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Biochemistry 7Th Edition Reginald H. Garrett - Ebook PDF Download

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biochemi str y
seventh edition

Reginald H. Garrett | Charles M. Grisham

University of Virginia

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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 earned his Minnesota, and educated at Benilde High School. He received
Ph.D. in biology in 1968. Since then, he has been at the University his B.S. in chemistry from the Illinois Institute of Technology in
of Virginia, where he is a Professor Emeritus of Biology. He is the 1969 and his Ph.D. in chemistry from the University of Minne-
author of previous editions of Biochemistry as well as Principles sota in 1973. Following a postdoctoral appointment at the Insti-
of Biochemistry (Cengage, Brooks/Cole) and numerous papers tute for Cancer Research in Philadelphia, he joined the faculty
and review articles on the biochemical, genetic, and molecular of the University of Virginia, where he is Professor of Chemis-
biological aspects of inorganic nitrogen metabolism. His research try. He is the author of previous editions of Biochemistry and
interests focused on the pathway of nitrate assimilation in Principles of Biochemistry (Cengage, Brooks/Cole) and numer-
filamentous fungi. His investigations contributed substantially ous papers and review articles on active transport of sodium,
to our understanding of the enzymology, genetics, and regula- potassium, and calcium in mammalian systems, on protein
tion of this major pathway of biological nitrogen acquisition. kinase C, and on the applications of NMR and EPR spectros-
More recently, he has collaborated in systems approaches to the copy to the study of biological systems. He also authored Inter-
metabolic basis of nutrition-related diseases. His research active Biochemistry CD-ROM and Workbook, a tutorial CD for
has been supported by the National Institutes of Health, the students. His work has been supported by the National Insti-
National Science Foundation, and private industry. He is a tutes of Health, the National Science Foundation, the Muscular
former Fulbright Scholar at the Universität für Bodenkultur in Dystrophy Association of America, the Research Corporation,
Vienna, Austria and served as Visiting Scholar at the University the American Heart Association, and the American Chemical
of Cambridge on two separate occasions. During the second, he Society. He is a Research Career Development Awardee of the
was the Thomas Jefferson Visiting Fellow in Downing College. National Institutes of Health, and in 1983 and 1984 he was a
In 2003, he was Professeur Invité at the Université Paul Sabatier/ Visiting Scientist at the Aarhus University Institute of Physiol-
Toulouse III and the Centre National de la Recherche ogy Denmark. In 1999, he was Knapp Professor of Chemistry at
Scientifique, Institute for Pharmacology and Structural Biology the University of San Diego. He has taught biochemistry, intro-
in France. He taught biochemistry at the University of Virginia ductory chemistry, and physical chemistry at the University of
for 46 years. He is a member of the American Society for Virginia for 48 years. He is a member of the American Society
Biochemistry and Molecular Biology. for Biochemistry and Molecular Biology.
Gene Runion

Reginald H. Garrett and Charles M. Grisham

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 29
3 Thermodynamics of Biological Systems 51
4 Amino Acids and the Peptide Bond 77
5 Proteins: Their Primary Structure and Biological Functions 105
6 Proteins: Secondary, Tertiary, and Quaternary Structure 145
7 Carbohydrates and the Glycoconjugates of Cell Surfaces 193
8 Lipids 237
9 Membranes and Membrane Transport 265
10 Nucleotides and Nucleic Acids 317
11 Structure of Nucleic Acids 345
12 Recombinant DNA, Cloning, Gene Editing, and Synthetic Biology—An Introduction 393

Part II Protein Dynamics 433

13 Enzymes—Kinetics and Specificity 433
14 Mechanisms of Enzyme Action 475
15 Enzyme Regulation 511
16 Molecular Motors 543

Part III Metabolism and Its Regulation 573

17 Metabolism: An Overview 573
18 Glycolysis 603
19 The Tricarboxylic Acid Cycle 635
20 Electron Transport and Oxidative Phosphorylation 671
21 Photosynthesis 713
22 Gluconeogenesis, Glycogen Metabolism, and the Pentose Phosphate Pathway 751
23 Fatty Acid Catabolism 791
24 Lipid Biosynthesis 821
25 Nitrogen Acquisition and Amino Acid Metabolism 871
26 Synthesis and Degradation of Nucleotides 921
27 Metabolic Integration and Organ Specialization 951

Part IV Information Transfer 981

28 DNA Metabolism: Replication, Recombination, and Repair 981
29 Transcription and the Regulation of Gene Expression 1033
30 Protein Synthesis 1089
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
v

Part I Molecular Components of Cells 1 eak Forces Restrict Organisms to a Narrow Range
W
of Environmental Conditions 16

1
Enzymes Catalyze Metabolic Reactions 17
Biomolecular Phenomena across the Time Scale of Life 17
1.5 What Are the Organization and Structure of
The Facts of Life: Chemistry Is the Logic of Cells? 17
The Eukaryotic Cell Likely Emerged from an Archaeal
Biological Phenomena 1 Lineage 18
1.1 What Are the Distinctive Properties of Living How Many Genes Does a Cell Need? 18
Systems? 1 Critical Developments in Biochemistry: Synthetic Life 19
1.2 What Kinds of Molecules Are Biomolecules? 4 Archaea and Bacteria Have a Relatively Simple
Biomolecules Are Carbon Compounds 5 Structural Organization 20
1.3 What Is the Structural Organization of Complex The Structural Organization of Eukaryotic Cells Is More
Biomolecules? 5 Complex Than That of Prokaryotic Cells 21
etabolites Are Used to Form the Building Blocks
M 1.6 What Are Viruses? 22
of Macromolecules 5 Foundational Biochemistry 25
Organelles Represent a Higher Order in Biomolecular Problems 25
Organization 8
Further Reading 27
Membranes Are Supramolecular Assemblies That Define

2
the Boundaries of Cells 9
The Unit of Life Is the Cell 9
1.4 How Do the Properties of Biomolecules Reflect Their
Fitness to the Living Condition? 10
Water: The Medium of Life 29
iological Macromolecules and Their Building Blocks
B
Have a “Sense” or Directionality 10 2.1 What Are the Properties of Water? 29
Biological Macromolecules Are Informational 11 Water Has Unusual Properties 30
Biomolecules Have Characteristic Hydrogen Bonding in Water Is Key to Its Properties 30
Three-Dimensional Architecture 12 The Structure of Ice Is Based on H-Bond
Weak Forces Maintain Biological Structure and Formation 30
Determine Biomolecular Interactions 12 Molecular Interactions in Liquid Water Are Based on
Van der Waals Forces Are Short-Range Interactions H Bonds 31
between Atoms in Nearby Molecules 12 The Solvent Properties of Water Derive from Its Polar
Hydrogen Bonds Form between H Atoms and Nature 32
Electronegative Atoms Like N and O 14 Water Can Ionize to Form H1 and OH2 36
Ionic Interactions Form between Oppositely Charged 2.2 What Is pH? 37
Groups or Molecules 14
Strong Electrolytes Dissociate Completely in Water 38
Hydrophobic Interactions Are the Result of Favorable
Weak Electrolytes Are Substances That Dissociate
Interactions between Water Molecules 14
Only Slightly in Water 39
The Defining Concept of Biochemistry Is
The Henderson–Hasselbalch Equation Describes the
“Molecular Recognition through Structural
Dissociation of a Weak Acid in the Presence of Its
Complementarity” 14
Conjugate Base 39
Biomolecular Recognition Is Mediated by Weak Chemical
Forces 15
vi

itration Curves Illustrate the Progressive

T tandard Reduction Potentials Are Measured
S
Dissociation of a Weak Acid 41 in Reaction Half-Cells 66
Phosphoric Acid Has Three Dissociable H1 42 %o9 Values Can Be Used to Predict the Direction
2.3 What Are Buffers, and What Do They Do? 43 of Redox Reactions 67
he Phosphate Buffer System Is a Major Intracellular
T %o9 Values Can Be Used to Analyze Energy Changes
Buffering System 43 in Redox Reactions 67
The Imidazole Group of Histidine Also Serves The Reduction Potential Depends on Concentration 69
as an Intracellular Buffering System 44 3.7 Why Are Coupled Processes Important to Living
The Bicarbonate Buffer System of Blood Plasma 44 Things? 69
Buffers Useful within Physiological pH Ranges 45 A Deeper Look: Coupling a Reaction to ATP Hydrolysis
Human Biochemistry: Blood pH and Respiration 46 Changes Its Keq by a Factor of 108 71

2.4 What Properties of Water Give It a Unique 3.8 What Is the Daily Human Requirement for ATP? 71
Role in the Environment? 46 Foundational Biochemistry 72
Foundational Biochemistry 47 Problems 73
Problems 47 Further Reading 75
Further Reading 49

3 4
Amino Acids and the Peptide Bond 77
Thermodynamics of Biological Systems 51 4.1 What Are the Structures and Properties of Amino Acids? 77
3.1 What Are the Basic Concepts of Thermodynamics? 51 Typical Amino Acids Contain a Central Tetrahedral
hree Quantities Describe the Energetics
T Carbon Atom 77
of Biochemical Reactions 52 Amino Acids Can Join via Peptide Bonds 78
All Reactions and Processes Follow There Are 20 Common Amino Acids 78
the Laws of Thermodynamics 53 Are There Other Ways to Classify Amino Acids? 82
A Deeper Look: Entropy, Information, and the A Deeper Look: Why Nature Chose Selenium 82
Importance of “Negentropy” 54 Amino Acids 21 and 22—and More? 83
Free Energy Provides a Simple Criterion for Equilibrium 54 Several Amino Acids Occur Only Rarely in Proteins 83
3.2 What Is the Effect of Concentration on Net 4.2 What Are the Acid–Base Properties of Amino Acids? 83
Free Energy Changes? 55 Amino Acids Are Weak Polyprotic Acids 83
3.3 How May Standard State, Equilibrium, and Cellular Critical Developments in Biochemistry: Adding New
Conditions Be Compared? 56 Chemistry to Proteins with Unnatural Amino Acids 84
3.4 What Are the Characteristics of High-Energy Side Chains of Amino Acids Undergo Characteristic
Biomolecules? 57 Ionizations 86
High Energy Phosphate Compounds 58 4.3 What Reactions Do Amino Acids Undergo? 89
A Deeper Look: Why Nature Chose Phosphates 59 4.4 What Are the Optical and Stereochemical Properties
ATP Is an Intermediate Energy-Shuttle Molecule 59 of Amino Acids? 89
The Hydrolysis of Phosphoric Acid Anhydrides Amino Acids Are Chiral Molecules 89
Is Highly Favorable 60 Chiral Molecules Are Described by the d,l and (R,S)
The Hydrolysis DG° of ATP and ADP Is Greater Than Naming Conventions 90
That of AMP 61 Critical Developments in Biochemistry: Green
Acetyl Phosphate and 1,3-Bisphosphoglycerate Fluorescent Protein—The “Light Fantastic”—from
Are Phosphoric-Carboxylic Anhydrides 61 Jellyfish to Gene Expression 91
Enol Phosphates Are Potent Phosphorylating Agents 62 4.5 What Are the Spectroscopic Properties of Amino
The Complex Equilibria Involved in ATP Hydrolysis 64 Acids? 91
3.5 How Do Group Transfer Potentials Quantify the henylalanine, Tyrosine, and Tryptophan
P
Reactivity of Functional Groups? 65 Absorb Ultraviolet Light 92
3.6 What Are Reduction Potentials, and How Are They Amino Acids Can Be Characterized by Nuclear Magnetic
Resonance 92
Used to Account for Free Energy Changes in Redox
Reactions? 66 Critical Developments in Biochemistry: Rules for
Description of Chiral Centers in the (R,S) System 93

