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BioChemistry 6th Edition By Reginald
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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
ActiveModels Library of Proteins and Nucleic Acids
ActiveModels presents an online library of macromolecular structures with accompanying
scripts detailing descriptions of structure-function relationships for the key proteins and
nucleic acids mentioned in the book and listed below. The hyperlinked text controls the
graphic display and presents a variety of perspectives and features. End-of-chapter prob-
lems written specifically to utilize this resource appear in most chapters.
Abl Kinase Cystic Fibrosis Transmembrane Conductance Regulator

Acetylcholinesterase (Recombinant Human) Cytidine Triphosphate Synthetase
Acetyl-CoA Carboxylase (Carboxyltransferase Domain) Cytochrome b Reductase
AcrB Channel Cytochrome c
Actin Cytochrome c Oxidase (Bos taurus)
Acyl-CoA Dehydrogenase Cytochrome c Oxidase (Rhodobacter sphaeroides)
Acyl-CoA Oxidase D2 Domain of NSf
Adenylosuccinate Lyase Dicer I
b-Adrenergic Receptor Di-Heme Cytochrome c
Alcohol Dehydrogenase 3,4-Dihydroxyphenylalanine Decarboxylase
Aldose Reductase DNA Polymerase h
a-Amylase (salivary) DrrA Guanine Nucleotide Exchange Factor
Amyloid beta-Peptide (Ab) Dual Specificity Phosphatase 6
Androgen Receptor E1 Helicase
Angiotension-1 Converting Enzyme (ACE) E1 Ubiquitin-like Protein Complex
Anthrax Lethal Factor EGFR Kinase Domain
Apoptosis-Inducing Factor Elastase
Aprotinin Enolase
Aqp1 Aquaporin (Water Channel) Enoyl-CoA Hydratase
ASAP3 (ARF GTPase) Estrogen Receptor
ATP/ADP Translocase-1 Farnesyl Transferase
Atrial Natriuretic Peptide Receptor Fatty Acid Transporter
Autotransporter (bacterial) Ferritin (human) and Bacterioferritin
BiP Chaperone Ferritin H Chain (human)
Bone Morphogenetic Protein 2 Ferrochelatase (human)
Bone Morphogenetic Protein Domain Fibrin (human)
BRCA 2 FKBP12-Rapamycin Complex
BtuB (Cobalamin transporter) Flavodoxin
Calmodulin FliG (Flagellar Rotor Protein)
Caspase-6 Fructose-1-6-Bisphosphatase
Cat Allergen GABA Receptor Associated Protein
Choline Acetyltranferase Galectin 1 (human)
Chorismate Mutase Glucose-6-Phosphate Dehydrogenase
Complex 1 (Electron Transport) Glutamine Synthetase
Complex 2 (Electron Transport) Glycogen Phosphorylase
Concanavalin GMP Synthetase
C-Reactive Protein (human) Grb2 Growth Factor Bound Protein 2 Signal Transduction Adaptor
Cu,Zn Superoxide Dismutase (human) GRD19p
Cyclin-Dependent Kinase-2 (human) GroEL-GroES Complex
Cyclooxygenase Hemoglobin S
xxviii
ActiveModels Library of Proteins and Nucleic Acids xxix
Hepatocyte Nuclear Factor 1b Bound to DNA MDM2 (Ubiquitin-Protein Ligase E3)

Hexokinase (human) Metalloprotease
HIV-1 Protease Methemoglobin (horse)
HIV Reverse Transcriptase with a Rival Purine Inhibitor Monoamine Oxidase B (human)
HIV Reverse Transcriptase with Inhibitor 7 Myoglobin
HLA A2 Class I MHC Myosin 2 - heavy and light chain
HMG-CoA Reductase Myosin 2 - heavy chain
Hsp90 Myosin 5
Influenza Virus Hemagglutinin Nc6.8 (monoclonal Ab) Fab In Complex With Sweetener
Interleukin 17 Receptor Complex Sc45647
Interleukin -4 and its Receptor Neuropsin (a Serine Protease)
Ire1 (Transmembrane Serine/Threonine Kinase) Nicotinic Acetylcholine Receptor
Isocitrate Dehydrogenase Niemann-Pick C1: Cholesterol
ITK-Sh2 Domain Bound to Phosphopeptide Nitrogenase Reductase
KIF1A (monomeric kinesin)-Microtubule Complex) N-Myristoyltransferase With Bound Myristoyl-CoA
Kinesin NSE/NS4A Protease Apostructure (Hepatitis C Virus)
Kinesin (rat) Nuclear Receptor X Heterodimers
b-Lactamase 2,3-Oxidosqualene Cyclase with Lanosterol
Lactate Dehydrogenase (Malarial) p53-DNA Complex (p53 DNA-Binding Domain)
LDL Receptor Pepsin 1 DMSO
Lipocalin (human) P-Glycoprotein (MDR)
Luciferase Inhibitor Complex (firefly) Phosphofructokinase (Trypanosoma)
Lysine Gingipain (Kgp) protein Phosphoglucoisomerase (Bacillus)
Malonyl-CoA-ACP Transferase
Laboratory Techniques in Biochemistry
All of our knowledge of biochemistry is the outcome of experiments. For the most part,
this text presents biochemical knowledge as established fact, but students should never lose
sight of the obligatory connection between scientific knowledge and its validation by obser-
vation and analysis. The path of discovery by experimental research is often indirect, tortu-
ous, and confounding before the truth is realized. Laboratory techniques lie at the heart of
scientific inquiry, and many techniques of biochemistry are presented within these pages to
foster a deeper understanding of the biochemical principles and concepts that they reveal.
Recombinant DNA Techniques Fluxomics Section 17.5

Restriction endonuclease digestion of DNA Section 10.6d Tumor diagnosis with positron emission tomography (PET)
Restriction mapping Section 10.6e–f Section 18.7
Nucleotide sequencing Section 11.1 Glucose monitoring devices Section 22.1
Nucleic acid hybridization Section 11.3 Fluoro-substituted analogs as therapeutic agents Section 26.8
Chemical synthesis of oligonucleotides Section 11.6 “Knockout” mice Section 28.7
Cloning; recombinant DNA constructions Section 12.1 Isolation/Purification of Macromolecules
Construction of genomic DNA libraries Section 12.2
Ion exchange chromatography Section 5.2
Combinatorial libraries of synthetic oligomers Section 12.2
Protein purification protocols Section 5.2
Screening DNA libraries by colony hybridization Section 12.2b
Dialysis and ultrafiltration Section 5.2
mRNA isolation Section 12.2e
Size exclusion chromatography Section 5.2
Construction of cDNA libraries Section 12.2e
SDS-polyacrylamide gel electrophoresis Section 5.2
Expressed sequence tags Section 12.2e
Isoelectric focusing Section 5.2
Southern blotting Section 12.2e
Two-dimensional gel electrophoresis Section 5.2
Gene chips (DNA microarrays) Section 12.2f
Hydrophobic interaction chromatography Section 5.2
Protein expression from cDNA inserts Section 12.3
High-performance liquid chromatography Section 5.2
Screening protein expression libraries with antibodies Section 12.3a
Affinity chromatography Section 5.2
Two-hybrid systems to identify protein:protein interactions Section 12.3c
Ultracentrifugation Section 5.2
Reporter gene constructs Section 12.3b
Fractionation of cell extracts by centrifugation Section 5.2
Polymerase chain reaction (PCR) Section 11.1b
Proteomic analysis by MudPIT (Multidimensional Protein
RT-qPCR (real-time quantitative PCR) Section 12.3a
Identification Technology) Section 5.9b
In vitro mutagenesis Section 12.3d
ChIP-Seq (chromatin immunoprecipitation-DNA sequencing) Analyzing the Physical and Chemical Properties
Section 12.3c of Biomolecules
RNAi Section 12.4 Titration of weak acids Section 2.2a
DNA laser printing Section 12.5b Preparation of buffers Section 2.3
BioBricks Section 12.7b Measurement of standard reduction potentials Section 3.9
CRISPR/Cas9 Section 12.7e Edman degradation Section 4.3
Probing the Function of Biomolecules Nuclear magnetic resonance (NMR) Section 4.5
Green fluorescent protein Section 4.3 Estimation of protein concentration Section 5.2
Plotting enzyme kinetic data Section 13.3j Amino acid analysis of proteins Section 4.6
Enzyme inhibition Section 13.4 Amino acid sequence determination Section 5.4
Optical trapping to measure molecular forces Section 16.2c Mass spectrometry of proteins Section 5.4i
Isotopic tracers as molecular probes Section 17.4b Peptide mass fingerprinting Section 5.4i
RNAi Section 12.4 Solid-phase peptide synthesis Section 5.6
NMR spectroscopy Section 17.4c Membrane lipid phase transitions Section 9.4b
Transgenic animals Section 28.8 DNA nanotechnology Section 10.5a
DNA footprinting Section 28.1 Nucleic acid hydrolysis Section 10.6
DNA sequencing Section 11.1
Techniques Relevant to Clinical Biochemistry Single-molecule DNA sequencing Section 11.1
Gene therapy Section 12.6a Density gradient (isopycnic) centrifugation Section 11.3
Metabolomic analysis Section 17.5
xxx
Preface
The Sixth Edition

Scientific understanding of the molecular nature of life is growing at an astounding rate.
Significantly, society is the prime beneficiary of this increased understanding. Cures for
diseases, better public health, remedies for environmental pollution, and the development
of cheaper and safer natural products are just a few practical benefits of this knowledge.
In addition, this expansion of information fuels, in the words of Thomas Jefferson,
“the illimitable freedom of the human mind.” Scientists can use the tools of biochemistry
and molecular biology to explore all aspects of an organism—from basic questions about
its chemical composition, through inquiries into the complexities of its metabolism, its
differentiation and development, to analysis of its evolution and even its behavior. New
procedures based on the results of these explorations lie at the heart of the many modern
medical miracles. Biochemistry is a science whose boundaries now encompass all aspects
of biology, from molecules to cells, to organisms, to ecology, and to all aspects of health
care. This sixth edition of Biochemistry embodies and reflects the expanse of this knowl-
edge. We hope that this new edition will encourage students to ask questions of their own
and to push the boundaries of their curiosity about science.
Making Connections
As the explication of natural phenomena rests more and more on biochemistry, its inclu-
sion in undergraduate and graduate curricula in biology, chemistry, and the health
sciences becomes imperative. The challenge to authors and instructors is a formidable
one: how to familiarize students with the essential features of modern biochemistry in an
introductory course or textbook. Fortunately, the increased scope of knowledge allows
scientists to make generalizations connecting the biochemical properties of living systems
with the character of their constituent molecules. As a consequence, these generalizations,
validated by repetitive examples, emerge in time as principles of biochemistry, principles
that are useful in discerning and describing new relationships between diverse biomolecular
functions and in predicting the mechanisms underlying newly discovered biomolecular
processes. Nevertheless, it is increasingly apparent that students must develop skills in
inquiry-based learning, so that, beyond this first encounter with biochemical principles
and concepts, students are equipped to explore science on their own. Much of the design
of this new edition is meant to foster the development of such skills.
We are both biochemists, but one of us is in a biology department, and the other is in
a chemistry department. Undoubtedly, we each view biochemistry through the lens of
our respective disciplines. We believe, however, that our collaboration on this textbook
represents a melding of our perspectives that will provide new dimensions of apprecia-
tion and understanding for all students.
Our Audience
This biochemistry textbook is designed to communicate the fundamental principles
governing the structure, function, and interactions of biological molecules to students
encountering biochemistry for the first time. We aim to bring an appreciation of
xxxi
xxxii Preface
biochemistry to a broad audience that includes undergraduates majoring in the life sci-
ences, physical sciences, or premedical programs, as well as medical students and graduate
students in the various health sciences for whom biochemistry is an important route to
understanding human physiology. To make this subject matter more relevant and inter-
esting to all readers, we emphasize, where appropriate, the biochemistry of humans.
Objectives and Building on Previous Editions

