Bacteriorhodopsin Uses Light Energy to Drive Proton
the Structure of a DNA Fragment 349
Transport 315
SUMMARY 349
9.10 How Is Secondary Active Transport Driven by Ion
Gradients? 316 Foundational Biochemistry 350
Na and H Drive Secondary Active Transport 316
1 1 PROBLEMS 351
AcrB Is a Secondary Active Transport System 316 Further Reading 352
SUMMARY 318
11 Structure of Nucleic Acids 353
11.1 How Do Scientists Determine the Primary Structure
PROBLEMS 319
of Nucleic Acids? 353
Further Reading 321 The Nucleotide Sequence of DNA Can Be Determined
from the Electrophoretic Migration of a Defined Set
10 Nucleotides and Nucleic Acids 325 of Polynucleotide Fragments 354
10.1 What Are the Structure and Chemistry Sanger’s Chain Termination or Dideoxy Method Uses
of Nitrogenous Bases? 326 DNA Replication to Generate a Defined Set
Three Pyrimidines and Two Purines Are Commonly Found of Polynucleotide Fragments 354
in Cells 326 Next-Generation Sequencing 356
xii Detailed Contents
High-Throughput DNA Sequencing by the Light 11.7 What Are the Secondary and Tertiary Structures
of Fireflies 356 of RNA? 386
Illumina Next-Gen Sequencing 358 Transfer RNA Adopts Higher-Order Structure Through
Emerging Technologies to Sequence DNA Are Based Intrastrand Base Pairing 387
on Single-Molecule Sequencing Strategies 358 Messenger RNA Adopts Higher-Order Structure Through
Human Biochemistry: The Human Genome Intrastrand Base Pairing 390
Project 360 Ribosomal RNA Also Adopts Higher-Order Structure
11.2 What Sorts of Secondary Structures Can Through Intrastrand Base Pairing 391
Double-Stranded DNA Molecules Adopt? 360 Aptamers Are Oligonucleotides Specifically Selected
Conformational Variation in Polynucleotide Strands 360 for Their Ligand-Binding Ability 393
DNA Usually Occurs in the Form of Double-Stranded SUMMARY 393
Molecules 362 Foundational Biochemistry 395
Watson–Crick Base Pairs Have Virtually Identical PROBLEMS 395
Dimensions 362 Further Reading 397
The DNA Double Helix Is a Stable Structure 362
A Deeper Look: Why Just Two Base Pairs? 363
12 Recombinant DNA, Cloning, Chimeric
Double Helical Structures Can Adopt a Number of Stable
Conformations 365 Genes, and Synthetic Biology 399
A-Form DNA Is an Alternative Form of Right-Handed 12.1 What Does It Mean “To Clone”? 399
DNA 366 Plasmids Are Very Useful in Cloning Genes 400
Z-DNA Is a Conformational Variation in the Form Shuttle Vectors Are Plasmids That Can Propagate
of a Left-Handed Double Helix 367 in Two Different Organisms 405
The Double Helix Is a Very Dynamic Structure 369 Artificial Chromosomes Can Be Created
Human Biochemistry: DNA Methylation, CpG Islands, from Recombinant DNA 405
and Epigenetics 369 12.2 What Is a DNA Library? 406
Alternative Hydrogen-Bonding Interactions Give Rise Genomic Libraries Are Prepared from the Total DNA
to Novel DNA Structures: Cruciforms, Triplexes, in an Organism 406
and Quadruplexes 371
Critical Developments in Biochemistry:
11.3 Can the Secondary Structure of DNA Be Denatured Combinatorial Libraries 406
and Renatured? 374 Libraries Can Be Screened for the Presence of Specific
Thermal Denaturation of DNA Can Be Observed Genes 407
by Changes in UV Absorbance 374 Probes for Screening Libraries Can Be Prepared in a
pH Extremes or Strong H-Bonding Solutes also Denature Variety of Ways 408
DNA Duplexes 375 PCR Is Used to Clone and Amplify Specific Genes 408
Single-Stranded DNA Can Renature to Form DNA cDNA Libraries Are DNA Libraries Prepared
Duplexes 375 from mRNA 409
The Rate of DNA Renaturation Is an Index of DNA Critical Developments in Biochemistry: Identifying
Sequence Complexity 375 Specific DNA Sequences by Southern Blotting
A Deeper Look: The Buoyant Density of DNA 376 (Southern Hybridization) 410
Nucleic Acid Hybridization: Different DNA Strands DNA Microarrays (Gene Chips) Are Arrays of Different
of Similar Sequence Can Form Hybrid Duplexes 376 Oligonucleotides Immobilized on a Chip 412
11.4 Can DNA Adopt Structures of Higher Complexity? 377 12.3 Can the Cloned Genes in Libraries
Supercoils Are One Kind of Structural Complexity Be Expressed? 413
in DNA 377 Expression Vectors Are Engineered So That the
11.5 What Is the Structure of Eukaryotic Chromosomes? 379 RNA or Protein Products of Cloned Genes Can Be
Expressed 413
Nucleosomes Are the Fundamental Structural Unit
in Chromatin 380 Reporter Gene Constructs Are Chimeric DNA Molecules
Composed of Gene Regulatory Sequences Positioned
Higher-Order Structural Organization of Chromatin
Next to an Easily Expressible Gene Product 416
Gives Rise to Chromosomes 381
Specific Protein–Protein Interactions Can Be Identified
SMC Proteins Establish Chromosome Organization
Using the Yeast Two-Hybrid System 417
and Mediate Chromosome Dynamics 383
In Vitro Mutagenesis 419
11.6 Can Nucleic Acids Be Synthesized Chemically? 383
Phosphoramidite Chemistry Is Used to Form
12.4 How Is RNA Interference Used to Reveal
Oligonucleotides from Nucleotides 384 the Function of Genes? 419
Genes Can Be Synthesized Chemically 385 RNAi Using Synthetic shRNAs 420
Detailed Contents xiii
12.5 How Does High-Throughput Technology Catalysts Lower the Free Energy of Activation
Allow Global Study of Millions of Genes or for a Reaction 443
Molecules at Once? 420 Decreasing DG‡ Increases Reaction Rate 444
High-Throughput Screening 421 13.3 What Equations Define the Kinetics
DNA Laser Printing 421 of Enzyme‑Catalyzed Reactions? 444
High-Throughput RNAi Screening of Mammalian The Substrate Binds at the Active Site of an Enzyme 445
Genomes 422 The Michaelis–Menten Equation Is the Fundamental
High-Throughput Protein Screening 422 Equation of Enzyme Kinetics 445
12.6 Is It Possible to Make Directed Changes Assume That [ES] Remains Constant During
in the Heredity of an Organism? 422 an Enzymatic Reaction 445
Human Gene Therapy Can Repair Genetic Deficiencies 423 Assume That Velocity Measurements Are Made
Viruses as Vectors in Human Gene Therapy 423 Immediately After Adding S 446
Human Biochemistry: The Biochemical Defects
The Michaelis Constant, Km , Is Defined as
in Cystic Fibrosis and ADA2 SCID 424 (k21 1 k2)/k1 446
When [S] 5 Km , v 5 Vmax /2 447
12.7 What Is the New Field of Synthetic Biology? 425
Plots of v Versus [S] Illustrate the Relationships Between
DNA as Code 425
Vmax , Km , and Reaction Order 447
iGEM and BioBricks (Registry of Standard
Turnover Number Defines the Activity of One Enzyme
Biological Parts) 425
Molecule 448
Metabolic Engineering 426
The Ratio, kcat /Km , Defines the Catalytic Efficiency
Genome Engineering 427 of an Enzyme 449
Genome Editing with CRISPR/Cas9 427 Linear Plots Can Be Derived from the Michaelis–Menten
CRITICAL DEVELOPMENTS IN BIOCHEMistry: Equation 450
CRISPR/Cas9—Exploiting the Biology of Prokaryotic Nonlinear Lineweaver–Burk or Hanes–Woolf Plots Are
Adaptive Immunity to Edit Genomes 428 a Property of Regulatory Enzymes 451
Synthetic Genomes 430 Enzymatic Activity Is Strongly Influenced by pH 451
SUMMARY 430 A Deeper Look: An Example of the Effect of Amino Acid
Foundational Biochemistry 432 Substitutions on Km and kcat: Wild-Type and Mutant
PROBLEMS 433 Forms of Human Sulfite Oxidase 452
The Response of Enzymatic Activity to Temperature
Further Reading 434
Is Complex 453
13.4 What Can Be Learned from the Inhibition of Enzyme
Activity? 453
Part II Protein Dynamics Enzymes May Be Inhibited Reversibly or Irreversibly 453
Reversible Inhibitors May Bind at the Active Site
13 Enzymes—Kinetics and Specificity 437 or at Some Other Site 453
Enzymes Are the Agents of Metabolic Function 438 A Deeper Look: The Equations of Competitive
13.1 What Characteristic Features Define Enzymes? 438 Inhibition 455
Catalytic Power Is Defined as the Ratio of the Enzyme- Enzymes Also Can Be Inhibited in an Irreversible Manner 458
Catalyzed Rate of a Reaction to the Uncatalyzed Rate 438 13.5 What Is the Kinetic Behavior of Enzymes Catalyzing
Specificity Is the Term Used to Define the Selectivity Bimolecular Reactions? 459
of Enzymes for Their Substrates 439 Human Biochemistry: Viagra—An Unexpected
Regulation of Enzyme Activity Ensures That the Rate Outcome in a Program of Drug Design 459
of Metabolic Reactions Is Appropriate to Cellular The Conversion of AEB to PEQ Is the Rate-Limiting Step in
Requirements 439 Random, Single-Displacement Reactions 460
Enzyme Nomenclature Provides a Systematic Way In an Ordered, Single-Displacement Reaction,
of Naming Metabolic Reactions 439 the Leading Substrate Must Bind First 461
Coenzymes and Cofactors Are Nonprotein Components Double-Displacement (Ping-Pong) Reactions Proceed Via
Essential to Enzyme Activity 440 Formation of a Covalently Modified Enzyme Intermediate 462
13.2 Can the Rate of an Enzyme-Catalyzed Reaction Exchange Reactions Are One Way to Diagnose Bisubstrate
Be Defined in a Mathematical Way? 441 Mechanisms 464
Chemical Kinetics Provides a Foundation for Exploring Multisubstrate Reactions Can Also Occur in Cells 465
Enzyme Kinetics 441 13.6 How Can Enzymes Be So Specific? 465
Bimolecular Reactions Are Reactions Involving Two The “Lock and Key” Hypothesis Was the First Explanation
Reactant Molecules 442 for Specificity 465
xiv Detailed Contents
The “Induced Fit” Hypothesis Provides a More Accurate A Deeper Look: Transition-State Stabilization
Description of Specificity 465 in the Serine Proteases 499
“Induced Fit” Favors Formation of the Transition State 466 The Mechanism of Action of Aspartic Proteases 500
Specificity and Reactivity 466 The AIDS Virus HIV-1 Protease Is an Aspartic Protease 501
13.7 Are All Enzymes Proteins? 466 Chorismate Mutase: A Model for Understanding
RNA Molecules That Are Catalytic Have Been Termed Catalytic Power and Efficiency 502
“Ribozymes” 466 Human Biochemistry: Protease Inhibitors Give Life
Antibody Molecules Can Have Catalytic Activity 469 to AIDS Patients 504
SUMMARY 507
13.8 Is It Possible to Design an Enzyme to Catalyze
Any Desired Reaction? 470 Foundational Biochemistry 507
SUMMARY 471 PROBLEMS 508
Foundational Biochemistry 472 Further Reading 510
PROBLEMS 473
Further Reading 475 15 Enzyme Regulation 513
15.1 What Factors Influence Enzymatic Activity? 513
14 Mechanisms of Enzyme Action 477 The Availability of Substrates and Cofactors Usually
14.1 What Are the Magnitudes of Enzyme-Induced Rate Determines How Fast the Reaction Goes 514
Accelerations? 477 As Product Accumulates, the Apparent Rate
14.2 What Role Does Transition-State Stabilization Play in of the Enzymatic Reaction Will Decrease 514
Enzyme Catalysis? 479 Genetic Regulation of Enzyme Synthesis and Decay
Determines the Amount of Enzyme Present at Any
14.3 How Does Destabilization of ES Affect Enzyme Moment 514
Catalysis? 480
Enzyme Activity Can Be Regulated Allosterically 514
14.4 How Tightly Do Transition-State Analogs Bind Enzyme Activity Can Be Regulated Through Covalent
to the Active Site? 481 Modification 514
A Deeper Look: Transition-State Analogs Make Our Regulation of Enzyme Activity Also Can Be Accomplished
World Better 482 in Other Ways 515
14.5 What Are the Mechanisms of Catalysis? 485 Zymogens Are Inactive Precursors of Enzymes 515
Enzymes Facilitate Formation of Near-Attack Isozymes Are Enzymes with Slightly Different Subunits 516
Conformations 485 15.2 What Are the General Features of Allosteric
Protein Motions Are Essential to Enzyme Catalysis 485 Regulation? 518
A Deeper Look: How to Read and Write Mechanisms 486 Regulatory Enzymes Have Certain Exceptional Properties 518
Covalent Catalysis 488
15.3 Can Allosteric Regulation Be Explained
General Acid–Base Catalysis 489 by Conformational Changes in Proteins? 519
Low-Barrier Hydrogen Bonds 490 The Symmetry Model for Allosteric Regulation Is Based on
Quantum Mechanical Tunneling in Electron and Proton Two Conformational States for a Protein 519
Transfers 491 The Sequential Model for Allosteric Regulation Is Based
HUMAN BIOCHEMISTRY: Antibiotic Resistance by on Ligand-Induced Conformational Changes 520
Superbugs 491 Changes in the Oligomeric State of a Protein Can Also
Metal Ion Catalysis 492 Give Allosteric Behavior 521
A Deeper Look: How Do Active-Site Residues Interact 15.4 What Kinds of Covalent Modification Regulate
to Support Catalysis? 492
the Activity of Enzymes? 521
CRITICAL DEVELOPMENTS IN BIOCHEMistry: Measuring
Covalent Modification Through Reversible
the Electric Fields That Accelerate an Enzyme
Phosphorylation 521
Reaction 493
Protein Kinases: Target Recognition and Intrasteric
14.6 What Can Be Learned from Typical Enzyme Control 521
Mechanisms? 494 Phosphorylation Is Not the Only Form of Covalent
Serine Proteases 494 Modification That Regulates Protein Function 523
The Digestive Serine Proteases 494 Acetylation Is a Prominent Modification
The Chymotrypsin Mechanism in Detail: Kinetics 495 for the Regulation of Metabolic Enzymes 524
The Serine Protease Mechanism in Detail: Events 15.5 Is the Activity of Some Enzymes Controlled
at the Active Site 497 by Both Allosteric Regulation and Covalent
The Aspartic Proteases 497 Modification? 525
Detailed Contents xv
The Glycogen Phosphorylase Reaction Converts 16 Molecular Motors 547