4.6 How Are Amino Acid Mixtures Step 6. Reconstruction of the Overall Amino Acid
Separated and Analyzed? 94 Sequence 120
Amino Acids Can Be Separated by Chromatography 94 The Amino Acid Sequence of a Protein Can Be
Determined by Mass Spectrometry 122
4.7 What Is the Fundamental Structural
Pattern in Proteins? 94 Sequence Databases Contain the Amino Acid Sequences
of Millions of Different Proteins 125
The Peptide Bond Has Partial Double-Bond Character 95
The Polypeptide Backbone Is Relatively Polar 97 5.4 What Is the Nature of Amino Acid Sequences? 126
Peptides Can Be Classified According to How Many omologous Proteins from Different Organisms Have
H
Amino Acids They Contain 97 Homologous Amino Acid Sequences 127
The Amino Acids in Polypeptides Can Be Released Computer Programs Can Align Sequences and Discover
by Acid Hydrolysis 98 Homology between Proteins 127
Proteins Are Composed of One or More Polypeptide Related Proteins Share a Common Evolutionary
Chains 98 Origin 130
Apparently Different Proteins May Share a Common
Foundational Biochemistry 100
Ancestry 131
Problems 101
A Mutant Protein Is a Protein with a Slightly Different
Further Reading 103 Amino Acid Sequence 131
5.5 How Are Polypeptides Synthesized

5 in the Laboratory? 131

Orthogonal Synthesis of Peptides 132
Solid-Phase Methods Are Very Useful in Peptide
Proteins: Their Primary Structure and Biological Synthesis 132
Functions 105 5.6 Do Proteins Have Chemical Groups Other Than
5.1 What Architectural Arrangements Amino Acids? 132
Characterize Protein Structure? 105 5.7 What Are the Many Biological Functions of
roteins Fall into Three Basic Classes According to Shape
P Proteins? 134
and Solubility 106 Proteins Are the Agents of Biological Function 135
Protein Structure Is Described in Terms of Four Levels of All Proteins Function through Specific Recognition and
Organization 107 Binding of Some Target Molecule 135
Noncovalent Forces Drive Formation of the Higher 5.8 What Is the Proteome and What Does It Tell Us? 137
Orders of Protein Structure 109
The Proteome Is Large and Dynamic 137
A Protein’s Conformation Can Be Described as Its Overall
Determining the Proteome of a Cell 137
Three-Dimensional Structure 109
Critical Developments in Biochemistry: Two New Suffixes
5.2 How Are Proteins Isolated and Purified from in Molecular Biology and Biochemistry: “-ome” and
Cells? 110 “-omics” 138
Number of Protein Separation Methods Exploit
A A Deeper Look: The Human Proteome Project and the
Differences in Size and Charge 110 Human Protein Atlas 139
A Deeper Look: Estimation of Protein Concentrations in Foundational Biochemistry 139
Solutions of Biological Origin 111
Problems 140
A Typical Protein Purification Scheme Uses a Series of
Separation Methods 111 Further Reading 142
A Deeper Look: Techniques Used in Protein

5.3
Purification 112
How Is the Primary Structure of a Protein
Determined? 115
6
Sanger Was the First to Determine the Sequence of a Proteins: Secondary, Tertiary, and Quaternary
Protein 116 Structure 145
Both Chemical and Enzymatic Methodologies Are Used 6.1 What Noncovalent Interactions Stabilize the Higher
in Protein Sequencing 116
Levels of Protein Structure? 146
Step 1. Separation of Polypeptide Chains 116
Hydrogen Bonds Are Formed Whenever Possible 146
A Deeper Look: The Virtually Limitless Number of
Hydrophobic Interactions Drive Protein Folding 146
Different Amino Acid Sequences 117
Ionic Interactions Usually Occur on the Protein
Step 2. Cleavage of Disulfide Bridges 117
Surface 147
Step 3. N- and C-Terminal Analysis 117
Van der Waals Interactions Are Ubiquitous 147
Steps 4 and 5. Fragmentation of the Polypeptide Chain 119

6.2 What Role Does the Amino Acid Sequence Play rtificial Intelligence Algorithms Predict Protein
A
in Protein Structure? 147 Structures Accurately 180
6.3 What Are the Elements of Secondary Structure in Critical Developments in Biochemistry: NMR and
Proteins, and How Are They Formed? 148 Cryo-EM — Revolutionary Methods that Probe Protein
Structure and Dynamics 180
he Amide Plane Is a Fundamental Determinant of
T
All Protein Structure 148 6.5 How Do Protein Subunits Interact at the Quaternary
The Alpha-Helix Is a Key Secondary Structure 150 Level of Protein Structure? 181
A Deeper Look: Knowing What the Right Hand and Left Human Biochemistry: Diseases of Protein Folding 182
Hand Are Doing 150 Human Biochemistry: Structural Genomics 183
Critical Developments in Biochemistry: X-ray There Is Symmetry in Quaternary Structures 183
Crystallography of Proteins 151 Quaternary Association Is Driven by Weak Forces 183
The b-Pleated Sheet Is a Core Structure in Proteins 153 Open Quaternary Structures Can Polymerize 185
Critical Developments in Biochemistry: In Bed with a There Are Structural and Functional Advantages to
Cold, Pauling Stumbles onto the α-Helix and a Nobel Quaternary Association 185
Prize 154 Human Biochemistry: Faster-Acting Insulin: Genetic
Helix–Sheet Composites Provide Flexibility and Engineering Solves a Quaternary Structure Problem 186
Strength in Spider Silk 156 Foundational Biochemistry 188
b-Turns Allow the Protein Strand to Change Direction 156
Problems 188
6.4 How Do Polypeptides Fold into Three-Dimensional Further Reading 190
Protein Structures? 157

7
A Deeper Look: The Coiled-Coil Motif in Proteins 158
Fibrous Proteins Usually Play a Structural Role 159
Globular Proteins Mediate Cellular Function 162
Helices and Sheets Make Up the Core of Most Globular Carbohydrates and the Glycoconjugates of Cell
Proteins 162
Critical Developments in Biochemistry: The Protein Data
Surfaces 193
Bank (PDB) 162 7.1 How Are Carbohydrates Named? 194
Water Molecules on the Protein Surface Stabilize the 7.2 What Are the Structure and Chemistry
Structure 163 of Monosaccharides? 194
Packing Considerations 163 Monosaccharides Are Classified as Aldoses and
Human Biochemistry: Collagen-Related Diseases 164 Ketoses 194
Protein Domains Are Nature’s Modular Strategy for Stereochemistry Is a Prominent Feature of
Protein Design 165 Monosaccharides 195
Denaturation Leads to Loss of Protein Structure and Monosaccharides Exist in Cyclic and Anomeric Forms 197
Function 165 Haworth Projections Are a Convenient Device for
Human Biochemistry: Domain-Based Engineering Drawing Sugars 198
of Proteins Forms the Basis of a Novel Cancer Monosaccharides Can Be Converted to Several Derivative
Treatment 167 Forms 200
Anfinsen’s Classic Experiment Proved That Sequence A Deeper Look: Honey—An Ancestral Carbohydrate
Determines Structure 169 Treat 202
Is There a Single Mechanism for Protein Folding? 169
7.3 What Are the Structure and Chemistry
What Is the Thermodynamic Driving Force for Protein of Oligosaccharides? 204
Folding? 172
Disaccharides Are the Simplest Oligosaccharides 204
Marginal Stability of the Tertiary Structure Makes Proteins
A Deeper Look: Trehalose—A Natural Protectant for
Flexible 172
Bugs 205
Motion in Globular Proteins 172
A Variety of Higher Oligosaccharides Occur in
The Folding Tendencies and Patterns of Globular Nature 206
Proteins 173
Human Biochemistry: Alpha-Gal and Red Meat
A Deeper Look: Metamorphic Proteins—A Consequence Allergy 207
of Dynamism and Marginal Stability 175
7.4 What Are the Structure and Chemistry
Proteins Can Be Classified on the Basis of Folding
Patterns 176 of Polysaccharides? 208
Molecular Chaperones Are Proteins That Help Other omenclature for Polysaccharides Is Based on Their
N
Proteins to Fold 177 Composition and Structure 208
Some Proteins Are Intrinsically Unstructured 178 Polysaccharides Serve Energy Storage, Structure, and
Protection Functions 209