We carry forward the clarity of purpose found in previous editions; namely, to illuminate
for students the principles governing the structure, function, and interactions of
biological molecules. At the same time, this new edition has been revised to reflect
tremendous developments in biochemistry. Significantly, emphasis is placed on the
interrelationships of ideas so that students can begin to appreciate the overarching
questions of biochemistry.
Features
●● Clarity of Instruction This edition was re-organized for increased clarity and read-
ability. Many of the lengthier figure legends were shortened and more information
was included directly within illustrations. These changes will help the more visual
reader.
●● Visual Instruction The richness of the Protein Data Bank (www.pdb.org) and avail-
ability of molecular graphics software has been exploited to enliven this text. Over
440 images of prominent proteins and nucleic acids involved with essential biological
functions illustrate and inform the subject matter and were prepared especially for
this book.
●● Essential Questions organization Each chapter in this book is framed around an
Essential Question that invites students to become actively engaged in their learning
and encourages curiosity and imagination about the subject matter. For example, the
Essential Question of Chapter 3 asks, “What are the laws and principles of thermo-
dynamics that allow us to describe the flows and interchanges of heat, energy, and
matter in biochemical systems?” The section heads then pose Key Questions that serve
as organizing principles for a lecture such as, “What is the daily human requirement
for ATP?” The subheadings are designed to be concept statements that respond to the
section headings. The end-of-chapter Summary then brings each question together
with a synopsis of the answer that summarizes the important concepts and facts to
aid students in organizing and understanding the material.
● Foundational Biochemistry At the end of each chapter, a new Foundational Biochem-
istry feature has been added. These sections provide a comprehensive list of the prin-
cipal facts and concepts that a student should understand after reading each chapter.
Presented as short statements or descriptive phrases, the items of the Foundational
Biochemistry list serve as guides to students of the knowledge they have acquired
from the chapter and as checklists the students can review in assessing their learning.
●● End-of-Chapter Problems More than 600 end-of-chapter problems are provided. They
serve as meaningful exercises that help students develop problem-solving skills useful
in achieving their learning goals. Some problems require students to employ calcula-
tions to find mathematical answers to relevant structural or functional questions.
Other questions address conceptual problems whose answers require application and
integration of ideas and concepts introduced in the chapter. Each set of problems
includes MCAT practice questions to aid students in their preparation for standard-
ized examinations such as the MCAT or GRE.
●● End-of-chapter problem headings allow students to place the problem within the con-
text of the subject matter they have learned.
●● Further Readings sections at the end of each chapter make it easy for students to find
up-to-date additional information about each topic.
Preface xxxiii
●● Critical Developments in Biochemistry essays emphasize recent and historical advances

in the field.
●● Human Biochemistry essays emphasize the central role of basic biochemistry in medi-
cine and the health sciences. These essays often present clinically important issues
such as diet, diabetes, and cardiovascular health.
●● A Deeper Look essays expand on the text, highlighting selected topics or experimental
observations.
●● Laboratory Techniques The experimental nature of biochemistry is highlighted, and a
list of laboratory techniques found in this book can be seen on page xxx.
Highlights of This Edition

●● ActiveModels Library of Proteins and Nucleic Acids is an optional online resource
(http://www.psafe.us) for exploration of over 1,000 protein and nucleic acid structures,
particularly those described in this text. Each structure is presented as a “Molecular
Document” using the ICM Browser Pro modeling program developed by Molsoft,
LLC in La Jolla, CA. These molecular documents were created by undergraduate
biochemistry students at the University of Virginia and illustrate macromolecular
structures with rich, vivid, state-of-the-art graphics accompanied by a script that
highlights pertinent structure-function correlations. Hyperlinks in the text window of
each entry control the graphic display and present a variety of perspectives and fea-
tures for each protein or nucleic acid. A number of end-of-chapter problems challenge
students to explore macromolecular structure and function through examination of
these molecular documents.
Recent Advances Highlighted in These Chapters Chapter 6 The higher-order structure of proteins. A Deeper Look
Chapter 1 The foundations of biochemistry. New highlight: The feature on protein sectors—evolutionary units of three-dimensional
eukaryotic cell likely emerged from an archaeal lineage. Contem- structure, and a new Deeper Look feature on metamorphic proteins,
porary eukaryotic cells are composites that harbor bacterial and which exist as an ensemble of structures of similar energies and
archaeal contributions. A new Critical Developments in Bio- stabilities. A new “Human Biochemistry” box on chimeric antigen
chemistry feature on synthetic life: the chemical synthesis of a receptor (CAR) T-cell therapies as the basis of novel cancer treat-
bacterial genome and its incorporation into host cells to create ments, and a new “A Deeper Look” box on friction in the protein
the first organism with a fully synthetic genome. folding process, as well as expanded coverage of intrinsically dis-
ordered proteins.
Chapter 2 This chapter reviews the properties of water, the nature
of hydrophobic interactions, ionic equilibria, the behavior of Chapter 7 The structure and chemistry of carbohydrates. The dis-
weak acids, the concept of pH, and the major buffer systems in covery that the dis accharide galactose-α-1,3-galactose (“alpha
organisms. gal”) triggers red meat allergy. A new “A Deeper Look” box on the
chemistry of cellulose crosslinks in wrinkle-free fabrics, and a new
Chapter 3 This chapter features a simplified, more student-accessible
“A Deeper Look” box on the role of N-linked oligosaccharides in
presentation of the basic concepts of thermodynamics, highlighted
protein folding.
by a new “A Deeper Look” box stressing the difference between
free energy changes under cellular conditions, standard-state free Chapter 8 The structure and chemistry of lipids. A new Deeper
energy changes (G), and the situation at equilibrium (G  0). Look feature on glycophospholipids that play a role in formation
Chapter 4 The structure and chemistry of amino acids. An intro- of plasma membrane signaling microdomains involved in cellular
duction to the Brainbow technique that enables labeling of many differentiation and maturation. Also a new Human Biochemistry
individual neurons. New A Deeper Look box on the unusual feature on the endocannabinoid signaling system that involves lipid-
amino acid selenocysteine and selenoproteins, and a new Critical soluble signals such as anandamide and 2-arachidonoylglycerol. The
Developments in Biochemistry box on incorporation of unnatural signaling effects of sphingosine-1-phosphate.
amino acids into proteins. Chapter 9 Membrane structure and function. A new Human
Chapter 5 Proteins as polymers of amino acids; proteins as mac- iochemistry feature on development of inhibitors of
B
romolecules of elaborate structure; proteins as the agents of bio- N-myristoyltransferase in T. brucei, the organism that causes
logical function. A new section defining the concept of the sleeping sickness in Africa. Also revised discussions of the roles of
proteome and what new insights emerge from such large-scale, sphingolipid and cholesterol in the formation of membrane rafts
global studies of all the proteins in a given cell or tissue. The pro- and the structures and functions of SNARE proteins and channel
teome is an excellent reflection of what a particular cell is doing at proteins. Five new end-of-chapter problems based on recent
a specific moment in time. research on membrane proteins and transport sytems.
xxxiv Preface
Chapter 10 The structure and chemistry of nucleotides and nucleic at a particular moment, as the most accurate representation of
acids. New appreciation of cyclic dinucleotides as signaling mole- what a cell is doing at any instant.
cules, including the role of cGAMP in triggering a program of gene Chapter 18 Glycolysis. A Critical Developments in Biochemistry
expression aimed at halting infection. An updated introduction to feature that describes a modern interpretation of the Warburg
the many roles of small RNAs in the regulation of gene expression: effect in cancer. Expanded coverage of glucokinase and its role as
miRNAs and the long, noncoding RNAs (lincRNAs). a glucose sensor that recognizes glucose and initiates a signaling
Chapter 11 The structure of nucleic acids and chromosomes. An pathway that results in glucose-induced insulin secretion. New
overview of the next-generation DNA sequencing technologies, information on protein kinase M2 (PK M2), including its newly-
including emerging technologies to sequence single molecules of discovered protein kinase activity, its stimulation by SAICAR (an
DNA. The techniques at the forefront of “personal genomics”: the intermediate in the purine biosynthetic pathway), and its role in
ability to carry out low-cost sequencing of an individual’s genome tumor proliferation. New coverage of the unregulated metabolism
and the implications of the information obtained on the diagnosis of dietary fructose in the liver, and its implications for insulin resis-
and treatment of disease. Also, creation of DNA molecules com- tance, metabolic syndrome, and obesity.
posed of not just two, but three, different base pairs opens up Chapter 19 The citric acid cycle. A new discussion of the structure
extraordinary potentials within synthetic biology. New structural of pyruvate dehydrogenase comple; a new Deeper Look feature on
models for chromatin at the level of its 30-nm fiber ‘secondary the role of anaplerosis in insulin secretion; and a section on the regu-
structure’ give insights into the long mysterious higher-order struc- lation of TCA cycle enzymes by acetylation. A new Human
ture of chromosomes. A discussion of how new biological roles of Biochemistry box on the roles of citric acid cycle metabolites in post-
RNA have come into sharper focus because of recent realizations translational modification of proteins, including acetylation, succi-
that their three-dimensional architectures are conformationally nylation, and succination reactions. New information on the operation
dynamic, endowing these RNAs with functional abilities, such as of the eight citric cycle enzymes as a supercomplex or metabolon.
ligand binding and even catalysis.
Chapter 20 Electron transport and oxidative phosphorylation.
Chapter 12 The strategies of recombinant DNA technology and
Discussion of the new structure of Complex I and new informa-
gene cloning. New features include a section devoted to high-
tion on supercomplexes in electron transport. New insights into
throughput technologies that allow global study of millions of
the mechanism of action of the F1F0-ATP synthase. A new
genes or proteins in a single experiment and a section devoted to
Human Biochemistry box describing mitochondrial dynamics and
the emerging field of synthetic biology, with special emphasis on
its role in cardiovascular, neurodegenerative, and endocrine dis-
the use of CRISPR/Cas9 to edit genes and genomes.
eases, as well as cancer. A new Human Biochemistry box on car-
Chapter 13 The equations of enzyme kinetics. A new perspective on diolipin and its stabilization of respiratory supercomplexes, the
the response of enzyme reaction rate to increasing temperature is biogenesis of mitochondrial proteins, and the fission and fusion
presented, wherein a temperature-dependent equilibrium between processes of mitochondria.
active enzyme and a catalytically inactive but not denatured state
Chapter 21 Photosynthesis—the most fundamental of all energy
of the enzyme affords a deeper understanding of enzyme kinetics.
transduction systems in nature: the biochemistry of photosyn-
Ribozymes, abzymes, and designer enzymes are featured here.
thesis; the transformation of light energy into chemical energy.
Chapter 14 Mechanisms of enzyme action. A new section on the New information on species variability in the c-subunit stoichi-
role of quantum mechanical tunneling in electron and proton ometry of CF1CF0-ATP synthases and the implications of this
transfer reactions of enzymes. New Human Biochemistry box on variability for the energetic cost of ATP formation. The recently
antibiotic resistance by (carbapenem-resistant) superbugs. New described structure of the Mn4CaO5 oxygen-evolving cluster at
Critical Developments in Biochemistry box on acceleration of the heart of Photosystem II is presented. Emphasis on the path-
enzyme reactions by electric fields. way of carbon dioxide fixation that synthesizes organic molecules
Chapter 15 Enzyme regulation. This chapter highlights allosteric from CO2, ultimately leading to cellulose and starch formation,
regulation and covalent modification of enzymes as important the two significant polysaccharides produced by plants.
modes of metabolic regulation and includes discussion of revers- Chapter 22 Gluconeogenesis, glycogen metabolism, and the pen-
ible acetylation, a newly appreciated means to regulate metabolic tose phosphate pathway. A Deeper Look feature on TIGAR, a
enzymes. The relationship between quaternary structure and allo- p53-induced enzyme that mimics fructose-2,6-bisphosphatase and
steric regulation is exemplified by a comparison of the oxygen- responds to cellular stresses such as oncogenesis and DNA dam-
binding proteins myoglobin and hemoglobin. age events; new information on O-GlcNAc signaling and the
Chapter 16 Motor proteins. A revised discussion of P-loop hexosamine biosynthetic pathway; and a new Critical Develop-
NTPases and their role in molecular motors and a revised sec ments in Biochemistry feature describing how consumption of
tion on the contraction cycle of skeletal muscle. New Human ATP promotes and supports the metabolism of cancer cells. The
Biochemistry box on the “tubulin code” post-translational modi- interplay of phosphorylation and O-GlcNAcylation in gluconeo-
fications that coordinate the functions of microtubules. genic gene transcription, particularly in the fasting state.
Chapter 17 An overview of metabolism, to prepare students for Chapter 23 Fatty acid oxidation. A new Deeper Look feature on
the ten chapters on metabolic pathways which follow. This edition the biochemistry of obesity describing the role of peroxisome
highlights metabolomics, the study of all the metabolites in a cell proliferator-activated receptors in regulation of gene expression in
Preface xxxv
fatty acid oxidation and triglyceride metabolism. A new A Deeper Chapter 28 DNA metabolism. The multiplicity of DNA poly-
Look box describing the trifunctional enzyme complex at the heart merases. A new section to integrate DNA replication, recom
of the β-oxidation pathway and migration of its fatty acyl sub- bination, and repair as interdependent aspects of DNA
strates along a negatively-charged substrate channel without diffus- metabolism introduces this chapter. Another new feature is
ing into the bulk solvent. The role of β-hydroxybutyrate as a an illustration of how homologous recombination helps to pre-
signaling metabolite that regulates gene expression, lipid metabo- vent cancer. Genetic recombination, protein diversity, and
lism, metabolic rate, and resistance to oxidative stress. immunology.
Chapter 24 Lipid biosynthesis. A Human Biochemistry box fea- Chapter 29 Transcription; DNA-dependent RNA polymerases.
turing the role of NPC1 and NPC2 proteins in cholesterol trans- Transcription regulation in bacteria and in eukaryotes, An
port in lysosomes and Niemann-Pick type C disease. Four new update of eukaryotic translation initiation events in eukaryotes
Human Biochemistry boxes: Lipins—phosphatases essential for and the emerging science of miRNAs and lncRNAs as key
triglyceride synthesis and other functions; Lipoxins—anti- regulators of post-transcriptional gene expression are presented,
inflammatory eicosanoid products of transcellular metabolism; along with new structural and functional information about
APOC3—an apolipoprotein that regulates plasma triglyceride Mediator and its role as a bridge between enhancers of tran-
levels; and new cholesterol-lowering drugs that target PCSK9, an scription and RNA polymerase II. The competing concepts of
LDL receptor chaperone. the histone code and histone crosstalk are discussed. The
Chapter 25 The assimilation of inorganic nitrogen into organic nitro- spliceosome.
gen metabolites and biosynthesis of the amino acids. Discussion of Chapter 30 Protein synthesis. The genetic code. Aminoacyl-tRNA
glutamine and its metabolic significance as the most abundant amino synthetases and the second genetic code. New features of the
acid in human body fluids and tissues; glutamine and cancer. Fur- G-protein family members, Ef-Tu and EF-G, and their interac-
ther, tryptophan catabolism by the kynurenine pathway is presented, tions with the ribosome, new structures for the ribosome RF-2
because this pathway has been implicated in human neurodegenera- termination complex, and the more richly detailed appreciation of
tive disorders such as Parkinson’s and Alzheimer’s disease. the events in eukaryotic translation initiation highlight this chap-
Chapter 26 Biosynthesis of purines and pyrimidines. Tetrahydrofo- ter. The ribosome as a ribozyme. Tethered ribosomes and new
late and 1-carbon metabolism. Purinosomes as multi-enzyme assem- frontiers in synthetic biology.
blages of the purine biosynthetic enzymes. The purine pathway Chapter 31 Completing the protein life cycle. Modes of post-
intermediate SAICAR as a key signal in reprogramming metabolism transcriptional modification that control the functional protein
in cancer cells. The structure of human ribonucleotide reductase with pool, Protein folding and neurodegenerative protein folding dis-
its revelations regarding regulation by nucleotides are presented. eases. A new Human Biochemistry box on chaperones that func-
Chapter 27 Summing up metabolism and the metabolic roles of the tion by stress-induced protein unfolding. A Human Biochemistry
various organs. AMP-kinase (AMPK) as the cell’s energy charge highlight on autophagy, the process by which cells recycle their
sensor and the newly appreciated protection of AMPK by ADP are materials. Expanded coverage of Htr proteins.
discussed. mTORC1 as the integrator of information about nutri- Chapter 32 Cell signaling and neurotransmission. Intracellular
ent status and as the regulator of cellular synthesis is introduced. responses to extracellular signals. Protein kinase cascades. Orga-
The regulation of eating behavior. The relationships between nutri- nization and integration of signaling pathways. Sensory systems.
ent intake, AMPK, SIRT1 and protein acetylation and the conse- A Human Biochemistry feature on neurexins and neuroligins,
quences that these relationships have for caloric intake control and which function as scaffolding proteins in the formation of syn-
the development of metabolic syndrome. These interactions illumi- apses and the regulation of synaptic transmission, learning, and
nate the underlying causes of the current obesity epidemic. memory.
Supporting Materials
For the Instructor
Please visit http://www.cengage.com/chemistry/garrett/biochem6e for more information
about instructor resources for this text.
For the Student