Glycogen into Readily Usable Fuel in the Form
of Glucose-1-Phosphate 525 16.1 What Is a Molecular Motor? 547
Glycogen Phosphorylase Is a Homodimer 525 16.2 What Is the Molecular Mechanism of Muscle
Glycogen Phosphorylase Activity Is Regulated Contraction? 548
Allosterically 526 Muscle Contraction Is Triggered by Ca21 Release
Covalent Modification of Glycogen Phosphorylase Trumps from Intracellular Stores 548
Allosteric Regulation 528 Human Biochemistry: Smooth Muscle Effectors
Enzyme Cascades Regulate Glycogen Phosphorylase Are Useful Drugs 549
Covalent Modification 528 The Molecular Structure of Skeletal Muscle Is Based
Special Focus: Is There an Example in Nature That on Actin and Myosin 549
Exemplifies the Relationship Between Quaternary The Mechanism of Muscle Contraction Is Based
Structure and the Emergence of Allosteric Properties? on Sliding Filaments 552
Hemoglobin and Myoglobin—Paradigms of Protein A Deeper Look: The P-Loop NTPases—Energy to Run
Structure and Function 529 the Motors 552
Human Biochemistry: The Molecular Defect
The Comparative Biochemistry of Myoglobin
and Hemoglobin Reveals Insights into Allostery 530 in Duchenne Muscular Dystrophy Involves
an Actin-Anchoring Protein 553
Myoglobin Is an Oxygen-Storage Protein 531
Critical Developments in Biochemistry: Molecular
O2 Binds to the Mb Heme Group 531
“Tweezers” of Light Take the Measure of a Muscle Fiber’s
O2 Binding Alters Mb Conformation 531 Force 557
A Deeper Look: The Oxygen-Binding Curves
16.3 What Are the Molecular Motors That Orchestrate the
of Myoglobin and Hemoglobin 532
Mechanochemistry of Microtubules? 558
Cooperative Binding of Oxygen by Hemoglobin
Filaments of the Cytoskeleton Are Highways That Move
Has Important Physiological Significance 533
Cellular Cargo 558
Hemoglobin Has an a2 b2 Tetrameric Structure 533
Three Classes of Motor Proteins Move Intracellular
Oxygenation Markedly Alters the Quaternary Structure Cargo 560
of Hb 534
Human Biochemistry: Effectors of Microtubule
Movement of the Heme Iron by Less Than 0.04 nm Polymerization as Therapeutic Agents 561
Induces the Conformational Change in Hemoglobin 534
Dyneins Move Organelles in a Plus-to-Minus Direction;
A Deeper Look: The Physiological Significance
Kinesins, in a Minus-to-Plus Direction—Mostly 563
of the Hb∶O2 Interaction 535
Cytoskeletal Motors Are Highly Processive 563
The Oxy and Deoxy Forms of Hemoglobin Represent Two
ATP Binding and Hydrolysis Drive Hand-over-Hand
Different Conformational States 535
Movement of Kinesin 564
The Allosteric Behavior of Hemoglobin Has Both
Human Biochemistry: Discovering the “Tubulin Code” 566
Symmetry (MWC) Model and Sequential (KNF) Model
Components 535 The Conformation Change That Leads to Movement
Is Different in Myosins and Dyneins 567
H1 Promotes the Dissociation of Oxygen from
Hemoglobin 536 16.4 How Do Molecular Motors Unwind DNA? 568
CO2 Also Promotes the Dissociation of O2 Negative Cooperativity Facilitates Hand-over-Hand
from Hemoglobin 536 Movement 569
A Deeper Look: Changes in the Heme Iron Papillomavirus E1 Helicase Moves along DNA
upon O2 Binding 537 on a Spiral Staircase 570
2,3-Bisphosphoglycerate Is an Important Allosteric 16.5 How Do Bacterial Flagella Use a Proton Gradient to
Effector for Hemoglobin 537 Drive Rotation? 573
BPG Binding to Hb Has Important Physiological The Flagellar Rotor Is a Complex Structure 574
Significance 538
Gradients of H1 and Na1 Drive Flagellar Rotors 574
Fetal Hemoglobin Has a Higher Affinity for O2 Because
The Flagellar Rotor Self-Assembles in a Spontaneous
It Has a Lower Affinity for BPG 538 Process 575
Human Biochemistry: Hemoglobin and Nitric Oxide 539
Flagellar Filaments Are Composed of Protofilaments
Sickle-Cell Anemia Is Characterized by Abnormal Red of Flagellin 575
Blood Cells 540 Motor Reversal Involves Conformation Switching
Sickle-Cell Anemia Is a Molecular Disease 540 of Motor and Filament Proteins 576
SUMMARY 541 SUMMARY 578
Foundational Biochemistry 542 Foundational Biochemistry 579
PROBLEMS 543 PROBLEMS 579
Further Reading 544 Further Reading 580
xvi Detailed Contents
Part III Metabolism and Its Regulation 18 Glycolysis 611