Polysaccharides Provide Stores of Energy 209 8.3 What Are the Structures and Chemistry
Polysaccharides Provide Physical Structure and Strength of Glycerophospholipids? 242
to Organisms 210 Glycerophospholipids Are the Most Common
A Deeper Look: Ruth Benerito and Wrinkle-Free Cotton Phospholipids 243
Fabrics 213 Ether Glycerophospholipids Include PAF and
Polysaccharides Provide Strength and Rigidity to Bacterial Plasmalogens 245
Cell Walls 214 Human Biochemistry: Platelet-Activating Factor: A
A Deeper Look: A Complex Polysaccharide in Red Potent Ether Glycerophospholipid Mediator 246
Wine—The Strange Story of Rhamnogalacturonan II 215 8.4 What Are Sphingolipids, and How Are They Important
Animals Display a Variety of Cell Surface for Higher Animals? 246
Polysaccharides 218
8.5 What Are Waxes, and How Are They Used? 246
7.5 What Are Glycoproteins, and How Do They Function A Deeper Look: Novel Lipids with Valuable
in Cells? 218 Properties 248
Carbohydrates on Proteins Can Be O-Linked or
8.6 What Are Terpenes, and What Is Their Relevance
N-Linked 218
to Biological Systems? 249
O-GlcNAc Signaling Is Altered in Diabetes and
A Deeper Look: Why Do Plants Emit Isoprene? 251
Cancer 220
Human Biochemistry: Coumadin or Warfarin—Agent of
O-Linked Saccharides Form Rigid Extended Extracellular
Life or Death 251
Structures 220
Polar Fish Depend on Antifreeze Glycoproteins 220 8.7 What Are Steroids, and What Are Their Cellular
N-Linked Oligosaccharides Can Affect the Physical Functions? 252
Properties and Functions of a Protein 221 Cholesterol 252
Human Biochemistry: Drug Research Finds a Sweet Steroid Hormones Are Derived from Cholesterol 252
Spot 222 Human Biochemistry: Plant Sterols and Stanols—
Sialic Acid Terminates the Oligosaccharides of Natural Cholesterol Fighters 254
Glycoproteins and Glycolipids 222 8.8 How Do Lipid Metabolites Act
Sialic Acid Cleavage Can Serve as a Timing Device for as Biological Signals? 254
Protein Degradation 223 Human Biochemistry: Beating COVID-19: Lipid
7.6 How Do Proteoglycans Modulate Processes Nanoparticles Make RNA Vaccines Practical and
in Cells and Organisms? 224 Effective 255
Functions of Proteoglycans Involve Binding to Other Human Biochemistry: The Endocannabinoid
Proteins 225 Signaling System: A Target for Next-Generation
Proteoglycans May Modulate Cell Growth Processes 226 Therapeutics 256
Proteoglycans Make Cartilage Flexible and Resilient 226 Human Biochemistry: Fingolimod—a Sphingosine-1-P
Mimic Is an Oral Drug for Multiple Sclerosis 258
7.7 How Do Carbohydrates Provide a Structural
Code? 226 8.9 What Can Lipidomics Tell Us about Cell, Tissue,
and Organ Physiology? 259
Lectins Translate the Sugar Code 228
Foundational Biochemistry 261
Selectins, Rolling Leukocytes, and the Inflammatory
Response 228 Problems 261
Galectins—Mediators of Inflammation, Immunity, and Further Reading 263
Cancer 229
Foundational Biochemistry 231
Problems 231
Further Reading 234
9
Membranes and Membrane Transport 265

8 9.1 What Are the Chemical and Physical

Properties of Membranes? 266
The Composition of Membranes Suits Their
Lipids 237 Functions 266
Lipids Form Ordered Structures Spontaneously in
8.1 What Are the Structures and Chemistry of Fatty
Water 267
Acids? 237
The Fluid Mosaic Model Describes Membrane
8.2 What Are the Structures and Chemistry Dynamics 269
of Triacylglycerols? 241
9.2 What Are the Structure and Chemistry of Membrane
A Deeper Look: Polar Bears Prefer Nonpolar Food 242
Proteins? 271

eripheral Membrane Proteins Associate Loosely

P 10.2 What Are Nucleosides? 319
with the Membrane 271 Human Biochemistry: Adenosine: A Nucleoside
Integral Membrane Proteins Are Firmly Anchored with Physiological Activity 320
in the Membrane 271 10.3 What Are the Structure and Chemistry
Lipid-Anchored Membrane Proteins Can Act as Switching of Nucleotides? 320
Devices 280
Cyclic Nucleotides Are Cyclic Phosphodiesters 322
9.3 How Are Biological Membranes Organized? 282 Nucleoside Diphosphates and Triphosphates Are
9.4 What Are the Dynamic Processes Nucleotides with Two or Three Phosphate Groups 322
That Modulate Membrane Function? 283 Human Biochemistry: cGAMP, a Cyclic Dinucleotide
L ipids and Proteins Undergo a Variety That Triggers a Response to Infection 322
of Movements in Membranes 283 NDPs and NTPs Are Polyprotic Acids 323
Membrane Lipids Can Be Ordered to Different Nucleoside 59-Triphosphates Are Carriers of Chemical
Extents 284 Energy 323
9.5 How Does Transport Occur across Biological 10.4 What Are Nucleic Acids? 324
Membranes? 293 The Base Sequence of a Nucleic Acid Is Its Defining
9.6 What Is Passive Diffusion? 294 Characteristic 325
9.7 How Does Facilitated Diffusion Occur? 294 10.5 What Are the Different Classes of Nucleic
Membrane Channel Proteins Facilitate Diffusion 295 Acids? 326
The Bacillus cereus NaK Channel Uses a Variation The Fundamental Structure of DNA Is a Double
on the K1 Selectivity Filter 297 Helix 326
CorA Is a Pentameric Mg21 Channel 298 Various Forms of RNA Serve Different Roles in
Cells 330
Chloride, Water, Glycerol, and Ammonia
Flow through Single-Subunit Pores 299 A Deeper Look: The RNA World and Early
Evolution 334
9.8 How Does Energy Input Drive Active Transport
The Chemical Differences between DNA and RNA Have
Processes? 300 Biological Significance 334
ll Active Transport Systems Are Energy-Coupling
A
Devices 300
10.6 Are Nucleic Acids Susceptible to Hydrolysis? 335
RNA Is Susceptible to Hydrolysis by Base, but DNA
Many Active Transport Processes Are Driven by
Is Not 335
ATP 301
The Enzymes That Hydrolyze Nucleic Acids Are
A Deeper Look: Cardiac Glycosides: Potent Drugs from
Phosphodiesterases 335
Ancient Times 305
Nucleases Differ in Their Specificity for Different Forms
ABC Transporters Use ATP to Drive Import and Export
of Nucleic Acid 335
Functions and Provide Multidrug Resistance 306
Restriction Enzymes Are Nucleases That Cleave
9.9 How Are Certain Transport Processes Driven by Light Double-Stranded DNA Molecules 337
Energy? 308
Type II Restriction Endonucleases Are Useful
9.10 How Is Secondary Active Transport Driven by Ion for Manipulating DNA in the Lab 337
Gradients? 310 Restriction Endonucleases Can Be Used to Map
Na1 and H1 Drive Secondary Active Transport 310 the Structure of a DNA Fragment 339
AcrB Is a Secondary Active Transport System 310 Foundational Biochemistry 341
Foundational Biochemistry 311 Problems 341
Problems 312 Further Reading 343
Further Reading 314

10 11
Structure of Nucleic Acids 345
Nucleotides and Nucleic Acids 317
11.1 How Do Scientists Determine the Primary Structure
10.1 What Are the Structure and Chemistry of Nucleic Acids? 345
of Nitrogenous Bases? 318 he Nucleotide Sequence of DNA Can Be Determined
T
Three Pyrimidines and Two Purines Are Commonly from the Electrophoretic Migration of a Defined Set of
Found in Cells 318 Polynucleotide Fragments 346
The Properties of Pyrimidines and Purines Can Be Traced Sanger’s Chain Termination or Dideoxy Method Uses
to Their Electron-Rich Nature 319 DNA Replication to Generate a Defined Set of
Polynucleotide Fragments 346

ext-Generation Sequencing by Synthesis 348

N MC Proteins Establish Chromosome Organization and
S
High-Throughput DNA Sequencing Based on Proton Mediate Chromosome Dynamics 375
Detection 349 11.6 How Can Nucleic Acids Be Synthesized
Single-Molecule Real-Time Sequencing 351 Chemically? 375
Human Biochemistry: The Human Genome hosphoramidite Chemistry Is Used to Form
P
Project 352 Oligonucleotides from Nucleotides 376
Oxford Nanopore Technologies (ONT) Real-Time Genes and Even Chromosomes Can Be Synthesized
Sequencing 352 Chemically 376
Bioinformatics—Functional Genomics, Proteomics, and 11.7 What Are the Secondary and Tertiary
More 353 Structures of RNA? 378
11.2 What Sorts of Secondary Structures Can ransfer RNA Adopts Higher-Order Structure Through
T
Double-Stranded DNA Molecules Adopt? 354 Intrastrand Base Pairing 380
Conformational Variation in Polynucleotide Messenger RNA Adopts Higher-Order Structure Through
Strands 354 Intrastrand Base Pairing 381
DNA Usually Occurs in the Form of Double-Stranded Ribosomal RNA Also Adopts Higher-Order Structure
Helices 355 Through Intrastrand Base Pairing 382
Watson–Crick Base Pairs Have Virtually Identical Aptamers Are Oligonucleotides Specifically Selected for
Dimensions 355 Their Ligand-Binding Ability 384
The DNA Double Helix Is a Stable Structure 355 Foundational Biochemistry 386
Double Helical Structures Can Adopt a Number of Stable Problems 387
Conformations 357
Further Reading 389
A-Form DNA Is an Alternative Form of Right-Handed