Please visit http://www.cengage.com/chemistry/garrett/biochem6e for more information
about student resources for this text.
Acknowledgments
We are indebted to the many experts in biochemistry and molecular biology who
carefully reviewed this book at several stages for their outstanding and invaluable advice
on how to construct an effective textbook.
xxxvi Preface
Weiguo Coa, Clemson University

Christine Smith, University of New Mexico
Anya Goodman, California Polytechnic
Cheryl Ingram-Smith, Clemson University
Larry Yet, University of South Alabama
Hiroshi Nakai, Georgetown University
Gregory Marks, Carroll College
Sandra Barnes, Alcorn State University
Stephen Campion, Alvernia College
We also wish to gratefully acknowledge many other people who assisted and encouraged us
in this endeavor. This book remains a legacy of publisher John Vondeling, who originally
recruited us to its authorship. We sense his presence still nurturing our book and we are
grateful for it. Maureen Rosener, our new Senior Product Manager, has brought enthusi-
asm and an unwavering emphasis on student learning as the fundamental purpose of our
collective enterprise. Sandi Kiselica, Senior Developmental Editor, shepherded the first
four editions of this text through conception to production. Any success this edition has
will become part of her legacy. Elizabeth Woods, the Content Developer for this edition,
has kept us focused on the matters at hand, the urgencies of the schedule, and limits of
scale in a textbook’s dimensions. She is truly a colleague in these endeavors. We also applaud
the unsung but absolutely indispensable contributions by those whose efforts transformed
a rough manuscript into this final product: Teresa Trego, Senior Content Project Manager;
Edward Dionne, Project Manager at MPS Limited. If this book has visual appeal and
editorial grace, it is due to them. The beautiful illustrations that not only decorate this text
but also explain its contents are a testament to the creative work of MPS Limited and to
the legacy of John Woolsey and Patrick Lane at J/B Woolsey Associates. Manojkirin Chan-
der at Lumina Datamatics Limited assisted in the selection of the wonderful photographs.
We are thankful to our many colleagues who provided original art and graphic images for
this work, particularly Professor Jane Richardson of Duke University. We are eager to
Jazmine and Jatszi
acknowledge the scientific and artistic contributions of Michal Sabat, Senior Scientist in
the Department of Materials Science and Engineering at the University of Virginia. Michal
was the creator of most of the PyMOL-based molecular graphics in this book. Much of
the visual appeal that you will find in these pages gives testimony to his fine craftsmanship
and his unflagging dedication to our purpose. Elizabeth Magnotti, recent B.S. (chemistry)
graduate of the University of Virginia, coordinated the student development of the Active-
Models library, a multi-faceted task requiring scientific knowledge and a sense of the
important. We owe a special thank you to Rosemary Jurbala Grisham, much loved spouse
of Charles and wonderfully tolerant friend of Reg. Also to be acknowledged with love and
pride are Georgia Cobb Garrett, spouse of Reg, and our children, Jeffrey, Randal, and
Robert Garrett, and David, Emily, and Andrew Grisham. Also to be appreciated is Jasper,
the Hungarian Puli whose unseeing eyes viewed life with an energetic curiosity we all
should emulate. Memories of Clancy, a Golden Retriever of epic patience and perspicuity;
Clancy Jazmine, the alpha dog of the Puli troika; and Jatszi and Jax, attendant to Charlie’s deepest
thoughts and daily activities, were a constant presence to our days as authors, our joys in
other pursuits, and our reflections on life. We hope this sixth edition of our textbook has
captured the growing sense of wonder and imagination that researchers, teachers, and stu-
dents share as they explore the ever-changing world of biochemistry.
“Imagination is more important than knowledge. For while knowledge defines all we cur-
rently know and understand, imagination points to all we might yet discover and create.”
—Albert Einstein
Reginald H. Garrett Charles M. Grisham

Charlottesville, VA Ivy, VA
Jax and Jasper November, 2015
The Facts of Life: 1 Part I
Molecular
Components
Chemistry Is the Logic of cells
of Biological Phenomena “…everything that living things do can be

understood in terms of the jigglings and
wigglings of atoms.”
Richard P. Feynman. Lectures on Physics,
Addison-Wesley, 1963
Marmaduke St. John/Alamy
 Sperm fertilizing an egg.
Essential Question KEY QUESTIONS

Molecules are lifeless. Yet, the properties of living things derive from the properties of 1.1 What Are the Distinctive Properties
molecules. Despite the spectacular diversity of life, the elaborate structure of biological of Living Systems?
molecules, and the complexity of vital mechanisms, are life functions ultimately 1.2 What Kinds of Molecules Are
interpretable in chemical terms? Biomolecules?
1.3 What Is the Structural Organization
of Complex Biomolecules?
M olecules are lifeless. Yet, in appropriate complexity and number, molecules com- 1.4 How Do the Properties of
Biomolecules Reflect Their Fitness to
pose living things. These living systems are distinct from the inanimate world
the Living Condition?
because they have certain extraordinary properties. They can grow, move, perform the
1.5 What Are the Organization and
incredible chemistry of metabolism, respond to stimuli from the environment, and, Structure of Cells?
most significantly, replicate themselves with exceptional fidelity. The complex struc-
1.6 What Are Viruses?
ture and behavior of living organisms veil the basic truth that their molecular constitu-
tion can be described and understood. The chemistry of the living cell resembles the
chemistry of organic reactions. Indeed, cellular constituents, or biomolecules, must
conform to the chemical and physical principles that govern all matter. Despite the
spectacular diversity of life, the intricacy of biological structures, and the complexity
of vital mechanisms, life functions are ultimately interpretable in chemical terms.
Chemistry is the logic of biological phenomena. Living organisms are self-sustaining sys-
tems of chemical reactions.
1.1 What Are the Distinctive Properties

of Living Systems?
First, the most obvious quality of living organisms is that they are complicated and highly
organized (Figure 1.1). For example, organisms large enough to be seen with the naked
eye are composed of many cells, typically of many types. In turn, these cells possess
subcellular structures, called organelles, which are complex assemblies of very large
2 Chapter 1 The Facts of Life: Chemistry Is the Logic of Biological Phenomena
Science Photo Library/Alamy