18.1 What Are the Essential Features of Glycolysis? 611
17 Metabolism: An Overview 583 18.2 Why Are Coupled Reactions Important in Glycolysis? 613
17.1 Is Metabolism Similar in Different Organisms? 583 18.3 What Are the Chemical Principles and Features
Living Things Exhibit Metabolic Diversity 584 of the First Phase of Glycolysis? 614
Oxygen Is Essential to Life for Aerobes 584 Reaction 1: Glucose Is Phosphorylated by Hexokinase
The Flow of Energy in the Biosphere and the Carbon or Glucokinase—The First Priming Reaction 614
and Oxygen Cycles Are Intimately Related 584 A Deeper Look: Glucokinase—An Enzyme with Different
A Deeper Look: Calcium Carbonate—A Biological Sink Roles in Different Cells 617
for CO2 585 Reaction 2: Phosphoglucoisomerase Catalyzes
17.2 What Can Be Learned from Metabolic Maps? 585 the Isomerization of Glucose-6-Phosphate 618
The Metabolic Map Can Be Viewed as a Set of Dots Reaction 3: ATP Drives a Second Phosphorylation by
and Lines 585 Phosphofructokinase—The Second Priming Reaction 619
Alternative Models Can Provide New Insights A Deeper Look: Phosphoglucoisomerase—
into Pathways 588 A Moonlighting Protein 620
Multienzyme Systems May Take Different Forms 589 Reaction 4: Cleavage by Fructose Bisphosphate Aldolase
Creates Two 3-Carbon Intermediates 620
17.3 How Do Anabolic and Catabolic Processes Form the
Reaction 5: Triose Phosphate Isomerase Completes
Core of Metabolic Pathways? 590
the First Phase of Glycolysis 621
Anabolism Is Biosynthesis 590
18.4 What Are the Chemical Principles and Features
Anabolism and Catabolism Are Not Mutually
Exclusive 591 of the Second Phase of Glycolysis? 622
The Pathways of Catabolism Converge to a Few End Reaction 6: Glyceraldehyde-3-Phosphate Dehydrogenase
Products 591 Creates a High-Energy Intermediate 622
Anabolic Pathways Diverge, Synthesizing an Astounding Reaction 7: Phosphoglycerate Kinase Is the Break-Even
Variety of Biomolecules from a Limited Set of Building Reaction 624
Blocks 591 Reaction 8: Phosphoglycerate Mutase Catalyzes
Amphibolic Intermediates Play Dual Roles 593 a Phosphoryl Transfer 625
Corresponding Pathways of Catabolism and Anabolism Reaction 9: Dehydration by Enolase Creates PEP 625
Differ in Important Ways 593 Reaction 10: Pyruvate Kinase Yields More ATP 626
ATP Serves in a Cellular Energy Cycle 593 HUMAN BIOCHEMISTRY: Pyruvate Kinase M2—
NAD1 Collects Electrons Released in Catabolism 594 A Moonlighting Protein Kinase in Cancer 628
NADPH Provides the Reducing Power for Anabolic 18.5 What Are the Metabolic Fates of NADH
Processes 595 and Pyruvate Produced in Glycolysis? 629
Coenzymes and Vitamins Provide Unique Chemistry Anaerobic Metabolism of Pyruvate Leads to Lactate
and Essential Nutrients to Pathways 595 or Ethanol 629
17.4 What Experiments Can Be Used to Elucidate Metabolic Lactate Accumulates Under Anaerobic Conditions
Pathways? 597 in Animal Tissues 629
Critical Developments in Biochemistry: The Warburg
Mutations Create Specific Metabolic Blocks 597
Effect and Cancer 631
Isotopic Tracers Can Be Used as Metabolic Probes 598
The Old Shell Game—How Turtles Survive the
NMR Spectroscopy Is a Noninvasive Metabolic Probe 599
Winter 632
Metabolic Pathways Are Compartmentalized
Within Cells 600 18.6 How Do Cells Regulate Glycolysis? 632
17.5 What Can the Metabolome Tell Us about a Biological 18.7 Are Substrates Other Than Glucose Used
System? 602 in Glycolysis? 632
Fructose Catabolism in Liver is Unregulated—and
17.6 What Food Substances Form the Basis of Human
Potentially Harmful 632
Nutrition? 605
Mannose Enters Glycolysis in Two Steps 633
Humans Require Protein 605
Galactose Enters Glycolysis via the Leloir Pathway 633
Carbohydrates Provide Metabolic Energy 606
Human Biochemistry: Tumor Diagnosis Using Positron
Lipids Are Essential, but in Moderation 606 Emission Tomography (PET) 634
SUMMARY 606 An Enzyme Deficiency Causes Lactose Intolerance 636
Foundational Biochemistry 607 Glycerol Can Also Enter Glycolysis 636
PROBLEMS 608 Human Biochemistry: Lactose—From Mother’s Milk
Further Reading 609 to Yogurt—and Lactose Intolerance 636
Detailed Contents xvii
18.8 How Do Cells Respond to Hypoxic Stress? 637 Human Biochemistry: TCA Metabolites Play Roles in
SUMMARY 638 Many Pathways Via Post-Translational Modifications 669
Foundational Biochemistry 639 The TCA Cycle Operates as a Metabolon 669
PROBLEMS 639 19.9 Can Any Organisms Use Acetate as Their Sole Carbon
Source? 670
Further Reading 641
The Glyoxylate Cycle Operates in Specialized Organelles 671
19 The Tricarboxylic Acid Cycle 643 Isocitrate Lyase Short-Circuits the TCA Cycle
by Producing Glyoxylate and Succinate 671
19.1 What Is the Chemical Logic of the TCA Cycle? 644
The Glyoxylate Cycle Helps Plants Grow in the Dark 672
The TCA Cycle Provides a Chemically Feasible Way
of Cleaving a Two-Carbon Compound 645 Glyoxysomes Must Borrow Three Reactions
from Mitochondria 672
19.2 How Is Pyruvate Oxidatively Decarboxylated
SUMMARY 673
to Acetyl-CoA? 645
A Deeper Look: The Coenzymes of the Pyruvate
Dehydrogenase Complex 647 PROBLEMS 674
Further Reading 675
19.3 How Are Two CO2 Molecules Produced from
Acetyl-CoA? 652 20 Electron Transport and Oxidative
The Citrate Synthase Reaction Initiates the TCA Cycle 652 Phosphorylation 679
Citrate Is Isomerized by Aconitase to Form Isocitrate 653
20.1 Where in the Cell Do Electron Transport
Isocitrate Dehydrogenase Catalyzes the First Oxidative
and Oxidative Phosphorylation Occur? 679
Decarboxylation in the Cycle 655
Mitochondrial Functions Are Localized in Specific
a-Ketoglutarate Dehydrogenase Catalyzes the Second
Compartments 680
Oxidative Decarboxylation of the TCA Cycle 656
Human Biochemistry: Mitochondrial Dynamics in
19.4 How Is Oxaloacetate Regenerated to Complete Human Diseases 681
the TCA Cycle? 656
The Mitochondrial Matrix Contains the Enzymes
Succinyl-CoA Synthetase Catalyzes Substrate-Level of the TCA Cycle 682
Phosphorylation 656
20.2 How Is the Electron-Transport Chain Organized? 682
Succinate Dehydrogenase Is FAD-Dependent 657
The Electron-Transport Chain Can Be Isolated
Fumarase Catalyzes the Trans-Hydration of Fumarate
in Four Complexes 682
to Form l-Malate 658
Complex I Oxidizes NADH and Reduces Coenzyme Q 683
Malate Dehydrogenase Completes the Cycle
by Oxidizing Malate to Oxaloacetate 659 Human Biochemistry: Solving a Medical Mystery
Revolutionized Our Treatment of Parkinson’s Disease 685
19.5 What Are the Energetic Consequences
Complex II Oxidizes Succinate and Reduces
of the TCA Cycle? 659 Coenzyme Q 687
A Deeper Look: Steric Preferences in NAD1-Dependent
Complex III Mediates Electron Transport from Coenzyme Q
Dehydrogenases 660 to Cytochrome c 688
The Carbon Atoms of Acetyl-CoA Have Different Fates Complex IV Transfers Electrons from Cytochrome c
in the TCA Cycle 660 to Reduce Oxygen on the Matrix Side 692
19.6 Can the TCA Cycle Provide Intermediates Proton Transport Across Cytochrome c Oxidase
for Biosynthesis? 662 Is Coupled to Oxygen Reduction 694
Human Biochemistry: Mitochondrial Diseases The Complexes of Electron Transport May Function
Are Rare 663 as Supercomplexes 695
19.7 What Are the Anaplerotic, or “Filling Up,” Electron Transfer Energy Stored in a Proton Gradient:
Reactions? 663 The Mitchell Hypothesis 696
A Deeper Look: Anaplerosis Plays a Critical Role 20.3 What Are the Thermodynamic Implications
in Insulin Secretion 664 of Chemiosmotic Coupling? 697
A Deeper Look: Fool’s Gold and the Reductive Citric Acid 20.4 How Does a Proton Gradient Drive the Synthesis
Cycle—The First Metabolic Pathway? 665 of ATP? 698
19.8 How Is the TCA Cycle Regulated? 665 ATP Synthase Is Composed of F1 and F0 698
Pyruvate Dehydrogenase Is Regulated The Catalytic Sites of ATP Synthase Adopt Three Different
by Phosphorylation/Dephosphorylation 667 Conformations 699
Isocitrate Dehydrogenase Is Strongly Regulated 668 Boyer’s 18O Exchange Experiment Identified
Regulation of TCA Cycle Enzymes by Acetylation 668 the Energy-Requiring Step 700
Two Covalent Modifications Regulate E. coli Isocitrate Boyer’s Binding Change Mechanism Describes
Dehydrogenase 668 the Events of Rotational Catalysis 701
xviii Detailed Contents
Proton Flow Through F0 Drives Rotation of the Motor PSI and PSII Participate in the Overall Process
and Synthesis of ATP 701 of Photosynthesis 727
How Many Protons Are Required to Make an ATP? The Pathway of Photosynthetic Electron Transfer Is Called
It Depends on the Organism 703 the Z Scheme 727
Racker and Stoeckenius Confirmed the Mitchell Model Oxygen Evolution Requires the Accumulation of Four
in a Reconstitution Experiment 703 Oxidizing Equivalents in PSII 729
Inhibitors of Oxidative Phosphorylation Reveal Insights Electrons Are Taken from H2O to Replace Electrons Lost
About the Mechanism 703 from P680 729
Uncouplers Disrupt the Coupling of Electron Transport Electrons from PSII Are Transferred to PSI
and ATP Synthase 705 via the Cytochrome b6 f Complex 729
Human Biochemistry: Endogenous Uncouplers— Plastocyanin Transfers Electrons from the Cytochrome b6 f
Novel Proteins with Many Beneficial Effects 705 Complex to PSI 730
ATP–ADP Translocase Mediates the Movement of ATP 21.4 What Is the Molecular Architecture of Photosynthetic
and ADP Across the Mitochondrial Membrane 706 Reaction Centers? 731
20.5 What Is the P/O Ratio for Mitochondrial Oxidative The R. viridis Photosynthetic Reaction Center
Phosphorylation? 707 Is an Integral Membrane Protein 731
20.6 How Are the Electrons of Cytosolic NADH Fed Photosynthetic Electron Transfer by the R. viridis Reaction
into Electron Transport? 708 Center Leads to ATP Synthesis 731
The Glycerophosphate Shuttle Ensures Efficient Use The Molecular Architecture of PSII Resembles
of Cytosolic NADH 708 the R. viridis Reaction Center Architecture 732
The Malate–Aspartate Shuttle Is Reversible 709 How Does PSII Generate O2 from H2O? 734
The Net Yield of ATP from Glucose Oxidation Depends on The Molecular Architecture of PSI Resembles
the Shuttle Used 709 the R. viridis Reaction Center and PSII Architecture 735
3.5 Billion Years of Evolution Have Resulted in a Very How Do Green Plants Carry Out Photosynthesis? 736
Efficient System 711 21.5 What Is the Quantum Yield of Photosynthesis? 737
20.7 How Do Mitochondria Mediate Apoptosis? 711 Calculation of the Photosynthetic Energy Requirements for
Cytochrome c Triggers Apoptosome Assembly 711 Hexose Synthesis Depends on H1/hy and ATP/H1 Ratios 737
Human Biochemistry: Cardiolipin—Key to 21.6 How Does Light Drive the Synthesis of ATP? 737
Mitochondrial Physiology 713 The Mechanism of Photophosphorylation
SUMMARY 714 Is Chemiosmotic 738
Foundational Biochemistry 715 CF1CF0 –ATP Synthase Is the Chloroplast Equivalent
of the Mitochondrial F1F0 –ATP Synthase 738
PROBLEMS 715
Photophosphorylation Can Occur in Either a Noncyclic
Further Reading 717 or a Cyclic Mode 738
21 Photosynthesis 719 Cyclic Photophosphorylation Generates ATP but Not
NADPH or O2 740
21.1 What Are the General Properties of Photosynthesis? 720
21.7 How Is Carbon Dioxide Used to Make Organic
Photosynthesis Occurs in Membranes 720
Molecules? 740
Photosynthesis Consists of Both Light Reactions
and Dark Reactions 721 Ribulose-1,5-Bisphosphate Is the CO2 Acceptor
in CO2 Fixation 741
Water Is the Ultimate e2 Donor for Photosynthetic NADP1
Reduction 722 2-Carboxy-3-Keto-Arabinitol Is an Intermediate in the
Ribulose-1,5-Bisphosphate Carboxylase Reaction 741
21.2 How Is Solar Energy Captured by Chlorophyll? 723 Ribulose-1,5-Bisphosphate Carboxylase Exists in Inactive
Chlorophylls and Accessory Light-Harvesting Pigments and Active Forms 742
Absorb Light of Different Wavelengths 723
CO2 Fixation into Carbohydrate Proceeds via
The Light Energy Absorbed by Photosynthetic Pigments the Calvin–Benson Cycle 742
Has Several Possible Fates 724
The Enzymes of the Calvin Cycle Serve Three Metabolic
The Transduction of Light Energy into Chemical Energy Purposes 742
Involves Oxidation–Reduction 725
The Calvin Cycle Reactions Can Account for Net Hexose
Photosynthetic Units Consist of Many Chlorophyll Synthesis 743
Molecules but Only a Single Reaction Center 726
The Carbon Dioxide Fixation Pathway Is Indirectly
21.3 What Kinds of Photosystems Are Used to Capture Activated by Light 745
Light Energy? 726 Protein–Protein Interactions Mediated by an Intrinsically
Chlorophyll Exists in Plant Membranes in Association with Unstructured Protein Also Regulate Calvin–Benson
Proteins 727 Cycle Activity 746
Detailed Contents xix
21.8 How Does Photorespiration Limit CO2 Fixation? 746 A Deeper Look: Carbohydrate Utilization in Exercise 775
Tropical Grasses Use the Hatch–Slack Pathway Human Biochemistry: von Gierke Disease—
to Capture Carbon Dioxide for CO2 Fixation 746 A Glycogen-Storage Disease 776
Cacti and Other Desert Plants Capture CO2 at Night 749 Critical Developments in Biochemistry: O-GlcNAc
SUMMARY 749 Signaling and the Hexosamine Biosynthetic Pathway 778
Foundational Biochemistry 750 22.6 Can Glucose Provide Electrons for Biosynthesis? 780
PROBLEMS 751 The Pentose Phosphate Pathway Operates Mainly
in Liver and Adipose Cells 780
Further Reading 753
The Pentose Phosphate Pathway Begins with Two
22 Gluconeogenesis, Glycogen Metabolism, Oxidative Steps 780
There Are Four Nonoxidative Reactions in the Pentose
and the Pentose Phosphate Pathway 755 Phosphate Pathway 782
22.1 What Is Gluconeogenesis, and How Does Human Biochemistry: Aldose Reductase and Diabetic
It Operate? 755 Cataract Formation 783
The Substrates for Gluconeogenesis Include Pyruvate, Utilization of Glucose-6-P Depends on the Cell’s Need for
Lactate, and Amino Acids 756 ATP, NADPH, and Ribose-5-P 786
Nearly All Gluconeogenesis Occurs in the Liver Critical Developments in Biochemistry: Integrating
and Kidneys in Animals 756 the Warburg Effect—ATP Consumption Promotes Cancer
Human Biochemistry: The Chemistry of Glucose Metabolism 788
Monitoring Devices 756 Xylulose-5-Phosphate Is a Metabolic Regulator 789
Gluconeogenesis Is Not Merely the Reverse of Glycolysis 757 SUMMARY 790
Gluconeogenesis—Something Borrowed, Something Foundational Biochemistry 790
New 757
PROBLEMS 791
Four Reactions Are Unique to Gluconeogenesis 757
Further Reading 792
Human Biochemistry: Gluconeogenesis Inhibitors
and Other Diabetes Therapy Strategies 762
23 Fatty Acid Catabolism 795
22.2 How Is Gluconeogenesis Regulated? 763
23.1 How Are Fats Mobilized from Dietary Intake
Critical Developments in Biochemistry:
and Adipose Tissue? 795
The Pioneering Studies of Carl and Gerty Cori 763
Modern Diets Are Often High in Fat 795
Gluconeogenesis Is Regulated by Allosteric
and Substrate-Level Control Mechanisms 764 Triacylglycerols Are a Major Form of Stored Energy
in Animals 795
A Deeper Look: TIGAR—a p53-Induced Enzyme
That Mimics Fructose-2,6-Bisphosphatase 766 Hormones Trigger the Release of Fatty Acids
from Adipose Tissue 796
Substrate Cycles Provide Metabolic Control Mechanisms 767
Degradation of Dietary Triacylglycerols Occurs Primarily
22.3 How Are Glycogen and Starch Catabolized in the Duodenum 796
in Animals? 767 Human Biochemistry: Serum Albumin—Tramp
Dietary Starch Breakdown Provides Metabolic Energy 767 Steamer of the Bloodstream 799
Metabolism of Tissue Glycogen Is Regulated 769 A Deeper Look: The Biochemistry of Obesity 800
22.4 How Is Glycogen Synthesized? 769 23.2 How Are Fatty Acids Broken Down? 800
Glucose Units Are Activated for Transfer by Formation Knoop Elucidated the Essential Feature of
of Sugar Nucleotides 769 b-Oxidation 800