12
DNA 357
Z-DNA Is a Conformational Variation in the Form of a
Left-Handed Double Helix 358
The Double Helix Is Flexible 361
Human Biochemistry: DNA Methylation, CpG Islands, Recombinant DNA, Cloning, Gene Editing, and
and Epigenetics 362 Synthetic Biology—An Introduction 393
Alternative Hydrogen-Bonding Interactions Give Rise to 12.1 What Is DNA Cloning? 394
Novel DNA Structures: Cruciforms, Triplexes, and
Plasmids Are Very Useful in Cloning Genes 394
Quadruplexes 362
Shuttle Vectors Are Plasmids That Can Propagate in Two
11.3 Can the Secondary Structure of DNA Different Organisms 399
Be Denatured and Renatured? 366 Artificial Chromosomes Can Be Created from
hermal Denaturation of DNA Can Be Observed by
T Recombinant DNA 399
Changes in UV Absorbance 367
12.2 What Is a DNA Library? 400
pH Extremes or Strong H-Bonding Solutes also Denature
Genomic Libraries Are Prepared from the Total DNA in an
DNA Duplexes 367
Organism 400
Single-Stranded DNA Can Renature to Form DNA
Critical Developments in Biochemistry: Combinatorial
Duplexes 367
Libraries 400
A Deeper Look: The Buoyant Density of DNA 368
Libraries Can Be Screened for the Presence of Specific
The Rate of DNA Renaturation Is an Index of DNA Genes 401
Sequence Complexity 368
Probes for Screening Libraries Can Be Prepared
Nucleic Acid Hybridization: Different DNA Strands of in a Variety of Ways 402
Similar Sequence Can Form Hybrid Duplexes 369
PCR Is Used to Clone and Amplify Specific
11.4 How Does DNA Adopt Structures of Genes 402
Higher Complexity? 370 Critical Developments in Biochemistry: Identifying
Supercoils Are One Kind of Structural Complexity in Specific DNA Sequences by Southern Blotting
DNA 370 (Southern Hybridization) 404
Supercoiled DNA Is Defined by Its Linking Number 370 cDNA Libraries Are DNA Libraries Prepared from
Enzymes Can Add or Remove Supercoils 371 mRNA 405
11.5 What Is the Structure of Eukaryotic DNA Microarrays (Gene Chips) Are Arrays of Different
Chromosomes? 372 Oligonucleotides Immobilized on a Chip 407
Nucleosomes Are the Fundamental Structural Unit in 12.3 Can the Genes in Libraries Be Transcribed
Chromatin 373 and Translated? 408
Higher-Order Structural Organization of Chromatin Gives Expression Vectors Are Engineered So That the RNA or
Rise to Chromosomes 374 Protein Products of Cloned Genes Can Be Synthesized 408

Reporter Gene Constructs Are Chimeric DNA Molecules Coenzymes and Cofactors Are Nonprotein Components
Composed of Gene Regulatory Sequences Positioned Essential to Enzyme Activity 437
Next to an Easily Expressible Gene Product 411 13.2 How Can the Rate of an Enzyme-Catalyzed Reaction
Specific Protein–Protein Interactions Can Be Identified Be Defined in a Mathematical Way? 438
Using the Yeast Two-Hybrid System 412
Chemical Kinetics Provides a Foundation for Exploring
In Vitro Mutagenesis—Introducing Changes into Enzyme Kinetics 438
Expressed Proteins 413
Bimolecular Reactions Are Reactions Involving Two
12.4 How Is RNA Interference Used to Reveal the Function Reactant Molecules 439
of Genes? 413 Catalysts Lower the Free Energy of Activation for a
12.5 Gene Therapy: Is It Possible for Scientists to Alter or Reaction 439
Rewrite the Genome of an Organism? 414 Decreasing DG‡ Increases Reaction Rate 440
Human Gene Therapy Can Repair Genetic 13.3 What Equations Define the Kinetics of Enzyme‑
Deficiencies 415 Catalyzed Reactions? 441
Viruses as Vectors in Human Gene Therapy 416 The Substrate Binds at the Active Site of an Enzyme 441
Genome Engineering 416 The Michaelis–Menten Equation Is the Fundamental
Genome Editing with CRISPR-Cas9 417 Equation of Enzyme Kinetics 442
A Deeper Look: The Biological Role of CRISPR-Cas Rate Calculations Assume That [ES] Remains Constant
Systems: Adaptive immunity in Bacteria 418 During an Enzymatic Reaction 442
Base Editing with CRISPR-Cas9 420 A Calculations Are Simplified If Velocity Measurements
Prime Editing with CRISPR-Cas9 421 Are Made Immediately after Adding S 442
Gene Silencing with CRISPR-Cas9 421 The Michaelis Constant, Km, Is Defined as
(k21 1 k2)/k1 443
12.6 How Does High-Throughput Technology Allow Global
When [S] 5 Km, v 5 Vmax/2 444
Study of Millions of Genes or Molecules at Once? 421
Plots of v versus [S] Illustrate the Relationships between
High-Throughput Screening 422
Vmax, Km, and Reaction Order 444
High-Throughput RNAi Screening of Mammalian
Turnover Number Defines the Activity of One Enzyme
Genomes 422
Molecule 445
High-Throughput Protein Screening 422
The Ratio, kcat/Km, Defines the Catalytic Efficiency of an
12.7 What Is the Field of Synthetic Biology? 423 Enzyme 445
iGEM and BioBricks (Registry of Standard Biological Linear Plots Can Be Derived from the Michaelis–Menten
Parts) 423 Equation 446
Metabolic Engineering 424 A Deeper Look: An Example of the Effect of Amino Acid
Synthetic Genomes 425 Substitutions on Km and kcat: Wild-Type and Mutant
Foundational Biochemistry 427 Forms of Human Sulfite Oxidase 448
Problems 428 Nonlinear Lineweaver–Burk or Hanes–Woolf Plots Are a
Property of Regulatory Enzymes 448
Further Reading 429
Enzymatic Activity Is Strongly Influenced by pH 448
The Response of Enzymatic Activity to Temperature Is
Complex 448
Part II Protein Dynamics 433
13.4 What Can Be Learned from the Inhibition of Enzyme

13
Activity? 449
Enzymes May Be Inhibited Reversibly or Irreversibly 449
Reversible Inhibitors May Bind at the Active Site or at
Some Other Site 450
Enzymes—Kinetics and Specificity 433
A Deeper Look: The Equations of Competitive
Enzymes Are the Agents of Metabolic Function 434 Inhibition 451
13.1 What Characteristic Features Define Enzymes? 434 Enzymes Also Can Be Inhibited in an Irreversible
Catalytic Power Is Defined as the Ratio of the Enzyme- Manner 453
Catalyzed Rate of a Reaction to the Uncatalyzed Rate 435 13.5 What Is the Kinetic Behavior of Enzymes Catalyzing
Specificity Is the Term Used to Define the Selectivity of Bimolecular Reactions? 455
Enzymes for Their Substrates 435
Human Biochemistry: Viagra—An Unexpected Outcome
Regulation of Enzyme Activity Ensures That the Rate of in a Program of Drug Design 456
Metabolic Reactions Is Appropriate to Cellular
The Conversion of AEB to PEQ Is the Rate-Limiting Step
Requirements 435
in Random, Single-Displacement Reactions 457
Enzyme Nomenclature Provides a Systematic Way of
In an Ordered, Single-Displacement Reaction, the
Naming Metabolic Reactions 435
Leading Substrate Must Bind First 458

Double-Displacement (Ping-Pong) Reactions Proceed Via Noncatalytic Residues May Still Play a Role in Catalysis in
Formation of a Covalently Modified Enzyme Enzyme Active Sites 490
Intermediate 459 14.6 What Can Be Learned from the Mechanisms of Some
Exchange Reactions Are One Way to Diagnose Typical Enzymes? 491
Bisubstrate Mechanisms 461
Serine Proteases 491
Multisubstrate Reactions Can Also Occur in Cells 461
The Digestive Serine Proteases 491
13.6 How Can Enzymes Be So Specific? 461 The Chymotrypsin Mechanism in Detail: Kinetics 493
The Lock-and-Key Hypothesis Was the First Explanation The Serine Protease Mechanism in Detail: Events at the
for Specificity 462 Active Site 493
The Induced-Fit Hypothesis Provides a More Accurate The Aspartic Proteases 496
Description of Specificity 462
The Mechanism of Action of Aspartic Proteases 497
Induced Fit Favors Formation of the Transition State 462
The HIV-1 Protease Is an Aspartic Protease 497
Specificity and Reactivity 462
Critical Developments in Biochemistry: Frances Arnold
13.7 Are All Enzymes Proteins? 463 and Directed Evolution of Enzymes 499
RNA Molecules That Are Catalytic Have Been Termed Chorismate Mutase: A Model for Understanding Catalytic
Ribozymes 463 Power and Efficiency 499
Antibody Molecules Can Have Catalytic Activity 464 Human Biochemistry: Protease Inhibitors-Game
13.8 Is It Possible to Design an Enzyme to Catalyze Any Changers for AIDS Patients 502
Desired Reaction? 466 Foundational Biochemistry 504
A Designer Enzyme for Bioremediation 467 Problems 505
A Case Study for Designer Enzyme Development — Kemp Further Reading 508
Eliminases 467

15
Foundational Biochemistry 468
Problems 469
Further Reading 471
Enzyme Regulation 511

14 15.1 What Factors Influence Enzymatic Activity? 511

he Availability of Substrates and Cofactors Usually
T
Determines How Fast the Reaction Goes 512
Mechanisms of Enzyme Action 475 As Product Accumulates, the Apparent Rate
14.1 What Are the Magnitudes of Enzyme-Induced Rate of the Enzymatic Reaction Will Decrease 512
Accelerations? 475 Genetic Regulation of Enzyme Synthesis Determines
the Amount of Enzyme Present at Any Moment 512
14.2 What Role Does Transition-State Stabilization Play in
Enzyme Activity Can Be Regulated Allosterically 512
Enzyme Catalysis? 477
Enzyme Activity Can Be Regulated through Covalent
14.3 How Does Destabilization of the Enzyme-Substrate Modification 513
Complex Affect Enzyme Catalysis? 478 Zymogens Are Inactive Precursors of Enzymes 513
14.4 What Are Transition State Analogs and How Tightly Isozymes Are Enzymes with Slightly Different Subunits
Do They Bind to the Active Sites of Enzymes? 479 and Kinetic Properties 514
A Deeper Look: Transition-State Analogs Make Our 15.2 What Are the General Features of Allosteric
World Better 480 Regulation? 516
14.5 What Are the Mechanisms of Enzyme Catalysis? 483 egulatory Enzymes Have Certain Exceptional
R
Enzymes Facilitate Formation of Near-Attack Properties 516
Conformations 483 15.3 Can Allosteric Regulation Be Explained by Conforma-
A Deeper Look: How to Read and Write Mechanisms 484 tional Changes in Proteins? 517
Protein Motions Are Essential to Enzyme Catalysis 484 he Symmetry Model for Allosteric Regulation Is Based
T
Covalent Catalysis 486 on Two Conformational States for a Protein 517
General Acid-Base Catalysis 487 The Sequential Model for Allosteric Regulation Is Based
Low-Barrier Hydrogen Bonds 488 on Ligand-Induced Conformational Changes 517
Quantum Mechanical Tunneling in Electron and Proton The Notable Difference between the MWC and KNF
Transfers 489 Models 519
Human Biochemistry: Antibiotic Resistance by Changes in the Oligomeric State of a Protein
Superbugs 489 Can Also Give Allosteric Behavior 519
Metal Ion Catalysis 490