Herbert Kehrer/Corbis
(a) (b)
Figure 1.1 (a) Gelada (Theropithecus gelada), a baboon native to the Ethiopian highlands.
(b) Tropical orchid (Masdevallia norops), Ecuador.
polymeric molecules, called macromolecules. These macromolecules themselves show

an exquisite degree of organization in their intricate three-dimensional architecture,
even though they are composed of simple sets of chemical building blocks, such as
sugars and amino acids. Indeed, the complex three-dimensional structure of a macro-
molecule, known as its conformation, is a consequence of interactions between the
monomeric units, according to their individual chemical properties.
Second, biological structures serve functional purposes. That is, biological structures
play a role in the organism’s existence. From parts of organisms, such as limbs and
organs, down to the chemical agents of metabolism, such as enzymes and metabolic
intermediates, a biological purpose can be given for each component. Indeed, it is this
functional characteristic of biological structures that separates the science of biology
from studies of the inanimate world such as chemistry, physics, and geology. In biology,
it is always meaningful to seek the purpose of observed structures, organizations, or
patterns; that is, to ask what functional role they serve within the organism.
Third, living systems are actively engaged in energy transformations. Maintenance of
the highly organized structure and activity of living systems depends on their ability to
extract energy from the environment. The ultimate source of energy is the sun. Solar
energy flows from photosynthetic organisms (organisms able to capture light energy by
the process of photosynthesis) through food chains to herbivores and ultimately to car-
nivorous predators at the apex of the food pyramid (Figure 1.2). The biosphere is thus
a system through which energy flows. Organisms capture some of this energy, be it from
photosynthesis or the metabolism of food, by forming special energized biomolecules,
of which ATP and NADPH are the two most prominent examples (Figure 1.3). (Com-
monly used abbreviations such as ATP and NADPH are defined on the inside back
cover of this book.) ATP and NADPH are energized biomolecules because they repre-
sent chemically useful forms of stored energy. We explore the chemical basis of this
stored energy in subsequent chapters. For now, suffice it to say that when these mole-
cules react with other molecules in the cell, the energy released can be used to drive en-
ergetically unfavorable processes. That is, ATP, NADPH, and related compounds are
the power sources that drive the energy-requiring activities of the cell, including biosyn-
thesis, movement, osmotic work against concentration gradients, and, in special in-
stances, light emission (bioluminescence). Only upon death does an organism reach
equilibrium with its inanimate environment. The living state is characterized by the flow
of energy through the organism. At the expense of this energy flow, the organism can
maintain its intricate order and activity far removed from equilibrium with its surround-
ings, yet exist in a state of apparent constancy over time. This state of apparent con-
stancy, or so-called steady state, is actually a very dynamic condition: Energy and
1.1 What Are the Distinctive Properties of Living Systems? 3
hν
Carnivores Carnivore product (0.4 g)
2° Consumers
Herbivores Herbivore product (6 g)

1° Consumers
Primary productivity (270 g)
Photosynthesis
1° Producers
Productivity per square meter of a Tennessee field

Figure 1.2 The food pyramid. Photosynthetic organisms at the base capture light energy. Herbivores
and carnivores derive their energy ultimately from these primary producers.
material are consumed by the organism and used to maintain its stability and order. In
contrast, inanimate matter, as exemplified by the universe in totality, is moving to a
condition of increasing disorder or, in thermodynamic terms, maximum entropy c. Entropy c A thermodynamic term used to designate
Fourth, living systems have a remarkable capacity for self-replication. Generation after that amount of energy in a system that is unavailable
generation, organisms reproduce virtually identical copies of themselves. This self- to do work.
replication can proceed by a variety of mechanisms, ranging from simple division in bacte-
ria to sexual reproduction in plants and animals; but in every case, it is characterized by an
astounding degree of fidelity (Figure 1.4). Indeed, if the accuracy of self-replication were
significantly greater, the evolution of organisms would be hampered. This is so because
evolution depends upon natural selection operating on individual organisms that vary
slightly in their fitness for the environment. The fidelity of self-replication resides ultimately
in the chemical nature of the genetic material. This substance consists of polymeric chains
of deoxyribonucleic acid, or DNA, which are structurally complementary to one another
(Figure 1.5). These molecules can generate new copies of themselves in a rigorously
NH2 O
H H
N N C NH2
O– O– O–
–O N N
P O P O P OCH2
N
O CH2
O O O O
–O O
H H P O
H H
OH OH O
OH OH NH2
ATP –O P O
N N
O CH2
O N N
OH O
–O P O–
Figure 1.3 ATP and NADPH, two biochemically important O

energy-rich compounds. NADPH
Randal Harrison Garrett

Reginald H. Garrett
(b)
(a)
Figure 1.4 Organisms resemble their parents. (a) The Garrett

lineage. Top-to-bottom, left-to-right: Reg Garrett; sons Jeffrey,
Randal, and Robert; grandchildren Jackson, Bella, Reggie, and
Ricky. (b) Orangutan with infant. (c) The Grisham family. Top-
to-bottom, left-to-right: Charles and Rosemary; son David,
daughter Emily with granddaughters Annie and May, son
Andrew.
Charles M. Grisham
(c)
A
A C C
G T G
5' T G G G A
T C C A T
C T 5'
C
A G T A 3'
3'
Figure 1.5 The DNA double helix. Two complementary polynucleotide chains running in opposite
directions can pair through hydrogen bonding between their nitrogenous bases. Their complementary
nucleotide sequences give rise to structural complementarity.
executed polymerization process that ensures a faithful reproduction of the original DNA
strands. In contrast, the molecules of the inanimate world lack this capacity to replicate. A
crude mechanism of replication must have existed at life’s origin.
1.2 What Kinds of Molecules Are Biomolecules?

The elemental composition of living matter differs markedly from the relative abun-
dance of elements in the earth’s crust (Table 1.1). Hydrogen, oxygen, carbon, and nitro-
gen constitute more than 99% of the atoms in the human body, with most of the H and
O occurring as H2O. Oxygen, silicon, aluminum, and iron are the most abundant atoms
in the earth’s crust, with hydrogen, carbon, and nitrogen being relatively rare (less than
1.2 What Kinds of Molecules Are Biomolecules? 5
Bond
table 1.1 Composition of the Earth’s Crust, Seawater, and the Human Body* Covalent energy
Earth’s Crust Seawater Human Body† Atoms e– pairing bond (kJ/mol)
Element % Compound mM Element % H + H H H H H 436
O 47 Cl2 548 H 63
C + H C H C H 414
Si 28 Na 1
470 O 25.5
Al 7.9 Mg21 54 C 9.5
Fe 4.5 SO4 22
28 N 1.4 C + C C C C C 343
Ca 3.5 Ca21 10 Ca 0.31
Na 2.5 K1 10 P 0.22
C + N C N C N 292
K 2.5 HCO32 2.3 Cl 0.08
Mg 2.2 NO32 0.01 K 0.06
Ti 0.46 HPO422 ,0.001 S 0.05 C + O C O C O 351
H 0.22 Na 0.03
C 0.19 Mg 0.01 C + C C C C C 615
*Figures for the earth’s crust and the human body are presented as percentages of the total number of atoms;
seawater data are in millimoles per liter. Figures for the earth’s crust do not include water, whereas figures for the
human body do.
C + N C N C N 615
†
Trace elements found in the human body serving essential biological functions include Mn, Fe, Co, Cu, Zn, Mo, I, Ni,
and Se.
C + O C O C O 686
O + O O O O O 142
0.2% each). Nitrogen as dinitrogen (N2) is the predominant gas in the atmosphere, and
carbon dioxide (CO2) is present at a level of 0.04%, a small but critical amount. Oxygen O + O O O O O 402
is also abundant in the atmosphere and in the oceans. What property unites H, O, C,
and N and renders these atoms so suitable to the chemistry of life? It is their ability to
N + N N N N N 946
form covalent bonds by electron-pair sharing. Furthermore, H, C, N, and O are among

the lightest elements of the periodic table capable of forming such bonds (Figure 1.6).
N + H N H N H 393
Because the strength of covalent bonds is inversely proportional to the atomic weights O + H O H O H 460
of the atoms involved, H, C, N, and O form the strongest covalent bonds. Two other
covalent bond-forming elements, phosphorus (as phosphate [O OPO322] derivatives) Figure 1.6 Covalent bond formation by e2 pair
and sulfur, also play important roles in biomolecules. sharing.
1.2a Biomolecules Are Carbon Compounds

All biomolecules contain carbon (C). The prevalence of C is due to its unparalleled
versatility in forming stable covalent bonds through electron-pair sharing. Carbon
can form as many as four such bonds by sharing each of the four electrons in its outer
shell with electrons contributed by other atoms. Atoms commonly found in covalent
linkage to C are C itself, H, O, and N. Hydrogen can form one such bond by contrib-
uting its single electron to the formation of an electron pair. Oxygen, with two
unpaired electrons in its outer shell, can participate in two covalent bonds, and
nitrogen, which has three unshared electrons, can form three such covalent bonds.
Furthermore, C, N, and O can share two electron pairs to form double bonds with one
another within biomolecules, a property that enhances their chemical versatility.
Carbon and nitrogen can even share three electron pairs to form triple bonds.
Two properties of carbon covalent bonds merit particular attention. One is the abil-
ity of carbon to form covalent bonds with itself. The other is the tetrahedral nature of
the four covalent bonds when carbon atoms form only single bonds. Together these
properties hold the potential for an incredible variety of linear, branched, and cyclic
compounds of C. This diversity is multiplied further by the possibilities for including N,
O, and H atoms in these compounds (Figure 1.7). We can therefore envision the ability
of C to generate complex structures in three dimensions. These structures, by virtue of
appropriately included N, O, and H atoms, can display unique chemistries suitable to
the living state. Thus, we may ask, is there any pattern or underlying organization that
brings order to this astounding potentiality?
LINEAR ALIPHATIC:
Stearic acid
HOOC (CH2)16 CH3 O CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH3
C CH2 CH2 CH2 CH2 CH2 CH2 CH2 CH2
OH
CYCLIC: CH3 H
Cholesterol H C CH2 CH2 CH2 C CH3

H3C CH3
H 3C
HO
BRANCHED:
-Carotene
H3 C
CH3 CH3
H3C CH3
CH3 CH3 H3C CH3

CH3
PLANAR:
Chlorophyll a
H3C CH2CH3
H2C HC CH3
N
2+
N Mg N
H3C N
O
C OCH3
H3C CH2
O
CH2
CH3 CH3 CH3 CH3
C
O O CH2 CH C CH2 CH2 CH2 CH CH2 CH2 CH2 CH CH2 CH2 CH2 CH CH3
Figure 1.7 Examples of the versatility of COC bonds in building complex structures: linear, cyclic,
branched, and planar.
1.3 What Is the Structural Organization of Complex Biomolecules? 7
1.3 What Is the Structural Organization of Complex