UDP–Glucose Synthesis Is Driven by Pyrophosphate Coenzyme A Activates Fatty Acids for Degradation 801
Hydrolysis 770 Carnitine Carries Fatty Acyl Groups Across the Inner
Glycogen Synthase Catalyzes Formation of a(18n4) Mitochondrial Membrane 802
Glycosidic Bonds in Glycogen 771 b-Oxidation Involves a Repeated Sequence of Four
Glycogen Branching Occurs by Transfer of Terminal Chain Reactions 803
Segments 771 Repetition of the b-Oxidation Cycle Yields a Succession of
Human Biochemistry: Advanced Glycation End Acetate Units 807
Products—A Serious Complication of Diabetes 772 A Deeper Look: A Trifunctional Protein Complex Provides
22.5 How Is Glycogen Metabolism Controlled? 773 a Substrate Channeling Pathway for Fatty Acid
Glycogen Metabolism Is Highly Regulated 773 Oxidation 808
Glycogen Synthase Is Regulated by Covalent Human Biochemistry: Exercise Can Reverse
Modification 773 the Consequences of Metabolic Syndrome 809
Hormones Regulate Glycogen Synthesis and Complete b-Oxidation of One Palmitic Acid Yields
Degradation 775 106 Molecules of ATP 809
xx Detailed Contents
Migratory Birds Travel Long Distances on Energy Phosphorylation of ACC Modulates Activation by Citrate
from Fatty Acid Oxidation 810 and Inhibition by Palmitoyl-CoA 829
Fatty Acid Oxidation Is an Important Source of Metabolic Acyl Carrier Proteins Carry the Intermediates in Fatty Acid
Water for Some Animals 811 Synthesis 830
23.3 How Are Odd-Carbon Fatty Acids Oxidized? 812 In Some Organisms, Fatty Acid Synthesis Takes Place
b-Oxidation of Odd-Carbon Fatty Acids Yields in Multienzyme Complexes 830
Propionyl-CoA 812 Decarboxylation Drives the Condensation of Acetyl-CoA
A B12-Catalyzed Rearrangement Yields Succinyl-CoA from and Malonyl-CoA 831
l-Methylmalonyl-CoA 812 A Deeper Look: Choosing the Best Organism for the
Net Oxidation of Succinyl-CoA Requires Conversion Experiment 831
to Acetyl-CoA 813 Reduction of the b-Carbonyl Group Follows
A Deeper Look: The Activation of Vitamin B12 813
a Now-Familiar Route 833
Eukaryotes Build Fatty Acids on Megasynthase
23.4 How Are Unsaturated Fatty Acids Oxidized? 814
Complexes 834
An Isomerase and a Reductase Facilitate the b-Oxidation
C16 Fatty Acids May Undergo Elongation and Unsaturation 836
of Unsaturated Fatty Acids 814
Unsaturation Reactions Occur in Eukaryotes
Degradation of Polyunsaturated Fatty Acids Requires
in the Middle of an Aliphatic Chain 837
2,4-Dienoyl-CoA Reductase 814
The Unsaturation Reaction May Be Followed by Chain
A Deeper Look: Can Natural Antioxidants in Certain
Elongation 838
Foods Improve Fat Metabolism? 816
Mammals Cannot Synthesize Most Polyunsaturated Fatty
23.5 Are There Other Ways to Oxidize Fatty Acids? 816 Acids 838
Peroxisomal b-Oxidation Requires FAD-Dependent Arachidonic Acid Is Synthesized from Linoleic Acid
Acyl-CoA Oxidase 816 by Mammals 838
Branched-Chain Fatty Acids Are Degraded Via Regulatory Control of Fatty Acid Metabolism
a-Oxidation 817 Is an Interplay of Allosteric Modifiers
v-Oxidation of Fatty Acids Yields Small Amounts and Phosphorylation–Dephosphorylation Cycles 839
of Dicarboxylic Acids 817 Hormonal Signals Regulate ACC and Fatty Acid
Human Biochemistry: Refsum’s Disease Is a Result Biosynthesis 839
of Defects in a-Oxidation 818 Human Biochemistry: v3 and v6—Essential Fatty
23.6 What Are Ketone Bodies, and What Role Do They Play Acids with Many Functions 840
in Metabolism? 818 24.2 How Are Complex Lipids Synthesized? 841
Ketone Bodies Are a Significant Source of Fuel Glycerolipids Are Synthesized by Phosphorylation
and Energy for Certain Tissues 818 and Acylation of Glycerol 842
Human Biochemistry: Large Amounts of Ketone Bodies Eukaryotes Synthesize Glycerolipids
Are Produced in Diabetes Mellitus 818 from CDP-Diacylglycerol or Diacylglycerol 842
b-Hydroxybutyrate Is a Signaling Metabolite 819 Human Biochemistry: Lipins—Phosphatases Essential
SUMMARY 820 for Triglyceride Synthesis and Other Functions 842
Foundational Biochemistry 821 Phosphatidylethanolamine Is Synthesized
from Diacylglycerol and CDP-Ethanolamine 843
PROBLEMS 821
Exchange of Ethanolamine for Serine Converts
Further Reading 823
Phosphatidylethanolamine to Phosphatidylserine 845
Eukaryotes Synthesize Other Phospholipids
24 Lipid Biosynthesis 825 Via CDP-Diacylglycerol 845
24.1 How Are Fatty Acids Synthesized? 826 Dihydroxyacetone Phosphate Is a Precursor
Formation of Malonyl-CoA Activates Acetate Units to the Plasmalogens 845
for Fatty Acid Synthesis 826 Platelet-Activating Factor Is Formed by Acetylation
Fatty Acid Biosynthesis Depends on the Reductive Power of 1-Alkyl-2-Lysophosphatidylcholine 848
of NADPH 826 Sphingolipid Biosynthesis Begins with Condensation
Cells Must Provide Cytosolic Acetyl-CoA and Reducing of Serine and Palmitoyl-CoA 848
Power for Fatty Acid Synthesis 826 Ceramide Is the Precursor for Other Sphingolipids
Acetate Units Are Committed to Fatty Acid Synthesis and Cerebrosides 848
by Formation of Malonyl-CoA 827 24.3 How Are Eicosanoids Synthesized, and What Are
Acetyl-CoA Carboxylase Is Biotin Dependent Their Functions? 851
and Displays Ping-Pong Kinetics 828 Eicosanoids Are Local Hormones 851
Acetyl-CoA Carboxylase in Animals Is a Multifunctional Prostaglandins Are Formed from Arachidonate
Protein 829 by Oxidation and Cyclization 851
Detailed Contents xxi
A Deeper Look: The Discovery of Prostaglandins 851 25 Nitrogen Acquisition and Amino Acid
A Variety of Stimuli Trigger Arachidonate Release Metabolism 877
and Eicosanoid Synthesis 853
“Take Two Aspirin and . . . ” Inhibit Your Prostaglandin 25.1 Which Metabolic Pathways Allow Organisms
Synthesis 853 to Live on Inorganic Forms of Nitrogen? 877
Human Biochemistry: Lipoxins—Anti-Inflammatory Nitrogen Is Cycled Between Organisms
Eicosanoid Products of Transcellular Metabolism 854 and the Inanimate Environment 877
A Deeper Look: The Molecular Basis for the Action Nitrate Assimilation Is the Principal Pathway
of Nonsteroidal Anti-inflammatory Drugs 855 for Ammonium Biosynthesis 878
Organisms Gain Access to Atmospheric N2 Via
24.4 How Is Cholesterol Synthesized? 856
the Pathway of Nitrogen Fixation 879
Mevalonate Is Synthesized from Acetyl-CoA Via
HMG-CoA Synthase 856 25.2 What Is the Metabolic Fate of Ammonium? 882
A Thiolase Brainteaser Asks Why Thiolase Can’t Be Used The Major Pathways of Ammonium Assimilation Lead
in Fatty Acid Synthesis 857 to Glutamine Synthesis 884
Critical Developments in Biochemistry: The Long 25.3 What Regulatory Mechanisms Act on Escherichia coli
Search for the Route of Cholesterol Biosynthesis 858 Glutamine Synthetase? 886
Squalene Is Synthesized from Mevalonate 858 Glutamine Synthetase Is Allosterically Regulated 887
Human Biochemistry: Statins Lower Serum Cholesterol Glutamine Synthetase Is Regulated by Covalent
Levels 860 Modification 887
Conversion of Lanosterol to Cholesterol Requires Glutamine Synthetase Is Regulated Through Gene
20 Additional Steps 862 Expression 889
24.5 How Are Lipids Transported Throughout the Body? 862 Glutamine in the Human Body 889
Lipoprotein Complexes Transport Triacylglycerols 25.4 How Do Organisms Synthesize Amino Acids? 890
and Cholesterol Esters 862 Human Biochemistry: Human Dietary Requirements
Human Biochemistry: APOC3—An Apolipoprotein for Amino Acids 891
That Regulates Plasma Triglyceride Levels 864 Amino Acids Are Formed from a-Keto Acids
Lipoproteins in Circulation Are Progressively Degraded by by Transamination 891
Lipoprotein Lipase 864 A Deeper Look: The Mechanism of the Aminotransferase
The Structure of the LDL Receptor Involves Five Domains 865 (Transamination) Reaction 892
The LDL Receptor b-Propellor Displaces LDL Particles The Pathways of Amino Acid Biosynthesis Can Be
in Endosomes 866 Organized into Families 892
Defects in Lipoprotein Metabolism Can Lead to Elevated The a-Ketoglutarate Family of Amino Acids Includes Glu,
Serum Cholesterol 866 Gln, Pro, Arg, and Lys 893
Human Biochemistry: New Cholesterol-Lowering The Urea Cycle Acts to Excrete Excess N Through Arg
Drugs Target PCSK9, an LDL Receptor Chaperone 867 Breakdown 894
Human Biochemistry: Niemann—Pick A Deeper Look: The Urea Cycle as Both an Ammonium
Type C Disease—A Hydrophobic Handoff and a Bicarbonate Disposal Mechanism 897
Fumbled 868 The Oxaloacetate Family of Amino Acids Includes Asp,
24.6 How Are Bile Acids Biosynthesized? 869 Asn, Lys, Met, Thr, and Ile 897
Human Biochemistry: Steroid 5a—Reductase— Human Biochemistry: Asparagine and
A Factor in Male Baldness, Prostatic Hyperplasia, and Leukemia 899
Prostate Cancer 870 The Pyruvate Family of Amino Acids Includes Ala, Val, and
24.7 How Are Steroid Hormones Synthesized and Leu 903
Utilized? 870 The 3-Phosphoglycerate Family of Amino Acids Includes
Ser, Gly, and Cys 903
Pregnenolone and Progesterone Are the Precursors
of All Other Steroid Hormones 870 The Aromatic Amino Acids Are Synthesized
from Chorismate 907
Steroid Hormones Modulate Transcription in the Nucleus 871
A Deeper Look: Amino Acid Biosynthesis Inhibitors
Cortisol and Other Corticosteroids Regulate a Variety
as Herbicides 911
of Body Processes 871
A Deeper Look: Intramolecular Tunnels Connect Distant
Anabolic Steroids Have Been Used Illegally to Enhance
Active Sites in Some Enzymes 912
Athletic Performance 872
Histidine Biosynthesis and Purine Biosynthesis Are
SUMMARY 872
Connected by Common Intermediates 912
25.5 How Does Amino Acid Catabolism Lead
PROBLEMS 874 into Pathways of Energy Production? 914
Further Reading 875
xxii Detailed Contents
The 20 Common Amino Acids Are Degraded 26.6 How Are Pyrimidines Degraded? 946
by 20 Different Pathways That Converge to Just 26.7 How Do Cells Form the Deoxyribonucleotides
7 Metabolic Intermediates 914
That Are Necessary for DNA Synthesis? 946
A Deeper Look: Histidine—A Clue to Understanding
E. coli Ribonucleotide Reductase Has Three Different
Early Evolution? 915
Nucleotide-Binding Sites 946
A Deeper Look: The Serine Dehydratase Reaction—
Thioredoxin Provides the Reducing Power
A b-Elimination 917
for Ribonucleotide Reductase 947
Animals Differ in the Form of Nitrogen That They Excrete 921
Both the Specificity and the Catalytic Activity
Human Biochemistry: Hereditary Defects in Phe of Ribonucleotide Reductase Are Regulated
Catabolism Underlie Alkaptonuria and Phenylketonuria 921 by Nucleotide Binding 948
SUMMARY 922 26.8 How Are Thymine Nucleotides Synthesized? 949
Foundational Biochemistry 923 A Deeper Look: Fluoro-Substituted Analogs
PROBLEMS 924 as Therapeutic Agents 951
Further Reading 925 Human Biochemistry: Fluoro-Substituted Pyrimidines
in Cancer Chemotherapy, Fungal Infections,
26 Synthesis and Degradation of Nucleotides 927 and Malaria 952
26.1 Can Cells Synthesize Nucleotides? 927 SUMMARY 952
26.2 How Do Cells Synthesize Purines? 928 Foundational Biochemistry 953
IMP Is the Immediate Precursor to GMP and AMP 928 PROBLEMS 954
A Deeper Look: Tetrahydrofolate and One-Carbon Further Reading 955
Units 930
HUMAN BIOCHEMISTRY: SAICAR Is a Key Signal for 27 Metabolic Integration and Organ
Metabolic Reprogramming in Cancer Cells 932
Specialization 957
Human Biochemistry: Folate Analogs as Antimicrobial
and Anticancer Agents 933 27.1 Can Systems Analysis Simplify the Complexity
AMP and GMP Are Synthesized from IMP 933 of Metabolism? 957
The Purine Biosynthetic Pathway Is Regulated at Several Only a Few Intermediates Interconnect the Major
Steps 934 Metabolic Systems 959
ATP-Dependent Kinases Form Nucleoside Diphosphates and ATP and NADPH Couple Anabolism and Catabolism 959
Triphosphates from the Nucleoside Monophosphates 935 Phototrophs Have an Additional Metabolic System—
26.3 Can Cells Salvage Purines? 936 The Photochemical Apparatus 959
26.4 How Are Purines Degraded? 936 27.2 What Underlying Principle Relates ATP Coupling
to the Thermodynamics of Metabolism? 959
Human Biochemistry: Lesch—Nyhan Syndrome—
HGPRT Deficiency Leads to a Severe Clinical Disorder 937 ATP Coupling Stoichiometry Determines the Keq
for Metabolic Sequences 961
The Major Pathways of Purine Catabolism Lead to
Uric Acid 937 ATP Has Two Metabolic Roles 961
Human Biochemistry: Severe Combined 27.3 Is There a Good Index of Cellular Energy Status? 961
Immunodeficiency Syndrome—A Lack of Adenosine Adenylate Kinase Interconverts ATP, ADP, and AMP 962
Deaminase Is One Cause of This Inherited Disease 938 Energy Charge Relates the ATP Levels to the Total Adenine
The Purine Nucleoside Cycle in Skeletal Muscle Serves as Nucleotide Pool 962
an Anaplerotic Pathway 938 Key Enzymes Are Regulated by Energy Charge 962
Xanthine Oxidase 938 Phosphorylation Potential Is a Measure of Relative ATP
Gout Is a Disease Caused by an Excess of Uric Acid 939 Levels 963
Different Animals Oxidize Uric Acid to Form Various 27.4 How Is Overall Energy Balance Regulated
Excretory Products 941 in Cells? 963
26.5 How Do Cells Synthesize Pyrimidines? 941 AMPK Targets Key Enzymes in Energy Production
“Metabolic Channeling” by Multifunctional Enzymes and Consumption 964
of Mammalian Pyrimidine Biosynthesis 943 AMPK Controls Whole-Body Energy Homeostasis 965
Human Biochemistry: Mammalian CPS-II Is Activated 27.5 How Is Metabolism Integrated in a Multicellular
In Vitro by MAP Kinase and In Vivo by Epidermal Growth
Organism? 966
Factor 944
The Major Organ Systems Have Specialized Metabolic
UMP Synthesis Leads to Formation of the Two Most
Roles 966
Prominent Ribonucleotides—UTP and CTP 944
Human Biochemistry: Athletic Performance
Pyrimidine Biosynthesis Is Regulated at ATCase
Enhancement with Creatine Supplements? 969
in Bacteria and at CPS-II in Animals 944
Detailed Contents xxiii
Human Biochemistry: Fat-Free Mice—A Snack Food 28.3 Why Are There So Many DNA Polymerases? 995
for Pampered Pets? No, A Model for One Form Cells Have Different Versions of DNA Polymerase,
of Diabetes 970 Each for a Particular Purpose 995
27.6 What Regulates Our Eating Behavior? 972 The Common Architecture of DNA Polymerases 995
The Hormones That Control Eating Behavior Come 28.4 How Is DNA Replicated in Eukaryotic Cells? 996
from Many Different Tissues 972 The Cell Cycle Controls the Timing of DNA Replication 996
Ghrelin and Cholecystokinin Are Short-Term Regulators of Proteins of the Prereplication Complex Are AAA1 ATPase
Eating Behavior 973 Family Members 998
Human Biochemistry: The Metabolic Effects of Alcohol
Geminin Provides Another Control Over Replication
Consumption 974 Initiation 998
Insulin and Leptin Are Long-Term Regulators of Eating Eukaryotic Cells Also Contain a Number of Different DNA
Behavior 974 Polymerases 998
AMPK Mediates Many of the Hypothalamic Responses to
These Hormones 975
28.5 How Are the Ends of Chromosomes Replicated? 999
Human Biochemistry: Telomeres—A Timely End
27.7 Can You Really Live Longer by Eating Less? 975 to Chromosomes? 999
Caloric Restriction Leads to Longevity 975
28.6 How Are RNA Genomes Replicated? 1001
Mutations in the SIR2 Gene Decrease Life Span 976
The Enzymatic Activities of Reverse Transcriptases 1001
SIRT1 Is a Key Regulator in Caloric Restriction 977
A Deeper Look: RNA as Genetic Material 1001
Resveratrol, a Compound Found in Red Wine, Is a Potent
Activator of Sirtuin Activity 977 28.7 How Is the Genetic Information Rearranged
SUMMARY 978
by Genetic Recombination? 1002
General Recombination Requires Breakage and Reunion of
DNA Strands 1002
PROBLEMS 981 Homologous Recombination Proceeds According
Further Reading 983 to the Holliday Model 1003
The Enzymes of General Recombination Include RecA,
RecBCD, RuvA, RuvB, and RuvC 1005
Part IV Information Transfer The RecBCD Enzyme Complex Unwinds dsDNA