15.4 What Kinds of Covalent Modification Regulate Human Biochemistry: Hemoglobin and Nitric Oxide 536
the Activity of Enzymes? 519 Sickle-Cell Disease Is Characterized by Abnormal Red
ovalent Modification through Reversible
C Blood Cells 537
Phosphorylation 519 Sickle-Cell Disease Has Been Characterized as a
Protein Kinases: Target Recognition and Intrasteric Molecular Disease 537
Control 519 Foundational Biochemistry 538
Phosphorylation Is Not the Only Form of Covalent Problems 539
Modification That Regulates Enzyme Function 522
Further Reading 541
Acetylation Is a Prominent Modification

16
for the Regulation of Metabolic Enzymes 522
15.5 Is the Activity of Some Enzymes Controlled by Both
Allosteric Regulation and Covalent Modification? 523
he Glycogen Phosphorylase Reaction Converts
T
Glycogen into Readily Usable Fuel in the Form of
Molecular Motors 543
Glucose-1-Phosphate 523 16.1 What Are the General Features of Molecular
Glycogen Phosphorylase Is a Homodimer 523 Motors? 543
Glycogen Phosphorylase Activity Is Regulated 16.2 What Is the Molecular Mechanism
Allosterically 524 of Muscle Contraction? 544
Covalent Modification of Glycogen Phosphorylase uscle Contraction Is Triggered by Ca 21 Release
M
Overrides Allosteric Regulation 526 from Intracellular Stores 544
Enzyme Cascades Regulate Glycogen Phosphorylase Human Biochemistry: Medical Applications of Smooth
Covalent Modification 526 Muscle Effectors 545
15.6 What Is the Relationship between Quaternary Structure The Molecular Structure of Skeletal Muscle
and Allosteric Regulation? 528 Is Based on Actin and Myosin 545
he Comparative Biochemistry of Myoglobin and
T The Mechanism of Muscle Contraction Is Based on
Hemoglobin Reveals Insights into Allostery 528 Sliding Filaments 548
Myoglobin Is an Oxygen-Storage Protein 529 A Deeper Look: The P-Loop NTPases—Energy to Run
O2 Binds to the Mb Heme Group 529 the Motors 549
O2 Binding Alters Mb Conformation 529 16.3 What Are the Molecular Motors That Orchestrate the
A Deeper Look: The Oxygen-Binding Curves of Mechanochemistry of Microtubules? 551
Myoglobin and Hemoglobin 530 ilaments of the Cytoskeleton Are Highways
F
Cooperative Binding of Oxygen by Hemoglobin That Move Cellular Cargo 552
Has Important Physiological Significance 531 Three Classes of Motor Proteins Move Intracellular
Hemoglobin Has an a2b2 Tetrameric Structure 531 Cargo 553
Oxygenation Markedly Alters the Quaternary Dyneins Move Organelles in a Plus-to-Minus Direction;
Structure of Hb 532 Kinesins, in a Minus-to-Plus Direction 554
Movement of the Heme Iron by Less Than 0.04 nm Human Biochemistry: Effectors of Microtubule
Induces the Conformational Change in Hemoglobin 532 Polymerization as Therapeutic Agents 555
The Physiological Significance of the Hb:O2 Cytoskeletal Motors Are Highly Processive 555
Interaction 532 ATP Binding and Hydrolysis Drive Hand-over-Hand
The Oxy and Deoxy Forms of Hemoglobin Represent Movement of Kinesin 557
Two Different Conformational States 533 Conformation Changes in a Hexameric Ring
The Allosteric Behavior of Hemoglobin Has Both Drive the Dynein Motor 558
Symmetry (MWC) Model and Sequential (KNF) 16.4 How Do Molecular Motors Unwind DNA? 558
Model Components 533 egative Cooperativity Facilitates Hand-over-Hand
N
H1 Promotes the Dissociation of Oxygen from Movement 561
Hemoglobin 533 Papillomavirus E1 Helicase Moves along DNA as on a
CO2 Also Promotes the Dissociation of O2 from Spiral Staircase 562
Hemoglobin 534
16.5 How Do Bacterial Flagella Use a Proton Gradient
2,3-Bisphosphoglycerate Is an Important Allosteric
to Drive Rotation? 564
Effector for Hemoglobin 535
The Flagellar Rotor Is a Complex Structure 565
BPG Binding to Hb Has Important Physiological
Significance 535 Gradients of H1 and Na1 Drive Flagellar Rotors 565
Fetal Hemoglobin Has a Higher Affinity for O2 The Flagellar Rotor Self-Assembles in a
Because It Has a Lower Affinity for BPG 535 Spontaneous Process 565

lagellar Filaments Are Composed of Protofilaments of

F Mutations Create Specific Metabolic Blocks 588
Flagellin 566 Isotopic Tracers Can Be Used as Metabolic Probes 588
Motor Reversal Involves Conformation Switching NMR Spectroscopy Is a Noninvasive Metabolic Probe 589
of Motor and Filament Proteins 566 Cell Fractionation Reveals Which Compartment Contains
Foundational Biochemistry 568 a Metabolic Pathway 589
Problems 568 Metabolic Pathways Are Also Time-Dependent 591
Further Reading 570 17.5 What Can the Metabolome Tell Us about a Biological
System? 592

Part III Metabolism and Its Regulation 573 17.6 What Food Substances Form the Basis
of Human Nutrition? 596

17
Humans Require Protein 596
Carbohydrates Provide Metabolic Energy 597
Lipids Are Essential, but in Moderation 597

Metabolism: An Overview 573 Foundational Biochemistry 597

Problems 598
17.1 Is Metabolism Similar in Different Organisms? 573
Further Reading 600
Living Things Vary in Their Carbon and Energy
Requirements 574
Oxygen Is Essential to Life for Aerobes 574
The Flow of Energy in the Biosphere and the Carbon and
Oxygen Cycles Are Intimately Related 574
18
A Deeper Look: Calcium Carbonate—A Biological Sink Glycolysis 603
for CO2 575 18.1 What Are the Essential Features of Glycolysis? 603
17.2 What Can Be Learned from Metabolic Maps? 575 18.2 Why Are Coupled Reactions Important in
The Metabolic Map Can Be Viewed as a Set of Dots and Glycolysis? 605
Lines 575
18.3 What Are the Chemical Principles and Features of the
Alternative Metabolic Pathway Models Can Provide New
First Phase of Glycolysis? 606
Insights into Pathways 577
eaction 1: Glucose Is Phosphorylated by Hexokinase
R
Metabolism Is a Network 578
or Glucokinase—The First Priming Reaction 606
Metabolic Pathways with Multiple Enzymes May Take
A Deeper Look: Glucokinase—An Enzyme with Different
Different Forms 579
Roles in Different Cells 609
17.3 How Do Anabolic and Catabolic Processes Form the Reaction 2: Phosphoglucoisomerase Catalyzes
Core of Metabolic Pathways? 580 the Isomerization of Glucose-6-Phosphate 609
Anabolism Is Biosynthesis 580 Reaction 3: ATP Drives a Second Phosphorylation
Anabolism and Catabolism Are Not Mutually Exclusive 580 by Phosphofructokinase—The Second Priming
The Pathways of Catabolism Converge to a Few End Reaction 610
Products 581 Reaction 4: Cleavage by Fructose Bisphosphate
Anabolic Pathways Diverge, Synthesizing an Astounding Aldolase Creates Two 3-Carbon Intermediates 612
Variety of Biomolecules from a Limited Set of Building Reaction 5: Triose Phosphate Isomerase
Blocks 581 Completes the First Phase of Glycolysis 613
Amphibolic Intermediates Play Dual Roles 583 Human Biochemistry: Methylglyoxal and Advanced
Corresponding Pathways of Catabolism and Anabolism Glycation End-Products—The Dark Side of
Differ in Important Ways 583 Glycolysis 614
Metabolic Regulation Requires Different Pathways for 18.4 What Are the Chemical Principles and Features of the
Oppositely Directed Metabolic Sequences 583 Second Phase of Glycolysis? 615
ATP Is Produced and Consumed in a Cellular Energy eaction 6: Glyceraldehyde-3-Phosphate Dehydrogenase
R
Cycle 583 Creates a High-Energy Intermediate 615
NAD1 Collects Electrons Released in Catabolism 584 Reaction 7: Phosphoglycerate Kinase Is the Break-Even
NADPH Provides the Reducing Power for Anabolic Reaction 615
Processes 585 Reaction 8: Phosphoglycerate Mutase Catalyzes a
Coenzymes and Vitamins Provide Unique Chemistry and Phosphoryl Transfer 617
Essential Nutrients to Pathways 586 Reaction 9: Dehydration by Enolase Creates PEP 618
17.4 What Experiments Can Be Used to Elucidate Reaction 10: Pyruvate Kinase Yields More ATP 618
Metabolic Pathways? 587 Human Biochemistry: Pyruvate Kinase M2 Moonlights
nzyme Inhibitors Can Be Used to Reveal Individual
E as a Protein Kinase in Cancer 620
Metabolic Reactions 587