Biomolecules?
Examination of the chemical composition of cells reveals a dazzling variety of or-
ganic compounds covering a wide range of molecular dimensions (Table 1.2). As this
complexity is sorted out and biomolecules are classified according to the similarities
of their sizes and chemical properties, an organizational pattern emerges. The bio-
molecules are built according to a structural hierarchy: Simple molecules are the
units for building complex structures.
The molecular constituents of living matter do not reflect randomly the infinite pos-
sibilities for combining C, H, O, and N atoms. Instead, only a limited set of the many
possibilities is found, and these collections share certain properties essential to the es-
tablishment and maintenance of the living state. The most prominent aspect of biomo-
lecular organization is that macromolecular structures are constructed from simple
molecules according to a hierarchy of increasing structural complexity. What properties
do these biomolecules possess that make them so appropriate for the condition of life?
1.3a M
etabolites Are Used to Form the Building Blocks
of Macromolecules
The major precursors for the formation of biomolecules are water, carbon dioxide, and
three inorganic nitrogen compounds—ammonium (NH41), nitrate (NO32), and dini-
trogen (N2). Metabolic processes assimilate and transform these inorganic precursors
through ever more complex levels of biomolecular order (Figure 1.8). In the first step,
table 1.2 Biomolecular Dimensions
The dimensions of mass* and length for biomolecules are given typically in daltons and nanometers,† respectively. One dalton (D) is approximately
equal to the mass of one hydrogen atom, 1.66 3 10224 g. One nanometer (nm) is 1029 m, or 10 Å (angstroms).
Mass
Length
Biomolecule (long dimension, nm) Daltons Picograms
Water 0.3 18
Alanine 0.5 89
Glucose 0.7 180
Phospholipid 3.5 750
Ribonuclease (a small protein) 4 12,600
Immunoglobulin G (IgG) 14 150,000
Myosin (a large muscle protein) 160 470,000
Ribosome (bacteria) 18 2,520,000
Bacteriophage fX174 (a very small bacterial virus) 25 4,700,000
Pyruvate dehydrogenase complex (a multienzyme complex) 60 7,000,000
Tobacco mosaic virus (a plant virus) 300 40,000,000 6.68 3 1025
Mitochondrion (liver) 1,500 1.5
Escherichia coli cell 2,000 2
Chloroplast (spinach leaf) 8,000 60
Liver cell 20,000 8,000
*Molecular mass is expressed in units of daltons (D) or kilodaltons (kD) in this book; alternatively, the dimensionless term molecular weight, symbolized by Mr, and defined as the ratio
of the mass of a molecule to 1 dalton of mass, is used.
†
Prefixes used for powers of 10 are
106 mega M 1023 milli m
103 kilo k 1026 micro m
1021 deci d 1029 nano n
1022 centi c 10212 pico p
10215 femto f
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falsehood shock the delicacy of his perceptions, as much as it would
shock the finest artist to be obliged to daub in a signpost, or scrawl a
caricature. He cannot make up his mind to derive any benefit from so
pitiful and disgusting a source. Tell me that a man is a
metaphysician, and at the same time that he is given to shallow and
sordid boasting, and I will not believe you. After striving to raise
himself to an equality with truth and nature by patient investigation
and refined distinctions (which few can make)—whether he succeed
or fail, he cannot stoop to acquire a spurious reputation, or to
advance himself or lessen others by paltry artifice and idle
rhodomontade, which are in every one’s power who has never known
the value or undergone the labour of discovering a single truth. Gross
personal and local interests bear the principal sway with the ignorant
or mere man of the world, who considers not what things are in
themselves, but what they are to him: the man of science attaches a
higher importance to, because he finds a more constant pleasure in
the contemplation and pursuit of general and abstracted truths.
Philosophy also teaches self-knowledge; and self-knowledge strikes
equally at the root of any inordinate opinion of ourselves, or wish to
impress others with idle admiration. Mathematicians have been
remarked for persons of strict probity and a conscientious and
somewhat literal turn of mind.[16] But are poets and romance-writers
equally scrupulous and severe judges of themselves, and martyrs to
right principle? I cannot acquit them of the charge of vanity, and a
wish to aggrandise themselves in the eyes of the world, at the
expense of a little false complaisance (what wonder when the world
are so prone to admire, and they are so spoiled by indulgence in self-
pleasing fancies?)—but in general they are too much taken up with
their ideal creations, which have also a truth and keeping of their
own, to misrepresent or exaggerate matters of fact, or to trouble their
heads about them. The poet’s waking thoughts are dreams: the liar
has all his wits and senses about him, and thinks only of astonishing
his hearers by some worthless assertion, a mixture of impudence and
cunning. But what shall we say of the clergy and the priests of all
countries? Are they not men of learning? And are they not, with few
exceptions, noted for imposture and time-serving, much more than
for a love of truth and candour? They are good subjects, it is true;
bound to keep the peace, and hired to maintain certain opinions, not
to inquire into them. So this is an exception to the rule, such as
might be expected. I speak of the natural tendencies of things, and
not of the false bias that may be given to them by their forced
combination with other principles.
The worst effect of this depression of spirits, or of the ‘scholar’s
melancholy,’ here spoken of, is when it leads a man, from a distrust
of himself, to seek for low company, or to forget it by matching below
himself. Gray is to be pitied, whose extreme diffidence or
fastidiousness was such as to prevent his associating with his fellow
collegians, or mingling with the herd, till at length, like the owl,
shutting himself up from society and daylight, he was hunted and
hooted at like the owl whenever he chanced to appear, and was even
assailed and disturbed in the haunts in which ‘he held his solitary
reign.’ He was driven from college to college, and subjected to a
persecution the more harassing to a person of his indolent and
retired habits. But he only shrunk the more within himself in
consequence—read over his favourite authors—corresponded with
his distant friends—was terrified out of his wits at the bare idea of
having his portrait prefixed to his works; and probably died from
nervous agitation at the publicity into which his name had been
forced by his learning, taste, and genius. This monastic seclusion and
reserve is, however, better than a career such as Porson’s; who from
not liking the restraints, or not possessing the exterior
recommendations of good society, addicted himself to the lowest
indulgences, spent his days and nights in cider-cellars and pot-
houses, cared not with whom or where he was, so that he had
somebody to talk to and something to drink, ‘from humble porter to
imperial tokay’ (a liquid, according to his own pun), and fell a
martyr, in all likelihood, to what in the first instance was pure
mauvaise honte. Nothing could overcome this propensity to low
society and sotting, but the having something to do, which required
his whole attention and faculties; and then he shut himself up for
weeks together in his chambers, or at the University, to collate old
manuscripts, or edite a Greek tragedy, or expose a grave pedant,
without seeing a single boon-companion, or touching a glass of wine.
I saw him once at the London Institution with a large patch of coarse
brown paper on his nose, the skirts of his rusty black coat hung with
cobwebs, and talking in a tone of suavity approaching to
condescension to one of the Managers. It is a pity that men should so
lose themselves from a certain awkwardness and rusticity at the
outset. But did not Sheridan make the same melancholy ending, and
run the same fatal career, though in a higher and more brilliant
circle? He did; and though not from exactly the same cause (for no
one could accuse Sheridan’s purple nose and flashing eye of a
bashfulness—‘modest as morning when she coldly eyes the youthful
Phœbus!’)—yet it was perhaps from one nearly allied to it, namely,
the want of that noble independence and confidence in its own
resources which should distinguish genius, and the dangerous
ambition to get sponsors and vouchers for it in persons of rank and
fashion. The affectation of the society of lords is as mean and low-
minded as the love of that of coblers and tapsters. It is that coblers
and tapsters may admire, that we wish to be seen in the company of
their betters. The tone of literary patronage is better than it was a
hundred or a hundred and fifty years ago. What dramatic author
would think now of getting a lady of quality to take a box at the first
night of a play to prevent its being damned by the pit? Do we not
read the account of Parson Adams taking his ale in Squire Booby’s
kitchen with mingled incredulity and shame? At present literature
has, to a considerable degree, found its level, and is hardly in danger,
‘deprived of its natural patrons and protectors, the great and noble,
of being trodden in the mire, and trampled under the hoofs of a
swinish multitude’—though it can never again hope, to be what
learning once was in the persons of the priesthood, the lord and
sovereign of principalities and powers. Fool that it was ever to forego
its privileges, and loosen the strong hold it had on opinion in bigotry
and superstition!
I remember hearing a lady of great sense and acuteness speak of it
as a painful consequence of the natural shyness of scholars, that from
the want of a certain address, or an acquaintance with the common
forms of society, they despair of making themselves agreeable to
women of education and a certain rank in life, and throw away their
fine sentiments and romantic tenderness on chambermaids and
mantua-makers. Not daring to hope for success where it would be
most desirable, yet anxious to realise in some way the dream of
books and of their youth, they are willing to accept a return of
affection which they count upon as a tribute of gratitude in those of
lower circumstances, (as if gratitude were ever bought by interest),
and take up with the first Dulcinea del Toboso that they meet with,
when, would they only try the experiment, they might do much
better. Perhaps so: but there is here also a mixture of pride as well as
modesty. The scholar is not only apprehensive of not meeting with a
return of fondness where it might be most advantageous to him; but
he is afraid of subjecting his self-love to the mortification of a
repulse, and to the reproach of aiming at a prize far beyond his
deserts. Besides, living (as he does) in an ideal world, he has it in his
option to clothe his Goddess (be she who or what she may) with all
the perfections his heart doats on; and he works up a dowdy of this
ambiguous description à son gré, as an artist does a piece of dull
clay, or the poet the sketch of some unrivalled heroine. The contrast
is also the greater (and not the less gratifying as being his own
discovery,) between his favourite figure and the back-ground of her
original circumstances; and he likes her the better, inasmuch as, like
himself, she owes all to her own merit—and his notice!
Possibly, the best cure for this false modesty, and for the
uneasiness and extravagances it occasions, would be, for the retired
and abstracted student to consider that he properly belongs to
another sphere of action, remote from the scenes of ordinary life, and
may plead the excuse of ignorance, and the privilege granted to
strangers and to those who do not speak the same language. If any
one is travelling in a foreign Diligence, he is not expected to shine
nor to put himself forward, nor need he be out of countenance
because he cannot: he has only to conform as well as he can to his
new and temporary situation, and to study common propriety and
simplicity of manners. Every thing has its own limits, a little centre
of its own, round which it moves; so that our true wisdom lies in
keeping to our own walk in life, however humble or obscure, and
being satisfied if we can succeed in it. The best of us can do no more,
and we shall only become ridiculous or unhappy by attempting it. We
are ashamed, because we are at a loss in things to which we have no
pretensions, and try to remedy our mistakes by committing greater.
An overweening vanity or self-opinion is, in truth, often at the
bottom of this weakness; and we shall be most likely to conquer the
one by eradicating the other, or restricting it within due and
moderate bounds.
THE MAIN-CHANCE
The New Monthly Magazine.]