and Cleaves Its Single Strands 1005
28 DNA Metabolism: Replication, Recombination, The RecA Protein Can Bind ssDNA and Then Interact with
and Repair 985 Duplex DNA 1006
DNA Metabolism 985 RuvA, RuvB, and RuvC Proteins Resolve the Holliday
Junction to Form the Recombination Products 1008
28.1 How Is DNA Replicated? 986
A Deeper Look: The Three Rs of Genomic
DNA Replication Is Bidirectional 986 Manipulation: Replication, Recombination, and
Replication Requires Unwinding of the DNA Helix 986 Repair 1009
DNA Replication Is Semidiscontinuous 987 A Deeper Look: “Knockout” Mice: A Method
The Biochemical Evidence for Semidiscontinuous to Investigate the Essentiality of a Gene 1009
DNA Replication 988 Recombination-Dependent Replication Restarts DNA
Initiation of DNA Replication 988 Replication at Stalled Replication Forks 1010
28.2 What Are the Functions of DNA Polymerases? 989 Homologous Recombination in Eukaryotes Helps to
Biochemical Characterization of DNA Polymerases 989 Prevent Cancer 1010
E. coli Cells Have Several Different DNA Polymerases 990 Human Biochemistry: The Breast Cancer Susceptibility
Genes BRCA1 and BRCA2 Are Involved in DNA Damage
E. coli DNA Polymerase III Holoenzyme Replicates
Control and DNA Repair 1010
the E. coli Chromosome 990
Transposons Are DNA Sequences That Can Move
A DNA Polymerase III Holoenzyme Sits at Each
from Place to Place in the Genome 1011
Replication Fork 992
DNA Polymerase I Removes the RNA Primers and Fills 28.8 Can DNA Be Repaired? 1012
in the Gaps 993 A Deeper Look: Transgenic Animals Are Animals
DNA Ligase Seals the Nicks Between Okazaki Carrying Foreign Genes 1015
Fragments 993 Mismatch Repair Corrects Errors Introduced During DNA
DNA Polymerase Is Its Own Proofreader 993 Replication 1016
DNA Replication Terminates at the Ter Region 993 Damage to DNA by UV Light or Chemical Modification
Can Also Be Repaired 1016
DNA Polymerases Are Immobilized in Replication
Factories 994 28.9 What Is the Molecular Basis of Mutation? 1017
A Deeper Look: A Mechanism for All Polymerases 994 Point Mutations Arise by Inappropriate Base-Pairing 1018
xxiv Detailed Contents
Mutations Can Be Induced by Base Analogs 1018 DNA;Protein Interactions and Protein;Protein Interactions
Chemical Mutagens React with the Bases in DNA 1019 Are Essential to Transcription Regulation 1051
Insertions and Deletions 1019 Proteins That Activate Transcription Work Through
Protein;Protein Contacts with RNA Polymerase 1052
Special Focus: Gene Rearrangements
DNA Looping Allows Multiple DNA-Binding Proteins
and Immunology—Is It Possible to Generate Protein
to Interact with One Another 1053
Diversity Using Genetic Recombination? 1021
Cells Active in the Immune Response Are Capable 29.3 How Are Genes Transcribed in Eukaryotes? 1053
of Gene Rearrangement 1021 Eukaryotes Have Three Classes of RNA Polymerases 1054
Immunoglobulin G Molecules Contain Regions RNA Polymerase II Transcribes Protein-Coding Genes 1054
of Variable Amino Acid Sequence 1021 The Regulation of Gene Expression Is More Complex
The Immunoglobulin Genes Undergo Gene in Eukaryotes 1056
Rearrangement 1022 Gene Regulatory Sequences in Eukaryotes Include
DNA Rearrangements Assemble an L-Chain Gene Promoters, Enhancers, and Response Elements 1057
by Combining Three Separate Genes 1023 Transcription Initiation by RNA Polymerase II Requires
DNA Rearrangements Assemble an H-Chain Gene TBP and the GTFs 1059
by Combining Four Separate Genes 1024 The Role of Mediator in Transcription Activation
V–J and V–D–J Joining in Light- and Heavy-Chain Gene and Repression 1060
Assembly Is Mediated by the RAG Proteins 1025 Mediator as a Repressor of Transcription 1062
Imprecise Joining of Immunoglobulin Genes Creates New Chromatin-Remodeling Complexes and Histone-
Coding Arrangements 1025 Modifying Enzymes Alleviate the Repression Due
Antibody Diversity Is Due to Immunoglobulin Gene to Nucleosomes 1062
Rearrangements 1026 Chromatin-Remodeling Complexes Are Nucleic Acid–
SUMMARY 1028 Stimulated Multisubunit ATPases 1062
Foundational Biochemistry 1029 Covalent Modification of Histones 1063
Covalent Modification of Histones Forms the Basis
PROBLEMS 1030
of the Histone Code 1064
Further Reading 1031
Methylation and Phosphorylation Act as a Binary Switch in
the Histone Code 1064
29 Transcription and the Regulation of Gene
Chromatin Deacetylation Leads to Transcription
Expression 1035 Repression 1065
29.1 How Are Genes Transcribed in Bacteria? 1035 Nucleosome Alteration and Interaction of RNA
A Deeper Look: Conventions Used in Expressing Polymerase II with the Promoter Are Essential Features in
the Sequences of Nucleic Acids and Proteins 1036 Eukaryotic Gene Activation 1065
Bacterial RNA Polymerases Use Their Sigma Subunits to A SINE of the Times 1066
Identify Sites Where Transcription Begins 1036 29.4 How Do Gene Regulatory Proteins Recognize Specific
The Process of Transcription Has Four Stages 1036 DNA Sequences? 1066
A Deeper Look: DNA Footprinting—Identifying Human Biochemistry: Storage of Long-Term Memory
the Nucleotide Sequence in DNA Where a Protein Depends on Gene Expression Activated by CREB-Type
Binds 1040 Transcription Factors 1067
29.2 How Is Transcription Regulated in Bacteria? 1042 a-Helices Fit Snugly into the Major Groove of
Transcription of Operons Is Controlled by Induction B-DNA 1067
and Repression 1043 Proteins with the Helix-Turn-Helix Motif Use One Helix
The lac Operon Serves as a Paradigm of Operons 1043 to Recognize DNA 1067
lac Repressor Is a Negative Regulator of the lac Operon 1044 Some Proteins Bind to DNA via Zn-Finger Motifs 1068
CAP Is a Positive Regulator of the lac Operon 1046 Some DNA-Binding Proteins Use a Basic Region-Leucine
Zipper (bZIP) Motif 1069
A Deeper Look: Quantitative Evaluation
of lac Repressor;DNA Interactions 1046 The Zipper Motif of bZIP Proteins Operates Through
Intersubunit Interaction of Leucine Side Chains 1069
Negative and Positive Control Systems Are Fundamentally
Different 1047 The Basic Region of bZIP Proteins Provides
the DNA-Binding Motif 1070
The araBAD Operon Is Both Positively and Negatively
Controlled by AraC 1047 29.5 How Are Eukaryotic Transcripts Processed and
The trp Operon Is Regulated Through a Co-Repressor– Delivered to the Ribosomes for Translation? 1070
Mediated Negative Control Circuit 1049 Eukaryotic Genes Are Split Genes 1070
Attenuation Is a Prokaryotic Mechanism for Post- The Organization of Exons and Introns in Split Genes
Transcriptional Regulation of Gene Expression 1049 Is Both Diverse and Conserved 1071
Detailed Contents xxv
Post-Transcriptional Processing of Messenger RNA 30.4 What Is the Structure of Ribosomes, and How Are
Precursors Involves Capping, Methylation, They Assembled? 1101
Polyadenylylation, and Splicing 1072 Prokaryotic Ribosomes Are Composed of 30S
Nuclear Pre-mRNA Splicing 1073 and 50S Subunits 1101
The Splicing Reaction Proceeds via Formation of a Lariat Prokaryotic Ribosomes Are Made from 50 Different
Intermediate 1074 Proteins and Three Different RNAs 1102
Splicing Depends on snRNPs 1074 Ribosomes Spontaneously Self-Assemble In Vitro 1103
snRNPs Form the Spliceosome 1076 Ribosomes Have a Characteristic Anatomy 1104
Alternative RNA Splicing Creates Protein Isoforms 1076 The Cytosolic Ribosomes of Eukaryotes Are Larger
Fast Skeletal Muscle Troponin T Isoforms Are an Example Than Prokaryotic Ribosomes 1104
of Alternative Splicing 1076 30.5 What Are the Mechanics of mRNA Translation? 1105
A Deeper Look: Inteins—Bizarre Parasitic Genetic Peptide Chain Initiation in Bacteria Requires
Elements Encoding a Protein-Splicing Activity 1077 a G-Protein Family Member 1106
RNA Editing: Another Mechanism That Increases Peptide Chain Elongation Requires Two G-Protein Family
the Diversity of Genomic Information 1078 Members 1108
29.6 Can Gene Expression Be Regulated Once The Elongation Cycle 1108
the Transcript Has Been Synthesized? 1079 Aminoacyl-tRNA Binding 1109
miRNAs Are Key Regulators in Post-Transcriptional Gene GTP Hydrolysis Fuels the Conformational Changes
Regulation 1079 That Drive Ribosomal Functions 1113
29.7 Can We Propose a Unified Theory of Gene A Deeper Look: Molecular Mimicry—The Structures
Expression? 1080 of EF-Tu;Aminoacyl-tRNA, EF-G, and RF-3 1113
RNA Degradation 1082 Peptide Chain Termination Requires Yet Another G-Protein
SUMMARY 1083 Family Member 1114
Foundational Biochemistry 1084 The Ribosomal Subunits Cycle Between 70S Complexes
and a Pool of Free Subunits 1114
PROBLEMS 1085
A Deeper Look: Tethered Ribosomes Open New
Further Reading 1086 Possibilities in Synthetic Biology 1116
Polyribosomes Are the Active Structures of Protein
30 Protein Synthesis 1091 Synthesis 1117
30.1 What Is the Genetic Code? 1092 30.6 How Are Proteins Synthesized in Eukaryotic Cells? 1117
The Genetic Code Is a Triplet Code 1092 Peptide Chain Initiation in Eukaryotes 1117
Codons Specify Amino Acids 1092 Control of Eukaryotic Peptide Chain Initiation Is One
A Deeper Look: Natural and Unnatural Variations Mechanism for Post-Transcriptional Regulation of Gene
in the Standard Genetic Code 1093 Expression 1120
30.2 How Is an Amino Acid Matched with Its Proper Peptide Chain Elongation in Eukaryotes Resembles
tRNA? 1094 the Prokaryotic Process 1120
Aminoacyl-tRNA Synthetases Interpret the Second Genetic Human Biochemistry: Diphtheria Toxin
Code 1094 ADP-Ribosylates eEF2 1121
Evolution Has Provided Two Distinct Classes Eukaryotic Peptide Chain Termination Requires Just One
of Aminoacyl-tRNA Synthetases 1096 Release Factor 1121
Aminoacyl-tRNA Synthetases Can Discriminate Between Inhibitors of Protein Synthesis 1122
the Various tRNAs 1096 SUMMARY 1124
Escherichia coli Glutaminyl-tRNAGln Synthetase Recognizes Foundational Biochemistry 1125
Specific Sites on tRNAGln 1098
PROBLEMS 1126
The Identity Elements Recognized by Some Aminoacyl-
tRNA Synthetases Reside in the Anticodon 1098 Further Reading 1127
A Single G;U Base Pair Defines tRNA Alas 1098 31 Completing the Protein Life Cycle: Folding,
30.3 What Are the Rules in Codon–Anticodon Processing, and Degradation 1131
Pairing? 1099
31.1 How Do Newly Synthesized Proteins Fold? 1132
Francis Crick Proposed the “Wobble” Hypothesis
for Codon–Anticodon Pairing 1099 Human Biochemistry: Alzheimer’s, Parkinson’s,
and Huntington’s Disease Are Late-Onset
Some Codons Are Used More Than Others 1099
Neurodegenerative Disorders Caused by
Nonsense Suppression Occurs When Suppressor the Accumulation of Protein Deposits 1133
tRNAs Read Nonsense Codons 1101
Chaperones Help Some Proteins Fold 1134
xxvi Detailed Contents
Hsp70 Chaperones Bind to Hydrophobic Regions 32.2 What Is Signal Transduction? 1163
of Extended Polypeptides 1134 Many Signaling Pathways Involve Enzyme Cascades 1164
A Deeper Look: How Does ATP Drive Chaperone- Signaling Pathways Connect Membrane Interactions
Mediated Protein Folding? 1135 with Events in the Nucleus 1164
The GroES–GroEL Complex of E. coli Is an Hsp60 Signaling Pathways Depend on Multiple Molecular
Chaperonin 1137 Interactions 1166
A Deeper Look: Chaperone Proteins That Function by
32.3 How Do Signal-Transducing Receptors Respond
Stress-Induced Unfolding 1139
to the Hormonal Message? 1167
The Eukaryotic Hsp90 Chaperone System Acts
The G-Protein–Coupled Receptors Are 7-TMS Integral
on Proteins of Signal Transduction Pathways 1139
Membrane Proteins 1168
A Deeper Look: Small Heat Shock Proteins: Nature’s
The Single TMS Receptors Are Guanylyl Cyclases
Molecular Sponges 1140
or Tyrosine Kinases 1168
31.2 How Are Proteins Processed Following RTKs and RGCs Are Membrane-Associated Allosteric
Translation? 1141 Enzymes 1169
Proteolytic Cleavage Is the Most Common Form The EGF Receptor Is Activated by Ligand-Induced
of Post-Translational Processing 1141 Dimerization 1170
31.3 How Do Proteins Find Their Proper Place in EGF Receptor Activation Forms an Asymmetric Tyrosine
the Cell? 1141 Kinase Dimer 1171
Proteins Are Delivered to the Proper Cellular The Insulin Receptor Mediates Several Signaling
Compartment by Translocation 1142 Pathways 1172
Prokaryotic Proteins Destined for Translocation Are The Insulin Receptor Adopts a Folded Dimeric Structure 1174
Synthesized as Preproteins 1142 Autophosphorylation of the Insulin Receptor Kinase
Eukaryotic Proteins Are Routed to Their Proper Opens the Active Site 1174
Destinations by Protein Sorting and Translocation 1143 Receptor Guanylyl Cyclases Mediate Effects of Natriuretic
Human Biochemistry: Autophagy—How Cells Recycle Hormones 1174
Their Materials 1146 A Symmetric Dimer Binds an Asymmetric Peptide
31.4 How Does Protein Degradation Regulate Cellular Ligand 1176
Levels of Specific Proteins? 1147 Nonreceptor Tyrosine Kinases Are Typified by pp60src 1176
Eukaryotic Proteins Are Targeted for Proteasome A Deeper Look: Nitric Oxide, Nitroglycerin, and Alfred
Destruction by the Ubiquitin Pathway 1147 Nobel 1177
Proteins Targeted for Destruction Are Degraded Soluble Guanylyl Cyclases Are Receptors for Nitric Oxide 1178
by Proteasomes 1149 32.4 How Are Receptor Signals Transduced? 1178
ATPase Modules Mediate the Unfolding of Proteins GPCR Signals Are Transduced by G Proteins 1178
in the Proteasome 1150 Cyclic AMP Is a Second Messenger 1179
Ubiquitination Is a General Regulatory Protein cAMP Activates Protein Kinase A 1180
Modification 1150
Ras and Other Small GTP-Binding Proteins Are
Small Ubiquitinlike Protein Modifiers Are Proto-Oncogene Products 1181
Post-transcriptional Regulators 1150
G Proteins Are Universal Signal Transducers 1181
HtrA Proteases Also Function in Protein Quality Control 1152
Specific Phospholipases Release Second Messengers 1182
Human Biochemistry: Proteasome Inhibitors in Cancer
Inositol Phospholipid Breakdown Yields Inositol-1,4,
Chemotherapy 1154
5-Trisphosphate and Diacylglycerol 1182
A Deeper Look: Protein Triage—A Model for Quality
Activation of Phospholipase C Is Mediated by G Proteins
Control 1155
or by Tyrosine Kinases 1182
SUMMARY 1155
Human Biochemistry: Cancer, Oncogenes, and Tumor
Foundational Biochemistry 1156 Suppressor Genes 1184
PROBLEMS 1156 Phosphatidylcholine, Sphingomyelin, and Glycosphingolipids
Further Reading 1157 Also Generate Second Messengers 1184
Calcium Is a Second Messenger 1184
32 The Reception and Transmission of Extracellular Intracellular Calcium-Binding Proteins Mediate
the Calcium Signal 1185
Information 1161 Calmodulin Target Proteins Possess a Basic Amphiphilic
32.1 What Are Hormones? 1163 Helix 1185
Steroid Hormones Act in Two Ways 1163 Human Biochemistry: PI Metabolism
Polypeptide Hormones Share Similarities of Synthesis and and the Pharmacology of Li1 1185
Processing 1163
Detailed Contents xxvii
32.5 How Do Effectors Convert the Signals to Actions Communication at Cholinergic Synapses Depends
in the Cell? 1187 upon Acetylcholine 1201
Protein Kinase A Is a Paradigm of Kinases 1187 There Are Two Classes of Acetylcholine Receptors 1201
A Deeper Look: Mitogen-Activated Protein Kinases The Nicotinic Acetylcholine Receptor Is a Ligand-Gated
and Phosphorelay Systems 1188 Ion Channel 1202
Protein Kinase C Is a Family of Isozymes 1188 Acetylcholinesterase Degrades Acetylcholine
Protein Tyrosine Kinase pp60 c-src Is Regulated in the Synaptic Cleft 1203
by Phosphorylation/Dephosphorylation 1189 Muscarinic Receptor Function Is Mediated
Protein Tyrosine Phosphatase SHP-2 Is a Nonreceptor by G Proteins 1203
Tyrosine Phosphatase 1190 Other Neurotransmitters Can Act Within Synaptic
Junctions 1203
32.6 How Are Signaling Pathways Organized