18.5 What Are the Metabolic Fates of NADH and Pyruvate 19.5 What Are the Energetic Consequences
Produced in Glycolysis? 621 of the TCA Cycle? 651
Anaerobic Metabolism of Pyruvate Leads to Lactate or he Carbon Atoms of Acetyl-CoA Have Different Fates in
T
Ethanol 621 the TCA Cycle 652
Lactate Accumulates Under Anaerobic Conditions in A Deeper Look: Steric Preferences in NAD1-Dependent
Animal Tissues 622 Dehydrogenases 654
Critical Developments in Biochemistry: The Warburg 19.6 Can the TCA Cycle Provide Intermediates
Effect and Cancer 623 for Biosynthesis? 654
18.6 How Do Cells Regulate Glycolysis? 624 Human Biochemistry: Leber’s Hereditary Optic
18.7 Are Substrates Other Than Glucose Neuropathy Arises from Mitochondrial DNA
Used in Glycolysis? 624 Mutations 655
ructose Catabolism in Liver Is Unregulated—
F 19.7 What Are the Anaplerotic, or Filling Up,
and Potentially Harmful 624 Reactions? 656
Mannose Enters Glycolysis in Two Steps 626 A Deeper Look: Anaplerosis Plays a Critical Role in
Galactose Enters Glycolysis via the Leloir Pathway 626 Insulin Secretion 657
Human Biochemistry: Tumor Diagnosis Using Positron A Deeper Look: Fool’s Gold and the Reductive Citric
Emission Tomography (PET) 626 Acid Cycle—The First Metabolic Pathway? 658
Glycerol Can Also Enter Glycolysis 628 19.8 How Is the TCA Cycle Regulated? 658
18.8 How Do Cells Respond to Hypoxic Stress? 628 yruvate Dehydrogenase Is Regulated
P
by Phosphorylation/Dephosphorylation 659
Human Biochemistry: Lactose and Lactose Intolerance:
From Mother’s Milk to Yogurt 629 Isocitrate Dehydrogenase Is Strongly Regulated 660
Foundational Biochemistry 631 Regulation of TCA Cycle Enzymes by Acetylation 660
Human Biochemistry: TCA Metabolites Play Roles in
Problems 631
Many Pathways via Post-Translational Modifications 661
Further Reading 633
Two Covalent Modifications Regulate E. coli Isocitrate
Dehydrogenase 661

19
TCA Metabolites Can Act as Cellular Signals 662
The TCA Cycle Operates as a Metabolon 662
19.9 Can Any Organisms Use Acetate as Their Sole Carbon
The Tricarboxylic Acid Cycle 635 Source? 662
he Glyoxylate Cycle Operates in Specialized
T
19.1 What Is the Chemical Logic of the TCA Cycle? 636
Organelles 663
19.2 How Is Pyruvate Oxidatively Decarboxylated Isocitrate Lyase Short-Circuits the TCA Cycle
to Acetyl-CoA? 639 by Producing Glyoxylate and Succinate 664
A Deeper Look: The Coenzymes of the Pyruvate The Glyoxylate Cycle Helps Plants Grow in the Dark 665
Dehydrogenase Complex 642
Glyoxysomes Must Borrow Three Reactions from
19.3 How Are Two CO2 Molecules Produced Mitochondria 665
from Acetyl-CoA? 644 Foundational Biochemistry 666
he Citrate Synthase Reaction Initiates the
T Problems 666
TCA Cycle 644
Further Reading 668
Citrate Is Isomerized by Aconitase to Form
Isocitrate 645
Isocitrate Dehydrogenase Catalyzes the First
Oxidative Decarboxylation in the Cycle 647
α-Ketoglutarate Dehydrogenase Catalyzes the Second
20
Oxidative Decarboxylation of the TCA Cycle 648 Electron Transport and Oxidative
19.4 How Is Oxaloacetate Regenerated to Complete Phosphorylation 671
the TCA Cycle? 648 20.1 Where in the Cell Do Electron Transport and Oxidative
uccinyl-CoA Synthetase Catalyzes Substrate-Level
S Phosphorylation Occur? 671
Phosphorylation 649 itochondrial Functions Are Localized in Specific
M
Succinate Dehydrogenase Is FAD-Dependent 650 Compartments 672
Fumarase Catalyzes the Trans-Hydration Human Biochemistry: Mitochondrial Dynamics in
of Fumarate to Form l-Malate 650 Human Diseases 673
Malate Dehydrogenase Completes the Cycle The Mitochondrial Matrix Contains the Enzymes of the
by Oxidizing Malate to Oxaloacetate 651 TCA Cycle 674

20.2 How Is the Electron-Transport Chain Organized? 674 20.7 How Do Mitochondria Mediate Apoptosis? 704
The Electron-Transport Chain Can Be Isolated in Four Cytochrome c Triggers Apoptosome Assembly 706
Complexes 675 Foundational Biochemistry 707
Complex I Oxidizes NADH and Reduces Coenzyme Q 676 Problems 707
Human Biochemistry: Solving a Medical Mystery
Further Reading 710
Revolutionized Our Treatment of Parkinson’s Disease 679

21
Complex II Oxidizes Succinate and Reduces Coenzyme
Q 680
Complex III Mediates Electron Transport from Coenzyme
Q to Cytochrome c 681
Complex IV Transfers Electrons from Cytochrome c Photosynthesis 713
to Reduce Oxygen on the Matrix Side 684 21.1 What Are the General Properties of
Proton Transport Across Cytochrome c Oxidase Photosynthesis? 714
Is Coupled to Oxygen Reduction 686 Photosynthesis Occurs in Membranes 714
Reversal of Complex II May Short-Circuit Photosynthesis Consists of Both Light Reactions
the Electron Transfer Pathway 687 and Dark Reactions 715
The Complexes of Electron Transport Water Is the Ultimate Electron Donor
May Function as Supercomplexes 687 for Photosynthetic NADP1 Reduction 716
Electron Transfer Energy Stored in a Proton
21.2 How Is Solar Energy Captured by Chlorophyll? 717
Gradient: The Mitchell Hypothesis 689
hlorophylls and Accessory Light-Harvesting Pigments
C
20.3 What Are the Thermodynamic Implications of Absorb Light of Different Wavelengths 717
Chemiosmotic Coupling? 690 The Light Energy Absorbed by Photosynthetic
20.4 How Does a Proton Gradient Drive Pigments Has Several Possible Fates 718
the Synthesis of ATP? 690 The Transduction of Light Energy into Chemical
ATP Synthase Is Composed of F1 and F0 Complexes 691 Energy Involves Oxidation–Reduction 719
he Catalytic Sites of ATP Synthase Adopt
T Photosynthetic Units Consist of Many Chlorophyll
Three Different Conformations 693 Molecules but Only a Single Reaction Center 720
Boyer’s 18O Exchange Experiment Identified the 21.3 What Kinds of Photosystems Are Used to Capture
Energy-Requiring Step 693 Light Energy? 721
The Binding Change Mechanism Describes hlorophyll Exists in Plant Membranes in Association
C
the Events of Rotational Catalysis 694 with Proteins 721
Proton Flow Through F0 Drives Rotation PSI and PSII Participate in the Overall Process of
of the Motor and Synthesis of ATP 694 Photosynthesis 721
How Many Protons Are Required to Make an ATP? The Pathway of Photosynthetic Electron Transfer Is Called
It Depends on the Organism 696 the Z Scheme 722
The Mitchell Model Has Been Confirmed Oxygen Evolution Requires the Accumulation of Four
in a Reconstitution Experiment 696 Oxidizing Equivalents in PSII 722
Inhibitors of Oxidative Phosphorylation Electrons Are Taken from H2O to Replace Electrons Lost
Reveal Insights About the Mechanism 697 from P680 724
Uncouplers Disrupt the Coupling of Electron Electrons from PSII Are Transferred to PSI via the
Transport and ATP Synthase 698 Cytochrome b6 f Complex 724
ATP–ADP Translocase Mediates the Movement of ATP Plastocyanin Transfers Electrons
and ADP Across the Mitochondrial Membrane 698 from the Cytochrome b6 f Complex to PSI 724
Human Biochemistry: Endogenous Uncouplers—Novel 21.4 What Is the Molecular Architecture of Photosynthetic
Proteins with Many Beneficial Effects 699
Reaction Centers? 725
20.5 What Is the P/O Ratio for Mitochondrial The R. viridis Photosynthetic Reaction Center Is an
Oxidative Phosphorylation? 700 Integral Membrane Protein 725
20.6 How Are the Electrons of Cytosolic NADH Photosynthetic Electron Transfer by the R. viridis
Fed into Electron Transport? 701 Reaction Center Leads to ATP Synthesis 726
Glycerophosphate Shuttle Ensures Efficient Use of
The The Molecular Architecture of PSII Resembles
Cytosolic NADH 701 the R. viridis Reaction Center Architecture 727
The Malate–Aspartate Shuttle Is Reversible 702 How Does PSII Generate O2 from H2O? 729
The Net Yield of ATP from Glucose Oxidation The Molecular Architecture of PSI Resembles the
Depends on the Shuttle Used 703 R. viridis Reaction Center and PSII Architecture 730
3.5 Billion Years of Evolution Have Resulted How Do Green Plants Carry Out Photosynthesis? 731
in a Very Efficient System 704

21.5 What Is the Quantum Yield of Photosynthesis? 731 Human Biochemistry: The Chemistry of Glucose
The H1/ATP Ratio Determines ATP Yield per Monitoring Devices 752
Quantum 732 Gluconeogenesis Is Not Merely the Reverse of
Calculation of the Photosynthetic Energy Requirements Glycolysis 753
for Hexose Synthesis Depends on H1/hy and ATP/H1 Gluconeogenesis—Something Borrowed, Something
Ratios 732 New 753
21.6 How Does Light Drive the Synthesis of ATP? 732 Four Enzyme Reactions Are Unique to
The Mechanism of Photophosphorylation Is Gluconeogenesis 755
Chemiosmotic 733 Human Biochemistry: Metformin—a Diabetes Drug
CF1CF0 –ATP Synthase Is the Chloroplast Equivalent with Multiple Actions 758
of the Mitochondrial F1F0 –ATP Synthase 733 22.2 How Is Gluconeogenesis Regulated? 759
Photophosphorylation Can Occur in Either Critical Developments in Biochemistry: The Pioneering
a Noncyclic or a Cyclic Mode 733 Studies of Carl and Gerty Cori 760
Cyclic Photophosphorylation Generates ATP but Not Gluconeogenesis Is Regulated by Allosteric and
NADPH or O2 734 Substrate-Level Control Mechanisms 760
21.7 How Is Carbon Dioxide Used to Make A Deeper Look: TIGAR—A p53-Induced Enzyme That
Organic Molecules? 735 Mimics Fructose-2,6-Bisphosphatase 762
ibulose-1,5-Bisphosphate Is the CO2 Acceptor in CO2
R Substrate Cycles Provide Metabolic Control
Fixation 736 Mechanisms 763
2-Carboxy-3-Keto-Arabinitol Is an Intermediate 22.3 How Are Glycogen and Starch Catabolized in
in the Ribulose-1,5-Bisphosphate Carboxylase Animals? 764
Reaction 736 Dietary Starch Breakdown Provides Metabolic Energy 764
Ribulose-1,5-Bisphosphate Carboxylase Exists in Metabolism of Tissue Glycogen Is Regulated 765
Inactive and Active Forms 737
22.4 How Is Glycogen Synthesized? 766
CO2 Fixation into Carbohydrate Proceeds
lucose Units Are Activated for Transfer by Formation of
G
via the Calvin–Benson Cycle 737
Sugar Nucleotides 766
Rubisco and the Enzymes of the Calvin Cycle
UDP–Glucose Synthesis Is Driven by Pyrophosphate
Serve Three Metabolic Purposes 738
Hydrolysis 766
The Calvin Cycle Reactions Can Account for Net Hexose
Glycogen Synthase Catalyzes Formation of α(18n4)
Synthesis 740
Glycosidic Bonds in Glycogen 767
The Carbon Dioxide Fixation Pathway Is Indirectly
Glycogen Branching Occurs by Transfer of Terminal
Activated by Light 740
Chain Segments 768
Protein–Protein Interactions Mediated by an Intrinsically
Unstructured Protein Also Regulate Calvin–Benson 22.5 How Is Glycogen Metabolism Controlled? 768
Cycle Activity 741 Glycogen Metabolism Is Highly Regulated 768
21.8 How Does Photorespiration Limit CO2 Fixation? 741 Human Biochemistry: Advanced Glycation End
Products—A Serious Complication of Diabetes 769
ropical Grasses Use the Hatch–Slack Pathway
T
to Capture Carbon Dioxide for CO2 Fixation 742 Glycogen Synthase Is Regulated by Covalent
Modification 770
Cacti and Other Desert Plants Capture CO2 at Night 744
Hormones Regulate Glycogen Synthesis and
Foundational Biochemistry 745
Degradation 772
Problems 746 Human Biochemistry: Carbohydrate Utilization in
Further Reading 747 Exercise 772
Critical Developments in Biochemistry: O-GlcNAc