[February, 1828.
‘Search then the ruling passion: there alone,
The wild are constant, and the cunning known;
The fool consistent, and the false sincere;
Priests, princes, women, no dissemblers here.
This clue once found unravels all the rest,
The prospect clears, and Wharton stands confest.’
Pope.
I am one of those who do not think that mankind are exactly

governed by reason or a cool calculation of consequences. I rather
believe that habit, imagination, sense, passion, prejudice, words
make a strong and frequent diversion from the right line of prudence
and wisdom. I have been told, however, that these are merely the
irregularities and exceptions, and that reason forms the rule or basis;
that the understanding, instead of being the sport of the capricious
and arbitrary decisions of the will, generally dictates the line of
conduct it is to pursue, and that self-interest, or the main-chance, is
the unvarying load-star of our affections, or the chief ingredient in all
our motives, that, thrown in as ballast, gives steadiness and direction
to our voyage through life. I will not take upon me to give a verdict in
this cause as judge; but I will try to plead one side of it as an
advocate, perhaps a biassed and feeble one.
As the passions are said to be subject to the control of reason, and
as reason is resolved (in the present case) into an attention to our
own interest, or a practical sense of the value of money, it will not be
amiss to inquire how much of this principle itself is founded in a
rational estimate of things, or is calculated for the end it proposes, or
how much of it will turn out (when analysed) to be mere madness
and folly or a mixture, like all the rest, of obstinacy, whim, fancy,
vanity, ill-nature, and so forth, or a nominal pursuit of good. This
passion, or an inordinate love of wealth, shows itself, when it is
strong, equally in two opposite ways, in saving or in spending—in
avarice (or stinginess) and in extravagance. To examine each of their
order. That lowest and most familiar form of covetousness,
commonly called stinginess, is at present (it must be owned) greatly
on the wane in civilised society; it has been driven out of fashion
either by ridicule and good sense, or by the spread of luxury, or by
supplying the mind with other sources of interest, besides those
which related to the bare means of subsistence, so that it may almost
be considered as a vice, or absurdity, struck off the list, as a set-off to
some that, in the change of manners and the progress of dissipation
have been brought upon the stage. It is not, however, so entirely
banished from the world, but that examples of it may be found to our
purpose. It seems to have taken refuge in the petty provincial towns,
or in old baronial castles in the North of Scotland, where it is still
triumphant. To go into this subject somewhat in detail, as a study of
the surviving manners of the last age.—Nothing is more common in
these half-starved, barren regions, than to stint the servants in their
wages, to allowance them in the merest necessaries, never to indulge
them with a morsel of savoury food, and to lock up every thing from
them as if they were thieves, or common vagabonds, broke into the
house. The natural consequence is, that the mistresses live in
continual hot water with their servants, keep watch and ward over
them—the pantry is in a state of siege—grudge them every mouthful,
every appearance of comfort, or moment of leisure, and torment
their own souls every minute of their lives about what, if left wholly
to itself, would not make a difference of five shillings at the year’s
end. There are families so notorious for this kind of surveillance and
meanness, that no servant will go to live with them; for, to clench the
matter, they are obliged to stay if they do; as, under these amiable
establishments, and to provide against an evasion of their signal
advantages, domestics are never hired but by the half-year. Instances
have been known where servants have taken a pleasant revenge on
their masters and mistresses without intending it; but where the
example of sordid saving and meanness set to them, having taken
possession of those even who were victims to it, they have
conscientiously applied it to the benefit of all parties, and scarcely
suffered a thing to enter the house for the whole six months they
stayed in it. To pass over, however, those cases which may plead
poverty as their excuse, what shall we say to a lady of fortune (the
sister of one of their old-fashioned lairds) allowing the fruit to rot in
the gardens and hot-houses of a fine old mansion in large quantities,
sooner than let any of it be given away in presents to the neighbours;
and, when peremptorily ordered by the master of the house to send a
basket-full every morning to a sick friend, purchasing a small pottle
for the purpose, and satisfying her mind (an intelligent and well-
informed one) with this miserable subterfuge? Nay, farther, the same
person, whenever they had green-peas, or other rarities, served up at
table, could hardly be prevailed on to help the guests to them, but, if
possible, sent them away, though no other use could now be made of
them, and she would never see them again! Is there common sense
in this; or is it not more like madness? But is it not, at the same time,
human nature? Let us stop to explain a little. In my view, the real
motive of action in this and other similar cases of grasping
penuriousness has no more reference to self-love (properly so called)
than artificial fruit and flowers have to natural ones. A certain form
or outside appearance of utility may deceive the mind, but the
natural, pulpy, wholesome, nutritious substance, the principle of
vitality is gone. To this callous, frigid habit of mind, the real uses of
things harden and crystallise; the pith and marrow are extracted out
of them, and leave nothing but the husk or shell. By a regular
process, the idea of property is gradually abstracted from the
advantage it may be of even to ourselves; and to a well-drilled,
thorough-bred, Northern housekeeper (such as I have supposed), the
fruits, or other produce of her garden, would come at last to be
things no more to be eaten or enjoyed, than her jewels or trinkets of
any description, which are, professedly, of no use but to be kept as
symbols of wealth, to be occasionally looked at, and carefully
guarded from the approach of any unhallowed touch. The calculation
of consequences, or of benefit to accrue to any living person, is so far
from being the mainspring in this mechanical operation that it is
never once thought of, or regarded with peevishness and impatience
as an unwelcome intruder, because it must naturally divert the mind
from the warped and false bias it has taken. The feeling of property is
here, then, removed from the sphere of practice to a chimerical and
fictitious one. In the case of not sending the fruit out of the house,
there might be some lurking idea of its being possibly wanted at
home, that it might be sent to some one else, or made up into
conserves: but when different articles of food are actually placed on
the table, to hang back from using or offering them to others, is a
deliberate infatuation. They must be destroyed, they could not
appear again; and yet this person’s heart failed her, and shrank back
from the only opportunity of making the proper use of them with a
petty, sensitive apprehension, as if it were a kind of sacrilege done to
a cherished and favourite object. The impulse to save was become, by
indulgence, a sort of desperate propensity and forlorn hope, no
longer the understood means, but the mistaken end: habit had
completely superseded the exercise and control of reason, and the
rage of making the most of every thing by making no use of it at all,
resisted to the last moment the shocking project of feasting on a
helpless dish of green-peas (that would fetch so much in the market)
as an outrage against the Goddess of stinginess, and torture to the
soul of thrift! The principle of economy is inverted; and in order to
avoid the possibility of wasting any thing, the way with such
philosophers and housewives is to abstain from touching it
altogether. Is not this a common error? Or are we conscious of our
motives in such cases? [Or do we not flatter ourselves by imputing
every such act of idle folly to the necessity of adopting some sure and
judicious plan to shun ruin, beggary, and the most profligate abuse of
wealth? An old maid in the same northern school of humanity calling
upon some young ladies, her neighbours, was so alarmed and
scandalized at finding the safe open in their absence, that she
engaged herself to drink tea the same afternoon, for the express
purpose of reading them a lecture on the unheard-of imprudence
and impropriety of such an example, and was mobbed on her way
home by the poor servant-girl (who had been made the subject of her
declamation) in return for her uncalled-for interference. She had
nothing to fear, nothing to lose: her safe was carefully locked up.
Why then all this flutter, fidgetty anxiety, and itch of meddling? Out
of pure romantic generosity—because the idea of any thing like
comfort or liberality to a servant shocked her economical and
screwed-up prejudices as much as the impugning any article of her
religious or moral creed could have done. The very truisms and
literal refinements of this passion are then sheer impertinence. The
housekeeper came into the parlour of a ‘big ha’ house,’ in the same
land of cakes and hospitality, to say that the workmen had refused to
eat their dinner.—‘Why so?’—Because there was nothing but sowins
and sour milk.—‘Then they must go without a dinner,’ said the young
mistress delighted; ‘there is nothing else in the house for them.’ Yet
the larder at that time groaned with cold rounds of beef, hams,
pasties, and the other plentiful remains of a huge entertainment the
day before. This was flippancy and ill-nature, as well as a wrong
notion of self-interest. Is it at all wonderful that a decent servant-girl,
when applied to to go to this place, laughed at the idea of a service
where there was nothing to eat? Yet this attention to the main-
chance on her part, had it come to the lady’s knowledge, would have
been treated as a great piece of insolence. So little conception have
such people of their own obligations on the claims of others! The
clergyman of the parish (prolific in this sort of anecdote), a hearty,
good sort of man enough, but irritable withal, took it into his head to
fly into a violent passion if ever he found the glasses or spoons left
out in the kitchen, and he always went into the kitchen to look after
this sort of excitement. He pretended to be mightily afraid that the
one would be broken (to his irreparable loss) and the other stolen,
though there was no danger of either: he wanted an excuse to fret
and fume about something. On the death of his wife he sent for her
most intimate friend to condole and consult with, and having made
some necessary arrangements, begged as a peculiar favour that she
would look into the kitchen to see if the glasses and silver spoons
were in their places. She repressed a smile at such a moment out of
regard to his feelings, which were serious and acute; but burst into a
fit of unrestrained laughter as soon as she got home. So ridiculous a
thing is human nature, even to ourselves! Either our actions are
absurd, or we are absurd in our constant censure and exposure of
others. I would not from choice go into these details, but I might be
required to fill up a vague outline; and the examples of folly, spite,
and meanness are unfortunately ‘sown like a thick scurf o’er life!’]
Let us turn the tables and look at the other side of this sober, solid,
ingrossing passion for property and its appendages. A man lays out a
thousand, nay, sometimes many thousand pounds in purchasing a
fine picture. This is thought, by the vulgar, a very fantastical folly,
and unaccountable waste of money. Why so? No one would give such
a sum for a picture, unless there were others ready to offer nearly the
same sum, and who are likely to appreciate its value, and envy him
the distinction. It is then a sign of taste, a proof of wealth to possess
it, it is an ornament and a luxury. If the same person lays out the
same sum of money in building or purchasing a fine house, or
enriching it with costly furniture, no notice is taken—this is supposed
to be perfectly natural and in order. Yet both are equally gratuitous
pieces of extravagance, and the value of the objects is, in either case,
equally ideal. It will be asked, ‘But what is the use of the picture?’
And what, pray, is the use of the fine house or costly furniture, unless
to be looked at, to be admired, and to display the taste and
magnificence of the owner? Are not pictures and statues as much
furniture as gold plate or jasper tables; or does the circumstance of
the former having a meaning in them, and appealing to the
imagination as well as to the senses, neutralize their virtue, and
render it entirely chimerical and visionary? It is true, every one must
have a house of some kind, furnished somehow, and the superfluity
so far grows imperceptibly out of the necessary. But a fine house, fine
furniture, is necessary to no man, nor of more value than the
plainest, except as a matter of taste, of fancy, of luxury and
ostentation. Again, no doubt, if a person is in the habit of keeping a
number of servants, and entertaining a succession of fashionable
guests, he must have more room than he wants for himself,
apartments suitably decorated to receive them, and offices and
stables for their horses and retinue. But is all this unavoidably
dictated as a consequence of his attention to the main-chance, or is it
not sacrificing the latter, and making it a stalking-horse to his vanity,
dissipation, or love of society and hospitality? We are at least as fond
of spending money as of making it. If a man runs through a fortune
in the way here spoken of, is it out of love to himself? Yet who
scruples to run through a fortune in this way, or accuses himself of
any extraordinary disinterestedness or love of others? One bed is as
much as any one can sleep in, one room is as much as he can dine in,
and he may have another for study or to retire to after dinner—but he
can only want more than this for the accommodation of his friends,
or the admiration of strangers. At Fonthill Abbey (to take an extreme
illustration), there was not a single room fit to sit, lie, or stand in: the
whole was cut up into pigeon holes, or spread out into long endless
galleries. The building this huge, ill-assorted pile cost, I believe,
nearly a million of money; and if the circumstance was mentioned, it
occasioned an expression of surprise at the amount of the wealth that
had been thus squandered—but if it was said that a hundred pounds
had been laid out on a highly-finished picture, there was the same
astonishment expressed at its misdirection. The sympathetic auditor
makes up his mind to the first and greatest loss, by reflecting that in
case of the worst the building materials alone will fetch something
considerable; or, in the very idea of stone-walls and mortar there is
something solid and tangible, that repels the charge of frivolous
levity or fine sentiment. This quaint excrescence in architecture,
preposterous and ill-contrived as it was, occasioned, I suspect, many
a heart-ache and bitter comparison to the throng of fashionable
visitants; and I conceive it was the very want of comfort and
convenience that enhanced this feeling, by magnifying, as it were
from contrast, the expense that had been incurred in realising an idle
whim. When we judge thus perversely and invidiously of the
employment of wealth by others, I cannot think that we are guided in
our own choice of means to ends by a simple calculation of
downright use and personal accommodation. The gentleman who
purchased Fonthill, and was supposed to be possessed of wealth
enough to purchase half a dozen more Fonthills, lived there himself
for some time in a state of the greatest retirement, rose at six and
read till four, rode out for an hour for the benefit of the air, and
dined abstemiously for the sake of his health. I could do all this
myself. What then became of the rest of his fortune? It was lying in
the funds, or embarked in business to make it yet greater, that he
might still rise at six and read till four, &c.—it was of no other earthly
use to him; for he did not wish to make a figure in the world, or to
throw it away on studs of horses, on equipages, entertainments,
gaming, electioneering, subscriptions to charitable institutions,
[mistresses,] or any of the usual fashionable modes of squandering
wealth for the amusement and wonder of others and our own fancied
enjoyment. Mr. F. did not probably lay out five hundred a-year on
himself: it cost Mr. Beckford, who led a life of perfect seclusion,
twenty thousand a-year to defray the expenses of his table and of his
household establishment. When I find that such and so various are
the tastes of men, I am a little puzzled to know what is meant by self-
interest, of which some persons talk so fluently, as if it was a Jack-in-
a-Box which they could take out and show you, and which they tell
you is the object that all men equally aim at. If money, is it for its
own sake or the sake of other things? Is it to hoard it or to spend it,
on ourselves or others? In all these points, we find the utmost
diversity and contradiction both of feeling and practice. Certainly, he
who puts his money into a strong-box, and he who puts it into a dice-
box must be allowed to have a very different idea of the main-
chance. If by this phrase be understood a principle of self-
preservation, I grant that while we live, we must not starve, and that
necessity has no law. Beyond this point, all seems nearly left to
chance or whim; and so far are all the world from being agreed in
their definition of this redoubtable term, that one half of them may
be said to think and act in diametrical opposition to the other.
Avarice is the miser’s dream, as fame is the poet’s. A calculation of
physical profit or loss is almost as much out of the question in the
one case as in the other. The one has set his mind on gold, the other
on praise, as the summum bonum or object of his bigoted idolatry
and darling contemplation, not for any private and sinister ends. It is
the immediate pursuit, not the remote or reflex consequence that
gives wings to the passion. There is, indeed, a reference to self in
either case that fixes and concentrates it, but not a gross or sordid
one. Is not the desire to accumulate and leave a vast estate behind us
equally romantic with the desire to leave a posthumous name behind
us? Is not the desire of distinction, of something to be known and
remembered by, the paramount consideration? And are not the
privations we undergo, the sacrifices and exertions we make for
either object, nearly akin? A child makes a huge snow-ball to show
his skill and perseverance and as something to wonder at, not that he
can swallow it as an ice, or warm his hands at it, and though the next
day’s sun will dissolve it; and the man accumulates a pile of wealth
for the same reason principally, or to find employment for his time,
his imagination, and his will. I deny that it can be of any other use to
him to watch and superintend the returns of millions, than to watch
the returns of the heavenly bodies, or to calculate their distances, or
to contemplate eternity, or infinity, or the sea, or the dome of St.
Peter’s, or any other object that excites curiosity and interest from its
magnitude and importance. Do we not look at the most barren
mountain with thrilling awe and wonder? And is it strange that we
should gaze at a mountain of gold with satisfaction, when we can
besides say, ‘This is ours, with all the power that belongs to it?’ Every
passion, however plodding and prosaic, has its poetical side to it. A
miser is the true alchemist, or, like the magician in his cell, who
overlooks a mighty experiment, who sees dazzling visions, and who
wields the will of others at his nod; but to whom all other hopes and
pleasures are dead, and who is cut off from all connexion with his
kind. He lives in a splendid hallucination, a waking trance, and so far
it is well: but if he thinks he has any other need or use for all this
endless store (any more than to swill the ocean) he deceives himself,
and is no conjuror after all. He goes on, however, mechanically
adding to his stock, and fancying that great riches is great gain, that
every particle that swells the heap is something in reserve against the
evil day, and a defence against that poverty which he dreads more,
the farther he is removed from it; as the more giddy the height to
which we have attained, the more frightful does the gulph yawn
below—so easily does habit get the mastery of reason, and so nearly
is passion allied to madness! ‘But he is laying up for his heirs and
successors.’ In toiling for them, and sacrificing himself, is he
properly attending to the main-chance?
This is the turn the love of money takes in cautious, dry, recluse,
and speculative minds. If it were the pure and abstract love of
money, it could take no other turn but this. But in a different class of
characters, the sociable, the vain, and imaginative, it takes just the
contrary one, viz. to expense, extravagance, and ostentation. It then
loves to display itself in every fantastic shape and with every
reflected lustre, in houses, in equipage, in dress, in a retinue of
friends and dependants, in horses, in hounds—to glitter in the eye of
fashion, to be echoed by the roar of folly, and buoyed up for a while
like a bubble on the surface of vanity, to sink all at once and
irrecoverably into an abyss of ruin and bankruptcy. Does it foresee
this result? Does it care for it? What then becomes of the calculating
principle that can neither be hoodwinked nor bribed from its duty?
Does it do nothing for us in this critical emergency? It is blind, deaf,
and insensible to all but the noise, confusion, and glare of objects by
which it is fascinated and lulled into a fatal repose! One man ruins
himself by the vanity of associating with lords, another by his love of
low company, one by his fondness for building, another by his rage
for keeping open house and private theatricals, one by philosophical
experiments, another by embarking in every ticklish and fantastic
speculation that is proposed to him, one throws away an estate on a
law-suit, another on a die, a third on a horse-race, a fourth on virtù,
a fifth on a drab, a sixth on a contested election, &c. There is no
dearth of instances to fill the page, or complete the group of
profound calculators and inflexible martyrs to the main-chance. Let
any of these discreet and well-advised persons have the veil torn
from their darling follies by experience, and be gifted with a double
share of wisdom and a second fortune to dispose of, and each of
them, so far from being warned by experience or disaster, will only
be the more resolutely bent to assert the independence of his choice,
and throw it away the self-same road it went before, on his vanity in
associating with lords, on his love of low company, on his fondness
for building, on his rage for keeping open house or private
theatricals, on philosophical experiments, on fantastic speculations,
on a law-suit, on a dice-box, on a favourite horse, on a picture, on a
mistress, or election contest, and so on, through the whole of the
chapter of accidents and cross-purposes. There is an admirable
description of this sort of infatuation with folly and ruin in Madame
D’Arblay’s account of Harrel in ‘Cecilia;’ and though the picture is
highly wrought and carried to the utmost length, yet I maintain that
the principle is common. I myself have known more than one
individual in the same predicament; and therefore cannot think that
the deviations from the line of strict prudence and wisdom are so
rare or trifling as the theory I am opposing represents them, or I
must have been singularly unfortunate in my acquaintance. Out of a
score of persons of this class I could mention several that have
ruined their fortunes out of mere freak, others that are in a state of
dotage and imbecility for fear of being robbed of all they are worth.
The rest care nothing about the matter. So that this boasted and
unfailing attention to the main-chance resolves itself, when strong,
into mad profusion or griping penury, or if weak, is null and yields to
other motives. Such is the conclusion, to which my observation of life
has led me: if I am quite wrong, it is hard that in a world abounding
in such characters I should not have met with a single practical
philosopher.[17]
A girl in a country-town resolves never to marry any one under a
duke or a lord. Good. This may be very well as an ebullition of spleen
or vanity; but is there much common sense or regard to her own
satisfaction in it? Were there any likelihood of her succeeding in her
resolution, she would not make it: for it is the very distinction to be
attained that piques her ambition, and leads her to gratify her
conceit of herself by affecting to look down on any lower matches.
Let her suffer ever so much mortification or chagrin in the
prosecution of her scheme, it only confirms her the more in it: the
spirit of contradiction, and the shame of owning herself defeated,
increase with every new disappointment and year of painful
probation. At least this is the case while there is any chance left. But
what, after all, is this haughty and ridiculous pretension founded on?
Is it owing to a more commanding view and a firmer grasp of
consequences, or of her own interest? No such thing: she is as much
captivated by the fancied sound of ‘my lady,’ and dazzled by the
image of a coronet-coach, as the girl who marries a footman is smit
with his broad shoulders, laced coat, and rosy cheeks. ‘But why must
I be always in extremes? Few misses make vows of celibacy or marry
their footmen.’ Take then the broad question:—Do they generally
marry from the convictions of the understanding, or make the choice
that is most likely to ensure their future happiness, or that they
themselves approve afterwards? I think the answer must be in the
negative; and yet love and marriage are among the weightiest and
most serious concerns of life. Mutual regard, good temper, good
sense, good character, or a conformity of tastes and dispositions,
have notoriously and lamentably little to say in it. On the contrary, it
is most frequently those things that pique and provoke opposition,
instead of those which promise concord and sympathy, that decide
the choice and inflame the will by the love of conquest or of
overcoming difficulty. Or it is a complexion, or a fine set of teeth, or
air, or dress, or a fine person, or false calves, or affected
consequence, or a reputation for gallantry, or a flow of spirits, or a
flow of words, or forward coquetry, or assumed indifference,
something that appeals to the senses, the fancy, or to our pride, and
determines us to throw away our happiness for life. Neither in this
case, on which so much depends, are the main-chance and our real
interest by any means the same thing.
‘Now, all ye ladies of fair Scotland,
And ladies of England that happy would prove,
Marry never for houses, nor marry for land,
Nor marry for nothing but only love.’[18]—Old Ballad.
Or take the passion of love where it has other objects and