and Integrated? 1190 Glutamate and Aspartate Are Excitatory Amino Acid
Neurotransmitters 1204
GPCRs Can Signal Through G-Protein–Independent
A Deeper Look: Tetrodotoxin and Saxitoxin Are
Pathways 1191
Na1 Channel Toxins 1205
G-Protein Signaling Is Modulated by RGS/GAPs 1191
Human Biochemistry: Neurexins and Neuroligins—
GPCR Desensitization Leads to New Signaling
the Scaffolding of Learning and Memory 1206
Pathways 1194
g-Aminobutyric Acid and Glycine Are Inhibitory
A Deeper Look: Whimsical Names for Proteins
Neurotransmitters 1208
and Genes 1195
Human Biochemistry: The Biochemistry of
Receptor Responses Can Be Coordinated
Neurological Disorders 1210
by Transactivation 1195
The Catecholamine Neurotransmitters Are Derived
Signals from Multiple Pathways Can Be Integrated 1195
from Tyrosine 1212
32.7 How Do Neurotransmission Pathways Control Various Peptides Also Act as Neurotransmitters 1212
the Function of Sensory Systems? 1197 SUMMARY 1213
Nerve Impulses Are Carried by Neurons 1197
Ion Gradients Are the Source of Electrical Potentials
in Neurons 1197 PROBLEMS 1214
Action Potentials Carry the Neural Message 1198 Further Reading 1216
The Action Potential Is Mediated by the Flow of Na1 Abbreviated Answers to Problems A-1
and K1 Ions 1199
Neurons Communicate at the Synapse 1200 Index I-1
Another random document with
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kingly favour. Alfonso XI. drew down upon himself the
1325–1350
wrath of pious Christians by employing Jewish
ministers in his treasury. Under this prince the Spanish Jews, indeed,
enjoyed what some writers have described as their Golden Age.
They were powerful at Court, and equally influential with the great
nobility, many Castilian magnates employing them as bailiffs and
advisers. Their wealth and their power cowed clerical and popular
fanaticism, and overawed the avaricious proclivities of impecunious
hidalgos. This prosperity lasted under Alfonso’s
1350–1369
successor, Don Pedro, or Peter the Cruel. Samuel
Levi, treasurer to the King and his victim, is reported to have left
behind him the princely fortune of 400,000 ducats; an affluence
which proved his undoing.
1333–1379 Nor was royal favour limited to one class of Jews,
any more than Jewish usefulness was limited to one
province of activity. Henry II. of Castile, the half-brother of Don
Pedro, and other Iberian sovereigns employed the talents of the
Jews in various capacities. Through their correspondence with their
brethren all over Europe and the East, the Jews were the best
agents for commercial and political negotiations. Their astronomical
science, and their skill in map-drawing and in the construction of
nautical instruments, recommended them to princes anxious to profit
by the exploration of new lands. Jewish pilots and navigators must
have been in great demand, for they subsequently helped Vasco da
Gama in his voyages; while Jewish capitalists and adventurers
participated in many of the great transatlantic expeditions of later
times. Jayme III., the last king of Mallorca, describes
1334
Juceff Faguin, a Jew of Barcelona, as a man who “had
navigated the whole of the then known world”; while Benjamin of
Tudela’s older Itinerary is a work of world-wide renown.
1404–1454
John II. of Castile, in the ensuing century, even sought
the assistance of Jews in the compilation of a national Cancionero,
for the Jews in Christian, as in Mohammedan, Spain attained high
distinction as troubadours. One of them, Santob de Carrion, who
flourished in Castile in the fourteenth century, produced a Spanish
Book of Maxims, which, thanks to its charming quaintness,
preserved its popularity far into the fifteenth. Not less important are
the contributions of Iberian Jews to the vernacular drama.
The Jew’s old aversion to the language of Titus, the destroyer of
the Temple, had also partially vanished from Spain, and many
Jewish politicians employed Latin in the diplomatic correspondence
which they conducted for their Christian masters, while the Spanish
language in the fourteenth century even bade fair to oust Hebrew,
the Book of Esther being, in some parts of the peninsula, read in the
vernacular on the Feast of Purim, for the benefit of the women, to
whom the sacred tongue was no longer intelligible. Naturally such
liberalism scandalised strait-laced pietists, who did their utmost to
prevent the profanation of Holy Writ. But the real check to the
gradual reconciliation between Jew and Gentile in Spain did not
proceed from the Jewish side, as we shall see.
1348 All this sunshine was already overshadowed by the
clouds which herald the storm. In the year of the Black
Death the charge of well-poisoning stirred up the mob of Barcelona
against the Jews, twenty of whom were slain and their houses
sacked, a wholesale massacre being averted only by the intervention
of the higher classes. A few days later a similar outbreak at Cervera
resulted in the murder of eighteen Jews and the flight of the rest.
Destruction threatened all the Jewish communities of Northern
Spain, and their members, panic-stricken, betook themselves to
prayer, fasting, and other precautions of a more practical character
against the impending attack, which, however, was prevented by the
nobility and by a Papal Bull, in which Clement VI.—who, though no
saint, was an accomplished gentleman and a broad-minded prince—
exposed the absurdity of the poison charge, and prohibited the
Christians from assaulting the Jews on pain of excommunication.
During the long civil war in Castile between Don Pedro and his
brother Don Henry, the heirs of Alfonso XI., the Jews had the
misfortune to back the losing side. They sustained heavy losses in
many a battle and siege, and suffered terribly at the hands of friend
and foe alike. The great community of Toledo was decimated out of
all recognition. Throughout Castile congregations once flourishing
were reduced to penury, and many of their members in sheer
despair embraced Christianity. The Jews of Burgos, even after Don
Pedro’s death, remained stubbornly loyal to his memory, and when
all Spain had recognised Don Henry’s rule they alone had the
courage to defy him—a constancy which moved the usurper’s
admiration, and secured to the besieged terms of submission
honourable to both sides alike. Peace was restored, but it brought
small comfort to Israel. Don Henry had always pretended that one of
the causes of his enmity to his brother was the latter’s partiality for
the Jews. The vanquished enemy’s favourites would now have been
made to suffer the extreme rigour of Henry’s vengeance but for the
financial straits in which the victor found himself. Instead of
annihilating, Don Henry preferred to exploit the Jews. But the King’s
forbearance roused the indignation of his followers, who felt
despoiled of the fruits of their victory. In 1371 the Cortes assembled
at Toro rebuked the King for employing the enemies of the faith at
Court, and for allowing them to farm the revenues of the Crown. The
representatives of the nation insisted that the Jews should be
excluded from State offices, confined within special quarters,
compelled to wear the badge, and forbidden to display their riches in
their apparel or equipages, or to bear Christian names. The King,
while dismissing most of these demands, thought it wise to concede
the last three, and he also decreed some measures intended to
restrain the rapacity of Jewish money-lenders. The clergy also, who
had sanctioned Don Henry’s usurpation of the throne, claimed a
reward in the shape of anti-Jewish legislation.
1375
Religious disputations were, therefore, revived, and
Jewish renegades were once more the protagonists in the sorry
farce.
At the same time the Church renewed its efforts to prevent the
Christians from mingling with the impure race. The necessity for this
persistent confirmation of anti-Jewish regulations shows that, though
the antipathy between Jew and Gentile was spontaneous, and
though both Church and Synagogue vied with each other in their
endeavours to keep the two elements in sempiternal alienation, yet
the social instinct which forms the strongest trait of human nature
often triumphed over the barriers set up by religious bigotry. But
human nature was allowed little opportunity for asserting itself. The
Council of Palencia passed a decision forbidding
1388
Catholics to dwell within the quarters assigned to the
Jews and Moors, under penalty of excommunication.
1390
Two years later the Jews of Majorca were forbidden to
carry arms. Next year, thanks to the eloquence of the
1391
fanatical priest Martinez, a series of wholesale
massacres took place in Castile and Aragon, in which thousands of
Jews were sacrificed to priestly and popular rage, and the cities of
Seville, Toledo, Cordova, Catalonia, Barcelona, Valencia, as well as
the island of Majorca, were coloured red with Jewish blood; while
great numbers of the unfortunate people sought safety in half-
hearted apostasy. Efforts were made to confirm the hold upon these
captured infidels, popularly known as Marranos, or “the Damned,” by
ecclesiastical preferment and by the bestowal of municipal dignities;
while many impecunious aristocrats, anxious to restore their
declining fortunes, brought riches to themselves and a lasting
reproach to their posterity by courting the fair daughters of converted
Israel; so much so that many a noble Castilian pedigree to this day
can be traced to such an alliance. But neither ecclesiastical or civic
honours nor social advancement were sufficiently potent to keep the
“new Christians” in the faith. There were, of course, exceptions to the
rule—a truism which we are apt to overlook in dealing with the
history of the Jews. Some, no doubt, who had honestly outgrown the
racial and religious swathings of Judaism, were glad enough to
adopt Christianity. Unfettered by spiritual convictions, they preferred
the creed which entailed no social stigma. They deserve as little
blame as admiration. Others, however, there were who, setting
worldly advantages, or the gratification of private grudges, above
principle, found both profit and pleasure in the persecution or
vilification of their former brethren. But neither of these classes
represented the majority. Most of the neophytes, as soon as they
safely could, slipped the suffocating cloak, and came forth in their
true character, while others vacillated between Church and
Synagogue, trying to serve two masters, and by so doing increased
the animosity of the priests against the race; for the theologian does
not agree with the psychologist in holding that a feigned or fictitious
faith is better than none at all. As in the time of the Visigoth tyrants,
so now thousands of Jews and forced converts fled to Africa. Many
towns on the coast, from Algiers westward, were filled with the
unfortunate refugees from Spain and Majorca, who found the African
Berbers more humane than the European Christians.
The recent tribulations and the anticipation of worse sufferings in
the near future gave rise to a new Messianic frenzy. According to the
Scriptures, the advent of the Redeemer was to be preceded by
terrible persecution. Three Messiahs appeared to voice
1391
the convictions and to try the faith of the hunted
people: Abraham of Granada, Shem-Tob, and Moses Botarel. All
three were mystics, the last one also an impostor.
The fifteenth century adds fresh scenes to the tale of sorrow,
new “black-letter days” to the Jewish Calendar, and more dark pages
to the history of Europe. In 1408 the anti-Jewish statutes of Alfonso
the Wise were revived. Ruinous fines were imposed upon any
Christian who should confer, or Jew who should accept, municipal or
other office. Four years later the intercourse of the
1412
Jews with the Christians was restricted, and their
commercial and industrial activity hampered by numerous
prohibitions. They were forbidden to act as physicians, apothecaries,
and stewards to the nobility; as bakers, millers, or vintners. They
were debarred from selling oil or butter; from exercising the
handicrafts of smith, carpenter, tailor, or shoemaker, and, of course,
from farming or collecting the public revenues. It was further decreed
that no Jew should carry any kind of arms, or be addressed as Don;
that the unclean people should live in special quarters (Juderias)
provided with not more than one gate each, and that they should not
employ Christian servants. Thus the seclusion which was at first
granted to the Jews as a privilege and a protection was now
enforced as a means of oppression. Furthermore, they were stripped
of their gay apparel, and compelled to wear a peculiar garment of
coarse stuff and to display the hated badge, except such as could
pay for permission to discard it, especially on their journeys. Lastly,
they were forbidden to have their hair cut or their beards shaved.
Confiscation of goods and corporal chastisement were the penalties
inflicted for any breach of these and other regulations, the aim of
which was, by humiliating and impoverishing the race, to induce it to
embrace Christianity. A contemporary Jewish writer thus describes
the sad effects of this edict: “Inmates of palaces were driven into
wretched nooks, and dark and lowly huts. Instead of rustling apparel,
we were obliged to wear miserable clothes which drew contempt
upon us. Prohibited from shaving the beard, we had to appear like
mourners. The rich tax-farmers sank into want, for they knew no
trade by which they could gain a livelihood, and the handicraftsmen
found no custom. Starvation stared everyone in the face. Children
70
died on their mothers’ knees from hunger and exposure.”
In the midst of all this suffering the Church was not idle. The
chief of the apostles was Vincent Ferrer, a Dominican friar and
indefatigable winner of souls, afterwards canonised for his exertions.
This sincere, though forbidding saint, who called his bigotry religion
and his hatred of heretics love of God, rushed from synagogue to
synagogue, crucifix in hand, preaching the gospel of peace in a
voice of thunder, and endeavouring to persuade the infidels to
repentance by promises of comfort in this world and by threats of
everlasting damnation in the next. Ferrer was more than an orator.
His sermons were accompanied with exhibitions of the priest’s
dramatic genius and of the saint’s thaumaturgic powers. Impressive
processions and sacred hymns, banners, crucifices, and assaults
upon the Jews heightened the effect of his impassioned appeals.
Thousands of wretches succumbed to Ferrer’s eloquence, and many
synagogues were turned into churches. This result was by
contemporary piety attributed to the fiery exhortations addressed to
the Jews, and to the miracles performed for their benefit, by St.
Vincent; but a twentieth century heretic, while admitting the efficacy
of exhortation and miracle, may be pardoned for suspecting that the
systematic persecution on the part of the State and the spontaneous
fury of the mob had at least some influence in turning the hearts of
the infidels.
1413 From Castile the preacher and persecution
travelled to Aragon. The newly-elected King Ferdinand,
who owed his elevation to Ferrer’s influence, showed his gratitude by
placing his conscience in the saint’s keeping and the royal power at
his disposal. St. Vincent, thus armed with both necessaries of
success—enthusiasm and means—journeyed to and fro in the
country, denouncing, exhorting, threatening, and baptizing; and the