22 22.6
Signaling and the Hexosamine Biosynthetic
Pathway 775
How Does Glucose Provide Electrons for
Gluconeogenesis, Glycogen Metabolism, and the Biosynthesis? 776
Pentose Phosphate Pathway 751 he Pentose Phosphate Pathway Operates Mainly in Liver
T
and Adipose Cells 776
22.1 What Is Gluconeogenesis, and How Does The Pentose Phosphate Pathway Begins with Two
It Operate? 752 Oxidative Steps 778
he Substrates for Gluconeogenesis Include Pyruvate,
T There Are Four Nonoxidative Reactions in the Pentose
Lactate, and Amino Acids 752 Phosphate Pathway 779
Nearly All Gluconeogenesis Occurs in the Liver and Human Biochemistry: Aldose Reductase and Diabetic
Kidneys in Animals 752 Cataract Formation 780

tilization of Glucose-6-P Depends on the Cell’s Need

U egradation of Polyunsaturated Fatty Acids Requires
D
for ATP, NADPH, and Ribose-5-P 783 2,4-Dienoyl-CoA Reductase 809
Critical Developments in Biochemistry: Integrating the A Deeper Look: Can Natural Antioxidants in Certain
Warburg Effect—ATP Consumption Promotes Cancer Foods Improve Fat Metabolism? 811
Metabolism 785 23.5 Are There Other Ways to Oxidize Fatty Acids? 811
Xylulose-5-Phosphate Is a Metabolic Regulator 786 Peroxisomal b-Oxidation Requires FAD-Dependent
Foundational Biochemistry 787 Acyl-CoA Oxidase 811
Problems 787 Branched-Chain Fatty Acids Are Degraded Via
Further Reading 789 a-Oxidation 812
v -Oxidation of Fatty Acids Yields Small Amounts of

23
Dicarboxylic Acids 813
23.6 What Are Ketone Bodies, and What Role Do They Play
in Metabolism? 813
Fatty Acid Catabolism 791 etone Bodies Are a Significant Source of Fuel and
K
Energy for Certain Tissues 813
23.1 How Are Fats Mobilized from Dietary Intake and
Human Biochemistry: Large Amounts of Ketone Bodies
Adipose Tissue? 791 Are Produced in Diabetes Mellitus 813
Modern Diets Are Often High in Fat 791 b-Hydroxybutyrate Is a Signaling Metabolite 815
Triacylglycerols Are a Major Form of Stored Energy in
Foundational Biochemistry 816
Animals 792
Problems 816
Hormones Trigger the Release of Fatty Acids from
Adipose Tissue 792 Further Reading 818
Degradation of Dietary Triacylglycerols Occurs Primarily
in the Duodenum 792
Human Biochemistry: Serum Albumin—Tramp Steamer
of the Bloodstream 795
24
A Deeper Look: The Biochemistry of Obesity 796 Lipid Biosynthesis 821
23.2 How Are Fatty Acids Broken Down? 797 24.1 How Are Fatty Acids Synthesized? 821
Coenzyme A Activates Fatty Acids for Degradation 798 Formation of Malonyl-CoA Activates Acetate Units for
Carnitine Carries Fatty Acyl Groups Across the Inner Fatty Acid Synthesis 822
Mitochondrial Membrane 799 Fatty Acid Biosynthesis Depends on the Reductive Power
b-Oxidation Involves a Repeated Sequence of Four of NADPH 822
Reactions 800 Cells Must Provide Cytosolic Acetyl-CoA and Reducing
Repetition of the b-Oxidation Cycle Yields a Succession Power for Fatty Acid Synthesis 822
of Acetate Units 803 Acetate Units Are Committed to Fatty Acid Synthesis by
Human Biochemistry: Exercise Can Reverse the Formation of Malonyl-CoA 824
Consequences of Metabolic Syndrome 804 Acetyl-CoA Carboxylase Is Biotin Dependent and Displays
Complete b-Oxidation of One Palmitic Acid Yields 113.7 Ping-Pong Kinetics 824
Molecules of ATP 805 Acetyl-CoA Carboxylase in Animals Is a Multifunctional
Migratory Birds Travel Long Distances on Energy from Protein 824
Fatty Acid Oxidation 805 Phosphorylation of ACC Modulates Activation by Citrate
Fatty Acid Oxidation Is an Important Source of Metabolic and Inhibition by Palmitoyl-CoA 826
Water for Some Animals 806 Acyl Carrier Proteins Carry the Intermediates in Fatty Acid
23.3 How Are Odd-Carbon Fatty Acids Oxidized? 807 Synthesis 826
-Oxidation of Odd-Carbon Fatty Acids Yields
b In Some Organisms, Fatty Acid Synthesis Takes Place in
Propionyl-CoA 807 Multienzyme Complexes 827
A B12-Catalyzed Rearrangement Yields Succinyl-CoA from Decarboxylation Drives the Condensation of Acetyl-CoA
l-Methylmalonyl-CoA 808 and Malonyl-CoA 827
Net Oxidation of Succinyl-CoA Requires Conversion to Reduction of the b-Carbonyl Group Follows a
Acetyl-CoA 808 Now-Familiar Route 829
A Deeper Look: The Activation of Vitamin B12 808 Eukaryotes Build Fatty Acids on Megasynthase
Complexes 830
23.4 How Are Unsaturated Fatty Acids Oxidized? 809
C16 Fatty Acids May Undergo Elongation and
n Isomerase and a Reductase Facilitate the b-Oxidation
A
Unsaturation 832
of Unsaturated Fatty Acids 809

Unsaturation Reactions Occur in Eukaryotes in the 24.5 How Are Lipids Transported Throughout the Body? 856
Middle of an Aliphatic Chain 833 Lipoprotein Complexes Transport Triacylglycerols and
The Unsaturation Reaction May Be Followed by Chain Cholesterol Esters 856
Elongation 834 Human Biochemistry: APOC3—An Apolipoprotein That
Mammals Cannot Synthesize Most Polyunsaturated Fatty Regulates Plasma Triglyceride Levels 857
Acids 834 Lipoproteins in Circulation Are Progressively Degraded by
Arachidonic Acid Is Synthesized from Linoleic Acid by Lipoprotein Lipase 857
Mammals 834 The Structure of the LDL Receptor Involves Five
Regulatory Control of Fatty Acid Metabolism Is an Domains 859
Interplay of Allosteric Modifiers and Defects in Lipoprotein Metabolism Can Lead to Elevated
Phosphorylation–Dephosphorylation Cycles 835 Serum Cholesterol 860
Hormonal Signals Regulate ACC and Fatty Acid Human Biochemistry: New Cholesterol-Lowering Drugs
Biosynthesis 835 Target PCSK9, an LDL Receptor Chaperone 861
Human Biochemistry: v3 and v6—Essential Fatty Acids 24.6 How Are Bile Acids Biosynthesized? 861
with Many Functions 836
Human Biochemistry: Niemann—Pick Type C
24.2 How Are Complex Lipids Synthesized? 837 Disease—A Hydrophobic Handoff Fumbled 862
Glycerolipids Are Synthesized by Phosphorylation and Human Biochemistry: Steroid 5α-Reductase—A Factor
Acylation of Glycerol 838 in Male Baldness, Prostatic Hyperplasia, and Prostate
Eukaryotes Synthesize Glycerolipids from Cancer 863
CDP-Diacylglycerol or Diacylglycerol 838 24.7 How Are Steroid Hormones Synthesized and
Human Biochemistry: Lipins—Phosphatases Essential Utilized? 864
for Triglyceride Synthesis and Other Functions 838
Pregnenolone and Progesterone Are the Precursors of All
Phosphatidylethanolamine Is Synthesized from Other Steroid Hormones 864
Diacylglycerol and CDP-Ethanolamine 841
Cortisol and Other Corticosteroids Regulate a Variety of
Exchange of Ethanolamine for Serine Converts Body Processes 864
Phosphatidylethanolamine to Phosphatidylserine 841
Foundational Biochemistry 866
Eukaryotes Synthesize Other Phospholipids Via
CDP-Diacylglycerol 841 Problems 866
Dihydroxyacetone Phosphate Is a Precursor to the Further Reading 868
Plasmalogens 843
Platelet-Activating Factor Is Formed by Acetylation of
1-Alkyl-2-Lysophosphatidylcholine 844
Sphingolipid Biosynthesis Begins with Condensation
25
of Serine and Palmitoyl-CoA 844 Nitrogen Acquisition and Amino Acid
Ceramide Is the Precursor for Other Sphingolipids and Metabolism 871
Cerebrosides 844
25.1 Which Metabolic Pathways Allow Organisms to Live
24.3 How Are Eicosanoids Synthesized, and What Are
on Inorganic Forms of Nitrogen? 871
Their Functions? 847
itrogen Is Cycled between Organisms and the
N
Eicosanoids Are Local Hormones 847
Inanimate Environment 872
Prostaglandins Are Formed from Arachidonate by
Nitrate Assimilation Is the Principal Pathway for
Oxidation and Cyclization 847
Ammonium Biosynthesis 872
A Variety of Stimuli Trigger Arachidonate Release and
Organisms Gain Access to Atmospheric N2 via the
Eicosanoid Synthesis 847
Pathway of Nitrogen Fixation 874
A Deeper Look: The Molecular Basis for the Action of
Nonsteroidal Anti-inflammatory Drugs 849 25.2 What Is the Metabolic Fate of Ammonium? 877
he Citric Acid Cycle Intermediate α-Ketoglutarate Is
T
24.4 How Is Cholesterol Synthesized? 851
Precursor to Both Glutamate and Glutamine 877
Mevalonate Is Synthesized from Acetyl-CoA Via
The Major Pathways of Ammonium Assimilation Lead to
HMG-CoA Synthase 851
Glutamine Synthesis 879
Why Can’t Thiolase Be Used in Fatty Acid Synthesis? 851
25.3 What Regulatory Mechanisms Act on Escherichia coli
Squalene Is Synthesized from Mevalonate 852
Glutamine Synthetase? 880
Human Biochemistry: Statins Lower Serum Cholesterol
Glutamine Synthetase Is Allosterically Regulated 880
Levels 854
Glutamine Synthetase Is Regulated by Covalent
Conversion of Lanosterol to Cholesterol Requires 20
Modification 882
Additional Steps 856