consequences in view. Is reason any match for the poison of this
passion, where it has been once imbibed? I might just as well be told
that reason is a cure for madness or the bite of a venomous serpent.
Are not health, fortune, friends, character, peace of mind, every thing
sacrificed to its idlest impulse? Are the instances rare, or are they not
common and tragical? The main-chance does not serve the turn
here. Does the prospect of certain ruin break the fascination to its
frail victim, or does it not rather enhance and precipitate the result?
Or does it not render the conquest more easy and secure that the
seducer has already triumphed over and deserted a hundred other
victims? A man à bonnes fortunes is the most irresistible personage
in the lists of gallantry. Take drunkenness again, that vice which till
within these few years (and even still) was fatal to the health, the
constitution, the fortunes of so many individuals, and the peace of so
many families in Great Britain. I would ask what remonstrance of
friends, what lessons of experience, what resolutions of amendment,
what certainty of remorse and suffering, however exquisite, would
deter the confirmed sot (where the passion for this kind of
excitement had once become habitual and the immediate want of it
was felt) from indulging his propensity and taking his full swing,
notwithstanding the severe and imminent punishment to follow
upon his incorrigible excess? The consequence of not abstaining
from his favourite beverage is not doubtful and distant (a thing in the
clouds) but close at his side, staring him in the face, and felt perhaps
in all its aggravations the very morning, yet the recollection of this
and of the next day’s dawn is of no avail against the momentary
craving and headlong impulse given by the first application of the
glass to his lips. The present temptation is indeed heightened by the
threatened alternative. I know this as a rule, that the stronger the
repentance, the surer the relapse and the more hopeless the cure!
The being engrossed by the present moment, by the present feeling,
whatever it be, whether of pleasure or pain, is the evident cause of
both. Few instances have been heard of, of a final reformation on this
head. Yet it is a clear case; and reason, if it were that Giant that it is
represented in any thing but ledgers and books of accounts, would
put down the abuse in an instant. It is true, this infirmity is more
particularly chargeable to the English and to other Northern nations,
and there has been a considerable improvement among us of late
years; but I suspect it is owing to a change of manners, and to the
opening of new sources of amusement (without the aid of ardent
spirits flung in to relieve the depression of our animal spirits,) more
than to the excellent treatises which have been written against the
‘Use of Fermented Liquors,’ or to an increasing, tender regard to our
own comfort, health, and happiness in the breast of individuals. We
still find plenty of ways of tormenting ourselves and sporting with
the feelings of others! I will say nothing of a passion for gaming here,
as too obvious an illustration of what I mean. It is more rare, and
hardly to be looked on as epidemic with us. But few that have
dabbled in this vice have not become deeply involved, and few (or
none) that have done so have ever retraced their steps or returned to
sober calculations of the main-chance. The majority, it is true, are
not gamesters; but where the passion does exist, it completely
tyrannizes over and stifles the voice of common sense, reason, and
humanity. How many victims has the point of honour! I will not
pretend that, as matters stand, it may not be necessary to fight a
duel, under certain circumstances and on certain provocations, even
in a prudential point of view, (though this again proves how little the
maxims and practices of the world are regulated by a mere
consideration of personal safety and welfare)—but I do say that the
rashness with which this responsibility is often incurred, and the
even seeking for trifling causes of quarrel, shows any thing but a
consistent regard to self-interest as a general principle of action, or
rather betrays a total recklessness of consequences, when opposed to
pique, petulance, or passion.
Before I proceed to answer a principal objection (and indeed a
staggering one at first sight) I will mention here that I think it
strongly confirms my view of human nature, that men form their
opinions much more from prejudice than reason. The proof that they
do so is that they form such opposite ones, when the abstract
premises and independent evidence are the same. How few
Calvinists become Lutherans! How few Papists Protestants! How few
Tories Whigs![19] Each shuts his eyes equally to facts or arguments,
and persists in the view of the subject that custom, pride, and
obstinacy dictate. Interest is no more regarded than reason; for it is
often at the risk both of life and fortune that these opinions have
been maintained, and it is uniformly when parties have run highest
and the strife has been deadliest that people have been most forward
to stake their existence and every thing belonging to them, on some
unintelligible dogma or article of an old-fashioned creed. Half the
wars and fightings, martyrdoms, persecutions, feuds, antipathies,
heart-burnings in the world have been about some distinction, ‘some
trick not worth an egg’—so ready are mankind to sacrifice their all to
a mere name! It may be urged, that the good of our souls or our
welfare in a future state of being is a rational and well-grounded
motive for these religious extravagances. And this is true, so far as
religious zeal falls in with men’s passions or the spirit of the times. A
bigot was formerly ready to cut his neighbour’s throat to go to
Heaven, but not so ready to reform his own life, or give up a single
vice or gratification for all the pains and penalties denounced upon
it, and of which his faith in Holy Church did not suffer him to doubt a
moment!
But it is contended here, that in matters not of doctrinal
speculation but of private life and domestic policy, every one consults
and understands his own interest; that whatever other hobbies he
may have, he minds this as the main object, and contrives to make
both ends meet, in spite of seeming inattention and real difficulties.
‘If we look around us’ (says a shrewd, hard-headed Scotchman) ‘and
take examples from the neighbourhood in which we live, we shall
find that allowing for occasional exceptions, diversities and
singularities, the main-chance is still stuck to with rigid and
unabated pertinacity—the accounts are wound up and every thing is
right at the year’s end, whatever freaks or fancies may have
intervened in the course of it. The business of life goes on (which is
the principal thing) and every man’s house stands on its own bottom.
This is the case in Nicholson-street, in the next street to it, and in the
next street to that, and in the whole of Edinburgh, Scotland, and
England to boot.’ This, I allow, is a home-thrust, and I must parry it,
how I can. It is a kind of heavy, broad-wheeled waggon of an
objection that makes a formidable, awkward appearance, and takes
up so much of the road, that I shall have a lucky escape if I can dash
by it in my light travelling gig without being upset or crushed to
atoms. The persons who in the present instance have the charge of it,
in its progress through the streets of Edinburgh, are a constitutional
lawyer, a political economist, an opposition editor, and an ex-officio
surveyor of the Customs—fearful odds against one poor
metaphysician! Their machine of human life, I confess, puts me a
little in mind of those square-looking caravans one sometimes meets
on the road in which they transport wild beasts from place to place;
and dull, heavy, safe, and flat as they look, the inmates continue their
old habits, the monkeys play their tricks, and the panthers lick their
jaws for human blood, though cramped and confined in their
excursions. So the vices and follies, when they cannot break loose, do
their worst inside this formal conveyance, the main-chance. As this
ovation is to pass up High-street, for the honour of the Scottish
capital, I should wish it to stop at the shop-door of Mr. Bartholine
Saddletree, to see if he is at home or in the courts. Also, to inquire
whether the suit of Peter Peebles is yet ended; and to take the
opinion of counsel, how many of the Highland lairds or Scottish
noblemen and gentlemen that were out in the fifteen and the forty-
five, perilled their lives and fortunes in the good cause from an eye to
the main-chance? The Baron of Bradwardine would have scorned
such a suggestion; nay, it would have been below Balmawhapple or
even Killancureit. But ‘the age of chivalry is gone, and that of
sophists, economists, and calculators has succeeded.’ I should say
that the risk, the secrecy, the possibility of the leaders having their
heads stuck on Temple-Bar, and their estates confiscated, were
among the foremost causes that inflamed their zeal and stirred their
blood to the enterprise. Hardship, danger, exile, death,—these words
‘smack of honour,’ more than the main-chance. The modern Scotch
may be loyal on this thriving principle: their ancestors found their
loyalty a very losing concern. Yet they persevered in it till and long
after it became a desperate cause. But patriotism and loyalty (true or
false) are important and powerful principles in human affairs,
though not always selfish and calculating. Honour is one great
standard-bearer and puissant leader in the struggle of human life;
and less than honour (a nickname or a bugbear) is enough to set the
multitude together by the ears, whether in civil, religious, or private
brawls. [But to return to our Edinburgh shop-keepers, those
practical models of wisdom, and authentic epitomes of human
nature. Say that by their ‘canny ways and pawky looks’ they keep
their names out of the ‘Gazette,’ yet still care (not the less perhaps)
mounts behind their counters, and sits in their back-shops. A
tradesman is not a bankrupt at the year’s end. But what does it
signify, if he is hen-pecked in the mean time, or quarrels with his
wife, or beats his apprentices, or has married a woman twice as old
as himself for her money, or has been jilted by his maid, or fuddles
himself every night, or is laying in an apoplexy by overeating himself,
or is believed by nobody, or is a furious Whig or Tory, or a knave, or
a fool, or one envious of the success of his neighbours, or dissatisfied
with his own, or surly, or eaten up with indolence and
procrastination, never easy but bashful and awkward in company
(though with a vast desire to shine) or has some personal defect or
weak side on which the Devil is sure to assail him, and the venting
his spleen and irritability on which, through some loop-hole or other,
makes the real business and torment of his life—that of his shop may
go on as it pleases. Such is the perfection of reason and the triumph
of the sovereign good, where there are no strong passions to disturb,
or no great vices to sully it! The humours collect, the will will have
head, the petty passions ferment, and we start some grievance or
other, and hunt it down every hour in the day, or the machine of still-
life could not go on even in North Britain. But were I to grant the full
force and extent of the objection, I should still say that it does not
bear upon my view of the subject or general assertion, that reason is
an unequal match for passion. Business is a kind of gaoler or task-
master, that keeps its vassals in good order while they are under its
eye, as the slave or culprit performs his task with the whip hanging
over him, and punishment immediately to follow neglect; but the
question is, what he would do with his recovered freedom, or what
course the mind will for the most part pursue, when in the range of
its general conduct it has its choice to make between a distant,
doubtful, sober, rational good (or average state of being), and some
one object of comparatively little value, that strikes the senses,
flatters our pride, gives scope to the imagination, and has all the
strength of passion and inclination on its side. The main-chance
then is a considerable exception, but not a fair one or a case in point,
since it falls under a different head and line of argument.] The fault
of reason in general, (which takes in the whole instead of parts,) is
that objects, though of the utmost extent and importance, are not
defined and tangible. This fault cannot be found with the pursuit of
trade and commerce. It is not a mere dry, abstract, undefined,
speculative, however steady and well-founded conviction of the
understanding. It has other levers and pulleys to enforce it, besides
those of reason and reflection. As follows:—
1. The value of money is positive or specific. The interest in it is a
sort of mathematical interest, reducible to number and quantity. Ten
is always more than one; a part is never greater than the whole; the