victims of his fervour in the two kingdoms are said to have exceeded
twenty thousand souls. Such is the persuasive power of theological
reasoning, when assisted by brute force. In the same year a
compulsory controversy between Hebrew renegades and Rabbis, on
the traditional lines, was begun in Tortosa.
No more splendid assembly ever met for the purpose of
enforcing the gospel of divine mercy by the gratification of human
vanity. The anti-pope Benedict XIII., clad in his pontifical robes, sat
on a lofty throne, surrounded by cardinals and prelates refulgent with
brocade of gold and gems. A thousand Spanish grandees thronged
behind this glorious group, while before it stood a small band of Jews
anxious to defend their faith, without imperilling their lives. The truth
of Christianity was beyond cavil. The falsity of Judaism, after the
advent of Christ, was equally clear. Does the Talmud recognise
Jesus as the Messiah or not? That was the question which was
debated in sixty-eight sittings extending over a period of twenty-one
months.
And so the ruin of the Jews was progressing satisfactorily. The
originators of the persecution passed away one after the other.
Benedict XIII. was deposed by the Council of Constance and
denounced by Vincent Ferrer as an “unfrocked and spurious Pope.”
The renegade Jew Geronimo vanished into his native obscurity. King
Ferdinand died in 1416, and St. Vincent was translated to heaven
three years later. But the tribulations of Israel did not cease. Pope
Martin V., indeed, surprised the world with a Bull of
1419
toleration, dictated, as one would gladly have believed,
by Christian charity; as documents prove, procured by bribery. But
the plant of anti-Judaism had taken too deep roots to be permanently
stunted by this tardy edict. Pope Eugenius IV.
1442
addressed another Bull to the Bishops of Castile and
Leon, withdrawing the indulgences granted to the Jews by his
predecessor, and he renewed all the old restrictions, adding that the
unclean people should be confined to their houses during Holy
Week. Autograph letters to the Castilian ecclesiastics exhorted them
to enforce the Pontiff’s orders without mercy. Pope
1447
Nicholas V. aggravated all these measures of
oppression.
The Spanish Jews were now regarded simply as outlaws. The
pious eschewed all dealings with them. Husbandmen deserted the
fields, and shepherds the flocks belonging to the proscribed people;
while the towns framed new regulations for their utter suppression.
King Henry IV. of Castile and Juan II. of Aragon, horror-struck at the
terrible cruelty of this treatment, or rather alarmed at its
consequences on the royal exchequer, endeavoured to mitigate the
sufferings of the Jews. But their efforts met with no success. The
campaign on the part of the Dominicans was carried on vigorously,
backsliders were scented out and punished, charges of child-murder
were preferred against the Jews, and the populace was stirred up to
acts of violence, which grew in ferocity and frequency as the years
rolled on. In 1468 a charge of this description led to a massacre at
Sepulveda. In the following year the Cortes of Ocaña
1469
insisted that the anti-Jewish edicts should be
stringently enforced. Despite Henry’s feeble protests, the Jews for
many years continued to be exposed to the utmost cruelty of the
priests and of the populace in an age when the priests and the
populace were most cruel. They were not members of the Church, of
the feudal aristocracy, or of the commercial and industrial
corporations. Though living among the Christians, they were not of
them. They were unpopular. They could not defend themselves; and
neither bishops, barons, nor burgesses would lift a finger in their
defence. They were, therefore, abandoned without reserve and
without remorse to the tender mercies of clerical and civic fanaticism.
The Marranos especially continued to be the pet aversion and
occupation of the Church.
A monastic writer of Andalusia, where the “new Christians” were
most numerous and now most miserable, quoted by Prescott,
summarises contemporary feeling regarding them in the following
eloquent lines: “This accursed race were either unwilling to bring
their children to be baptized, or, if they did, they washed away the
stain on returning home. They dressed their stews and other dishes
with oil, instead of lard; abstained from pork; kept the Passover; ate
meat in Lent; and sent oil to replenish the lamps of their synagogues;
with many other abominable ceremonies of their religion. They
entertained no respect for monastic life, and frequently profaned the
sanctity of religious houses by the violation or seduction of their
inmates. They were an exceedingly politic and ambitious people,
engrossing the most lucrative municipal offices, and preferred to gain
their livelihood by traffic, in which they made exorbitant gains, rather
than by manual labour or mechanical arts. They considered
themselves in the hands of the Egyptians, whom it was a merit to
deceive and plunder. By their wicked contrivances they amassed
great wealth, and they were often able to ally themselves by
marriage with noble Christian families.” Here we find all the old
sources of the Gentile’s hatred towards the Jew: antipathy due to
diversity of character—as manifested in occupation, daily diet, and
conduct; steeled by economic jealousy, and edged by religious
bigotry.
1469 Oct. 19 Such was the frame of the public mind, when
short-sighted statecraft, in the person of Ferdinand,
King of Aragon, was wedded to narrow piety in that of Isabella,
heiress to the Crown of Castile. The legitimate offspring of such a
union could be no other than persecution. But, even if the sovereigns
were enlightened and tolerant, it is doubtful whether they could have
stemmed the current. In 1473 the mob massacred the Constable of
Castile at Jaen, because he attempted to repress its fury, and, after
Isabella the Catholic’s accession to the throne, petitions poured in
from all sides clamouring for the extirpation of the “Jewish heresy.”
The bigots of Seville, headed by the Dominican prior of the
monastery of St. Paul, agitated for the introduction of the Inquisition
—a tribunal originally established during Innocent III.’s pontificate at
the beginning of the thirteenth century for the suppression of heresy
—and their demand was seconded by the Papal Nuncio. In 1477
Friar Philip de Barberi, Inquisitor for Sicily, arrived in Seville to
persuade the Spanish monarchs of the manifold virtues of his
remedy for infidelity. The prospect of plunder lured Ferdinand, while
Isabella’s feminine tenderness was assailed by the importunities and
the casuistry of her spiritual advisers. Torquemada, the narrow-
hearted Dominican of universal notoriety, had already poisoned the
Queen’s mind with his pernicious maxims of intolerance, when he
acted as the guardian of her conscience in early youth. In that
susceptible age he had extorted from his pupil the promise that she
would devote her life “to the extirpation of heresy, for the glory of
God and the exaltation of the Catholic faith.” He now reappears on
the scene to claim the fulfilment of the fatal vow. The young queen,
noble and generous though she was by nature, could not long
withstand the unanimous exhortations of persons whose sanctity her
religion taught her to revere, and the superiority of whose wisdom
her own modesty prompted her to accept without question. Much
less could she resist her own beloved husband’s solicitations. All that
was good or engaging in her conspired with all that was ignoble in
her counsellors to warp her judgment, to silence the voice of her
heart, and to force her to give her consent to one of the greatest
crimes of any time.
It required but little effort to induce Pope Sixtus IV. to allow the
establishment of the Holy Office in Castile for the detection and
punishment of backsliders to Judaism, and the necessary Bull was
issued on November 1st, 1478. But the Queen still hesitated to make
use of the dread weapon, while her husband was not without
misgivings regarding the absolute power claimed by the tribunal. As
a last resource, before proceeding to extremes, the monarchs
commanded Cardinal Mendoza, the Archbishop of Seville, to set
forth the doctrines of the Catholic faith in a short catechism, and to
cause his clergy to diffuse the light among the benighted Marranos
throughout his diocese. This worthy and humane ecclesiastic gladly
obeyed the royal command, and betook himself to the work of
friendly persuasion. But with little success. The Christians were
incited to acts of hostility by rumours of Jewish plots against the
Church and the State, and of Jewish crimes of the traditional type,
such as sacrifices of children and insults offered to the Host. The
Government, yielding to public clamour, expelled the Jews from
Seville and Cordova in 1478, and renewed the severe measures of
repression in 1480. Furthermore, an ill-advised Jew, by the
publication of a caustic criticism of Christianity at that inopportune
moment, threw oil into the fire, and precipitated a catastrophe which
perhaps no power on earth could have averted in any case. A people
whose inflexibility had triumphed over the temptations and the
persecutions of fifteen centuries was hardly likely to be bent by the
good Archbishop’s catechism; and, after two years’ fruitless
endeavour, a Commission appointed for the purpose returned a
highly disappointing report. The term of grace having expired, the
71
only remaining alternative was the Inquisition.
On September 17th, 1480, the tribunal was constituted of two
Dominicans and two other ecclesiastics appointed by the Crown, and
was ordered to commence operations at Seville without delay. The
civil authorities were instructed to lend the assistance of the secular
arm to the Judges; but, owing to the opposition which the latter at
first encountered on the part of the high-spirited Castilians, they were
obliged to confine their activity for a while within those districts of
Andalusia which depended directly from the Crown. However, limited
as the field at first was, it proved more than sufficient for the
purpose. The new year, 1481, was inaugurated with an edict,
published on January 2nd, bidding all true Catholics to aid the
tribunal in the fulfilment of its mission, by indicating any person that
might be known as, or suspected of, entertaining heretical opinions.
The result was a monster hunt with men for quarry and hounds, and
Satan for their master. Soon the number of victims grew to such an
extent that the court was obliged to exchange its seat in the
monastery of St. Paul, within the city of Seville, for the larger castle
of Triana, in the environs. There it established its headquarters and
blasphemed the Deity whom it professed to serve by the following
inscription, engraven over the portal: Exsurge, Domine; judica
causam tuam; capite nobis vulpes, “Arise, O Lord; judge thine own
cause; capture for us the foxes.”
Day after day the Satanic sport went on, and the number of
“foxes” increased apace. The Jews were not even allowed the
privilege accorded to the animal. Flight was forbidden under penalty
of death, and was prevented by guards posted at the gates of the
city. None the less, some of the victims succeeded in escaping to
Granada, France, Germany, and Italy, where they made an appeal to
the Holy See from the barbarity of the Holy Office. Sixtus IV.
contented himself with a gentle rebuke of his subalterns for their
excessive zeal, soon followed by a request for more strenuous
“purification,” addressed to Ferdinand and Isabella.
Never, perhaps, since the fall of the Roman Empire did the
detestable trade of the informer flourish so lustily as it did during the
ensuing years in Castile. Bigotry, malice, cupidity were all invited to
contribute to the havoc, and, as the accuser’s identity was
sedulously concealed from the accused, the last motive for self-
restraint was removed. A new coat or a clean shirt on Saturday
morning, a cold hearth on Friday evening, avoidance of food popular
among the Christians, or a taste for a kind of drink affected by the
Jews, a visit to a Jewish house,—these were some of the proofs of
Judaism accepted as conclusive evidence by this model court of
justice. The grave itself afforded no refuge from its clutches. A
person who was observed to turn his face to the wall when dying
was at once pounced upon, and his body shared the fate of living
heretics.
The Inquisition had been in existence for three days when six
wretches suffered at the stake. Seventeen more followed in March,
and at the end of ten months the “bag” had reached the number of
two hundred and ninety-eight, in Seville alone, in addition to many
effigies of those who had been fortunate enough to escape. The
plague which devastated Seville in that year of evil omen did not
interrupt the other plague. The Inquisition once more moved its
racks, and continued its infernal work in Aracena. Meanwhile, its
branch establishments carried on a brisk business in human lives in
other parts of Andalusia, and their diligence is proved by the fact,
which we owe to the Jesuit historian Mariana, that the net total of
victims for the year amounted to two thousand burnt alive, and
seventeen thousand sentenced to loss of property, loss of civil rights,
or incarceration—mercies which figured in the balance sheet under
the comprehensive euphemism “reconciliation.” In the
1483
third year Thomas de Torquemada was appointed by
Sixtus IV. Inquisitor-General of Castile and Aragon, invested with full
powers to draw up a new constitution for the Holy Office. His labours
resulted in the modern Inquisition, which for centuries after blasted
the Iberian Peninsula and supplied historians, novelists, and
dramatists with an inexhaustible mine of horrors. The Spaniards
were not pleased to see the extension of the grim tribunal’s
operations, and Pedro Arbués, the first Inquisitor who, in spite of
popular protests, ventured to make his appearance in Aragon, was
murdered in the Cathedral of Saragossa. But all
1485
opposition was soon silenced.
Year after year edicts were issued and read in every church on
the first two Sundays of Lent, spurring the faithful, on pain of eternal
damnation, to denounce their fellow-citizens, and often their nearest
and dearest; for loyalty to the cause cancelled all other bonds.
Neither friendship nor family affection was permitted to interfere with
the course of fanaticism, and the vilest crimes against nature and
morality were hallowed by the blessings of the Church. The
Marranos and their Jewish sympathisers and abettors, against whom
the terrible engine continued to be almost exclusively directed under
Torquemada’s management, were decimated, mulcted, and
mutilated at the average annual rate of six thousand roasted or
“reconciled,” not including an unknown number of orphaned children
doomed to starvation or vice by the confiscation of their patrimony.
None were spared, but the most exalted were the first to be laid
low; judges and municipal officers, noblemen, and even clergymen
suspected of Judaism were mysteriously snatched from their homes,
conveyed to the subterranean dungeons of the Inquisition, and there,
amid the terrors of darkness and solitude, were kept for a while in
strict ignorance of the specific crime with which they were charged.
When sufficiently bewildered in his lonely, cold, and lightless cell, the
prisoner was dragged before the court and asked to give straight and
lucid answers to crooked and vague questions. It was accepted as a
principle of judicial procedure that every prisoner was guilty until he
proved himself to be innocent, and that it was better that ten
innocents should suffer than one infidel escape. Denial of guilt was
visited with torture, persistence in denial with more torture, and
confession of sin—to obtain which was an essential element in the
Inquisitorial process—with sentence of death or confiscation of
goods, the greater part of which went to defray the expenses of the
prisoner’s trial and to fill the pockets of his judges, while the
remainder was swallowed up by the Royal Treasury.
Thus the martyrs, mangled by the rack, emaciated by privation,
and almost maddened by mental suffering, were led to the place of
execution. The spectacle partook of the pomp of a Roman pageant
and of the horror of a cannibal feast. Noble Castilians, arrayed in the
dark livery of the Holy Office, disdained not to act as banner-bearers
and body-guards to the monastic executioners. A brilliant throng of
gorgeously apparelled ecclesiastics added to the magnificence of the
procession and enhanced by contrast the humiliation of the convicts,
who, clad in coarse yellow frocks made hideous with a scarlet cross
and designs of demons and hell-flames, haggard and already half-
dead with torture and terror, tottered to the funeral pyre. This was
piled on the Quemadero—a spacious stone platform, with the
statues of the four major prophets erected at the four corners, to
which the victims were bound. The semi-decomposed bodies of
those convicted after death, torn out of their tombs, were placed
upon the pile, the fuel was ignited, and the same flames gradually
and slowly reduced the quick and the dead to ashes.
The havoc of war and the massacres due to sudden eruptions of
popular fury have frequently surpassed these hecatombs in number
of victims. But in sustained and cold-blooded ferocity authentic
history contains nothing, and feverish fiction little, that can compare
with one of them. And yet the Inquisitors were men—no doubt
honest, pious, and honourable men, most of them; some perhaps
amiable, nay even charitable men. Unfortunately they imagined
themselves to be something more—ministers of Heaven’s will on
earth. It was this fatal certainty of the righteousness of their cause
that turned the Inquisitors into monsters. Man would less often
become a fiend if he never mistook himself for an angel.
Torquemada himself, who has been execrated through the ages
as the red-handed protagonist of the appalling tragedy, hardly
deserves his great reputation. There is little originality in his crime.
He was not more cruel, but only more conscientious, courageous,
and consistent than millions of the men of his generation and creed.
When in the nineteenth century we find Cardinal Newman—an
English gentleman and scholar—preaching that “To spare a
heresiarch is a false and dangerous pity. It is to endanger the souls
72
of thousands, and it is uncharitable towards himself,” can we
wonder that a Spanish priest should have acted on that principle in
the fifteenth century? Strong convictions do not, of course, excuse
unscrupulous and unrelenting brutality, but they explain it. Given
such a conviction, persecution becomes a duty and toleration a sin.
If the persecutor cannot command our respect, he is at least entitled
to our compassion. Torquemada deserves our pity almost as much
as his victims. The drama in which he distinguished himself was an
example of that highest kind of tragedy which needs no villain. Faith
had spun the plot; chance supplied the actor.
Year after year the hunt went on. But, in spite of Torquemada’s
unremitting endeavours, few Israelites hesitated in the option
between the font and the stake offered to them. Few chose the first,
and, even with these, conversion was merely a device for escape
from death. Inquisitors come and Inquisitors go, but Israel endures
for ever; and the hope of a better future supplied an indomitable
patience with the present. Disappointment infuriated the persecutors,
but failed to increase the ranks of the proselytes. It was in vain that
ancient calumnies were revived, and fresh ones invented. It was in
vain that the spies redoubled their activity, and the judges strained
their murderous ingenuity. It was in vain that a tempest of execration
and derision raged round the children of Israel. Torquemada and his
accomplices were at last forced to recognise the fact that Judaism
could not be extirpated, save by the extirpation of the Jews. And
forthwith all his influence was brought to bear on persuading the
sovereigns to drive the unclean and accursed race out of the
country.
This was an unexpected blow for the wretched Jews, who feared
exile even more than execution. They had borne imprisonment,
ignominy, penury, and mutilation unflinchingly, in the hope that time
would soften the heart, or at least wear out the arm, of persecution.
But final banishment, with all the terrible perils of shipwreck, of
famine, of attack by pirates and of disease which a large and
unprotected crowd voyaging the high seas was certain to encounter
in those days, would mean irretrievable ruin for the whole race.
73
Moreover the Jews loved Spain with passionate devotion, as is
shown by the mediaeval Hebrew poetry which assumes some of its
most glowing eloquence in praise of Andalusia. So, in order to avoid
expatriation, the leading Jews offered thirty—some say three
hundred—thousand ducats to the sovereigns as a ransom for their
people.
Ferdinand and Isabella, intent on bringing their costly Moorish
campaign to a successful issue, were not disinclined to listen to a
proposal which promised a reinforcement of their military resources.
They received the Jewish deputy in audience, and there was every
prospect of the negotiations coming to a happy conclusion, when, at
the psychological moment, Torquemada, the sleepless and ruthless,
burst into the apartment of the palace where the interview was held,
and, lifting up a crucifix, which he drew forth from beneath his
cassock, thundered at the King and Queen: “Judas Iscariot sold his
master for thirty pieces of silver. Your Highnesses would sell Him
anew for thirty thousand; here He is, take Him and barter Him away.”
With these words the terrible actor cast the crucifix upon the table
and left the room.
The effect of the scene on the sovereigns’ minds was such as
the crafty priest had anticipated. His sudden and opportune
appearance, and his equally sudden disappearance, savoured of the
miraculous; his solemn warning seemed to issue from Heaven. The
same superstitious subservience to ghostly influence which had
induced Isabella more than a dozen years before to sanction the
persecution of the Jews, now induced her to order their expulsion.
Nor was there a voice to protest. The Castilians who would have
bitterly resented the arbitrary banishment of one of themselves,
heard with complacency a similar decision taken against a whole
nation. For Israel was a people apart. They had no share in its
interests; and it had no share in their rights.
1492 It was the month of March in 1492, a year of
incomparable moment for Spain, for Europe, and for
the world at large. That year witnessed the capitulation of Granada,
and the downfall of the Mohammedan Empire in the West; a victory
for the Cross which was received with hearty thanksgivings
throughout Christendom as a providential compensation for the loss
of Constantinople. The same year saw the departure of Christopher
Columbus, under the flag of the Spanish monarchs, on that
memorable voyage which was to result in a triumph wherein the
whole of mankind had reason to rejoice. The same hands which
signed those two glorious treaties now affixed their signatures to the
edict that banished the Jews from the land in which they had lived
longer than their persecutors, which they had loved as much, and
adorned more than they.
The end of July was fixed as the limit for their preparations. They
were permitted to liquidate their possessions and to carry away the
proceeds in bills of exchange, but not in gold or silver, for an existing
law forbade the exportation of precious metals from the country. The
consequence of the edict was that the Jews were forced to sell or
barter away some of their effects at a nominal price, and to leave the
greater portion behind them. If contemporary witnesses are to be
believed, a house was seen bartered for an ass, and a vineyard for a
suit of clothes. In Aragon the property of the Jews was sequestered
by the authorities for the benefit of their creditors, and the people
constantly reviled for their excessive wealth and usury were found to
owe more than they possessed!
The last months of the Jews’ sojourn in Spain were spent by the
priests in frantic efforts at conversion. But those who had opposed
an adamant firmness to temptation when they had much to lose,
could not be expected to yield when reduced to beggary. The
consciousness of suffering for the Idea brought with it an exaltation
that shed a halo over their misery. This affliction also was a fatherly
rod, to be borne with fortitude; an ordeal to be endured as a test of
faith; a humiliation that contained in it a promise of future glory. The
God of their fathers, who had led them out of the house of bondage
and fed them in the wilderness in the days of old, would not suffer
his children to perish. The waters would again be divided for them,
and the sea made dry land. This last expectation, confidently
encouraged by the Rabbis, proved vain when the exiles reached the
coast. But failure did not shake the faith of the children of Israel. The
severer the martyrdom, the greater the certainty of beatitude.
Scattered and scorned though they were, the day would dawn when
they would once more be gathered under Jehovah’s parent pinion.
The light of Zion still shone in the distance undimmed.
Thus, poor in worldly possessions, but rich in hope; defenceless,
yet strong in faith, they journeyed from all parts of the country to the
frontiers: the healthy and the sick, old men bending over their staffs,
little footsore children tottering by their fathers’ sides, and infants
clinging to their mothers’ breasts. Venerable Rabbis and scholars,
delicately nurtured maidens, young gentlemen, yesterday proud
cavaliers, to-day penniless and broken-spirited paupers—they all
dragged their weary limbs in various directions: some north, others
south; one group to the east and another to the west. Many a wet
eye followed the melancholy processions, and many a warm
Spanish heart melted to pity, but no hand was held out to the
wanderers, no word of comfort was addressed to them: the fear of
God restrained many; the fear of Torquemada more. The time of
year added to the sadness of the spectacle. Andalusia was bathing
in the exuberant beauty of a Spanish summer; the sky smiled blue
and bright overhead, the earth was spangled with flowers beneath,
the birds warbled blithely in the trees and bushes, the air was sweet
with the scent of orange blossoms; Nature seemed to hold a carnival
of joy in mockery of the misery and heartlessness of man.
The banishment of the Jews from England at the close of the
thirteenth century was mere child’s play compared with their
expulsion from Spain at the close of the fifteenth. The Jews who left
England had only been in the country for two centuries; those who
now left Spain had lived there more than twelve. The English exiles
had borne small part in England’s greatness; the Spanish Jews had
served the state in the highest capacities, had won universal fame in
art, science and literature, and had become to the rest of the world’s
Jewries an exemplar of that harmonious combination of piety with
culture which was nowhere, outside Spain, so prominent a feature of
mediaeval life. And in quantity as in quality the Spanish banishment
far surpassed its English prototype. The exiles from England
amounted at most to sixteen thousand; those from Spain were
computed at least as one hundred and sixty thousand. Some
accounts even raise them to five times that number. It was a
movement on a scale comparable only to that of the exodus of Israel
from Egypt, with the sole difference that, whereas the Jews had
dwelt in Egypt as strangers and bondsmen in the land, in Spain they
had become in many respects Spaniards. But the crime, augmented
by a similar crime against the Moors, brought its penalty with it. Even
accepting the lowest estimate as nearest the correct one, the price in
skill, industry and intelligence, which Spain—despite her recent
military achievements and her budding power beyond the seas—had
to pay for the gratification of her religious fanaticism cannot easily be
calculated; but it can be seen to this day. The same yoke which
crushed the alien and the infidel could not but cramp the native and
the Christian. Freedom of thought, speech, or action was dead.
Intellectual culture was soon to be succeeded by monasticism, and
material prosperity by mendicity. Meanwhile the value of Ferdinand
and Isabella’s Hebrew subjects could not but have been realised
immediately on their departure. The Spanish Government, prompted
by the Spanish Church, had said to the Jews: “Be baptized or be
gone!” The Jews went, and the life of Spain went with them. Stately
mansions fell into mossy decay, rich cornfields and vineyards were
turned into waste land, busy and populous cities were suddenly
silenced as by a magician’s black art. In return, Spain nursed the
cold comfort of having served the cause of the gloomy and
bloodthirsty monster that the age called God.
Nothing throws a clearer light on the spirit of the times than the
comments of contemporary writers on Ferdinand and Isabella’s
suicidal policy. The Spanish historians join in a chorus of
indiscriminate panegyric; the Spanish poets sing pæans to the
triumph of the Faith. Foreign spectators, while deprecating the
severity of the methods employed, have nothing but praise for the
motive. They all applaud the deed as a sacrifice of temporal to
spiritual interests. It is true that Ferdinand’s treasury was the richer
for the confiscated property of the Jews. But, though lust for plunder
may be regarded as the mainspring of his own policy, it was not the
primary motive of the Dominicans, nor had it any share in Isabella’s
conduct. This amiable princess has laid her soul bare in the
confession: “In the love of Christ and his maiden mother I have
caused great misery, and have depopulated towns and districts,
provinces and kingdoms.” The expulsion of the Jews, like the autos-
da-fé, was a crime committed principally por amor de Dios.

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BioChemistry 6th Edition By Reginald

Reginald H. Garrett | Charles M. Grisham

With molecular graphic images

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Georgia Cobb Garrett

Charles M. Grisham and Reginald H. Garrett

Part I Molecular Components of Cells 1

Part II Protein Dynamics 437

Part III Metabolism and Its Regulation 583

Part IV Information Transfer 985

Part I Molecular Components of Cells Critical Developments in Biochemistry: Synthetic

The Glycogen Phosphorylase Reaction Converts 16 Molecular Motors 547

Part III Metabolism and Its Regulation 18 Glycolysis 611

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