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BioChemistry 6th Edition By Reginald

Reginald H. Garrett | Charles M. Grisham

With molecular graphic images

Australia ● Brazil ● Mexico ● Singapore ● United Kingdom ● United States

Text Designer: John Walker Loose-leaf Edition:

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Printed in the United States of America

To our grandchildren Jackson, Bella, Reggie, Ricky, Charlotte

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

Abl Kinase Cystic Fibrosis Transmembrane Conductance Regulator

Hepatocyte Nuclear Factor 1b Bound to DNA MDM2 (Ubiquitin-Protein Ligase E3)

Recombinant DNA Techniques Fluxomics Section 17.5

The Sixth Edition

Objectives and Building on Previous Editions

●● Critical Developments in Biochemistry essays emphasize recent and historical advances

Highlights of This Edition

For the Student

Weiguo Coa, Clemson University

Reginald H. Garrett Charles M. Grisham

of Biological Phenomena “…everything that living things do can be

 Sperm fertilizing an egg.

Essential Question KEY QUESTIONS

1.1 What Are the Distinctive Properties

Science Photo Library/Alamy

polymeric molecules, called macromolecules. These macromolecules themselves show

Herbivores Herbivore product (6 g)

Productivity per square meter of a Tennessee field

Figure 1.3 ​ATP and NADPH, two biochemically important O

Randal Harrison Garrett

Figure 1.4 ​Organisms resemble their parents. (a) The Garrett

1.2 What Kinds of Molecules Are Biomolecules?

form covalent bonds by electron-pair sharing. Furthermore, H, C, N, and O are among

1.2a Biomolecules Are Carbon Compounds

Cholesterol H C CH2 CH2 CH2 C CH3

CH3 CH3 H3C CH3

1.3 What Is the Structural Organization of Complex

table 1.2 Biomolecular Dimensions

The New Monthly Magazine.]

I am one of those who do not think that mankind are exactly

Or take the passion of love where it has other objects and

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Figure 1.3 ATP and NADPH, two biochemically important O

Figure 1.4 Organisms resemble their parents. (a) The Garrett