Glutamine Synthetase Is Regulated through Gene Human Biochemistry: Folate Analogs as Antimicrobial
Expression 882 and Anticancer Agents 928
Glutamine in the Human Body 883 AMP and GMP Are Synthesized from IMP 928
25.4 How Do Organisms Synthesize Amino Acids? 884 The Purine Biosynthetic Pathway Is Regulated at Several
Human Biochemistry: Human Dietary Requirements for Steps 929
Amino Acids 885 ATP-Dependent Kinases Form Nucleoside Diphosphates
Amino Acids Are Formed from α-Keto Acids by and Triphosphates from the Nucleoside
Transamination 886 Monophosphates 930
A Deeper Look: The Mechanism of the 26.3 Can Cells Salvage Purines? 931
Aminotransferase (Transamination) Reaction 886 26.4 How Are Purines Degraded? 931
The α-Ketoglutarate Family of Amino Acids Includes Glu, Human Biochemistry: Lesch–Nyhan Syndrome—
Gln, Pro, Arg, and Lys 887 HGPRT Deficiency Leads to a Severe Clinical
The Urea Cycle Acts to Excrete Excess N through Arg Disorder 932
Breakdown 889 The Major Pathways of Purine Catabolism Lead to Uric
A Deeper Look: The Urea Cycle as Both an Ammonium Acid 932
and a Bicarbonate Disposal Mechanism 891 Human Biochemistry: Severe Combined
The Oxaloacetate Family of Amino Acids Includes Asp, Immunodeficiency Syndrome—A Lack of Adenosine
Asn, Lys, Met, Thr, and Ile 893 Deaminase Is One Cause of This Inherited Disease 933
The Pyruvate Family of Amino Acids Includes Ala, Val, The Purine Nucleoside Cycle in Skeletal Muscle Serves as
and Leu 897 an Anaplerotic Pathway 933
The 3-Phosphoglycerate Family of Amino Acids Includes Xanthine Oxidase 933
Ser, Gly, and Cys 897 Gout Is a Disease Caused by an Excess of Uric Acid 934
The Aromatic Amino Acids Are Synthesized from Different Animals Oxidize Uric Acid to Form Various
Chorismate 902 Excretory Products 935
A Deeper Look: Amino Acid Biosynthesis Inhibitors as 26.5 How Do Cells Synthesize Pyrimidines? 935
Herbicides 906
he Pyrimidine Biosynthetic Pathway from Carbamoyl-P
T
Histidine Biosynthesis and Purine Biosynthesis Are and Aspartate to UMP 936
Connected by Common Intermediates 907
UMP Synthesis Leads to Formation of the Two Most
25.5 How Does Amino Acid Catabolism Lead into Prominent Ribonucleotides—UTP and CTP 936
Pathways of Energy Production? 909 P yrimidine Biosynthesis Is Regulated at ATCase in
he 20 Common Amino Acids Are Degraded by 20
T Bacteria and at CPS-II in Animals 938
Different Pathways That Converge to Just 7 Metabolic “Metabolic Channeling” by Multifunctional Enzymes of
Intermediates 909 Mammalian Pyrimidine Biosynthesis 939
Human Biochemistry: Amino Acid Metabolism and
26.6 How Are Pyrimidines Degraded? 939
Cancer 916
Animals Differ in the Form of Nitrogen That They 26.7 How Do Cells Form the Deoxyribonucleotides
Excrete 916 That Are Necessary for DNA Synthesis? 940
Human Biochemistry: Hereditary Defects in . coli Ribonucleotide Reductase Has Three Different
E
Phe Catabolism Underlie Alkaptonuria and Nucleotide-Binding Sites 940
Phenylketonuria 916 Thioredoxin Provides the Reducing Power for
Foundational Biochemistry 917 Ribonucleotide Reductase 941
Both the Specificity and the Catalytic Activity of
Problems 918
Ribonucleotide Reductase Are Regulated by Nucleotide
Further Reading 919 Binding 942

26
26.8 How Are Thymine Nucleotides Synthesized? 943
Human Biochemistry: Fluoro-Substituted Pyrimidines
in Cancer Chemotherapy, Fungal Infections, and
Malaria 944
Synthesis and Degradation of Nucleotides 921 A Deeper Look: Fluoro-Substituted Analogs Are Good
26.1 How Do Cells Synthesize Nucleotides? 921 Trojan Horse Inhibitors 945

26.2 How Do Cells Synthesize Purines? 922 Foundational Biochemistry 945

IMP Is the Immediate Precursor to GMP and AMP 922 Problems 946
A Deeper Look: Tetrahydrofolate and One-Carbon Further Reading 948
Units 924
Human Biochemistry: SAICAR Is a Key Signal for
Metabolic Reprogramming in Cancer Cells 926

27
MPK Mediates Many of the Hypothalamic
A
Responses to These Hormones 971
27.7 Can You Really Live Longer by Eating Less? 971
aloric Restriction Leads to Longevity 971
C
Metabolic Integration and Organ
Mutations in the SIR2 Gene Decrease Life Span 972
Specialization 951 SIRT1 Is a Key Regulator in Caloric Restriction 973
27.1 Can Systems Analysis Simplify the Complexity SIRT1, mTORC1, AMPK, CR, and Metabolic Syndrome 973
of Metabolism? 951 Foundational Biochemistry 974
nly a Few Intermediates Interconnect the Major
O
Problems 975
Metabolic Systems 953
ATP and NADPH Couple Anabolism and Catabolism 953 Further Reading 977
Phototrophs Have an Additional Metabolic Part IV Information Transfer 981
System—The Photochemical Apparatus 953

28
27.2 What Underlying Principle Relates ATP Coupling to the
Thermodynamics of Metabolism? 954
The Three Types of Stoichiometries in Cells 954
ATP Coupling Stoichiometry Determines DNA Metabolism: Replication, Recombination,
the Keq for Metabolic Sequences 955
ATP Has Two Metabolic Roles 956
and Repair 981
DNA Metabolism 981
27.3 Is There a Good Index of Cellular Energy Status? 956
denylate Kinase Interconverts ATP, ADP, and AMP 956
A 28.1 How Is DNA Replicated? 982
Energy Charge Relates the ATP Levels to the Total NA Replication Is Bidirectional 982
D
Adenine Nucleotide Pool 956 Replication Requires Unwinding of the DNA Helix 982
Key Enzymes Are Regulated by Energy Charge 957 DNA Replication Is Semidiscontinuous 983
Phosphorylation Potential Is a Measure of Relative ATP The Biochemical Evidence for Semidiscontinuous DNA
Levels 957 Replication 984
27.4 How Is Overall Energy Balance Regulated in Cells? 957 Initiation of DNA Replication 985
The Structure and Regulation of AMPK 958 28.2 What Are the Functions of DNA Polymerases? 985
AMPK Targets Key Enzymes in Energy Production and iochemical Characterization of DNA Polymerases 985
B
Consumption 959 E. coli Cells Have Several Different DNA Polymerases 986
AMPK Controls Whole-Body Energy Homeostasis 959 E. coli DNA Polymerase III Holoenzyme Replicates the E. coli
AMPK Inhibits mTORC1, the Master Growth Regulator Chromosome 986
of Eukaryotic Cells 959 A DNA Polymerase III Holoenzyme Sits at Each
27.5 How Is Metabolism Integrated in a Multicellular Replication Fork 988
Organism? 962 DNA Polymerase I Removes the RNA Primers and
The Brain Accounts for 20% of the Body’s Oxygen Fills in the Gaps 989
Consumption 963 DNA Polymerase I Also Plays a Role in DNA Double-
Muscle Metabolism Is Fueled by Glucose and Free Fatty Strand Break Repair 989
Acids 963 DNA Ligase Seals the Nicks Between Okazaki
Human Biochemistry: Athletic Performance Enhancement Fragments 990
with Creatine Supplements? 965 DNA Polymerase Is Its Own Proofreader 990
The Heart Prefers Fatty Acids as Fuel 966 DNA Replication Terminates at the Ter Region 990
Adipose Tissue Is Hormonally Active 966 A Deeper Look: A Mechanism for All Polymerases 990
Human Biochemistry: Fat-Free Mice—A Model for DNA Polymerases Are Immobilized in Replication
Diabetes 966 Factories 991
The Liver Is the Body’s Metabolic Processing Center 967 28.3 Why Are There So Many DNA Polymerases? 991
Human Biochemistry: The Metabolic Effects of Alcohol ells Have Different Versions of DNA Polymerase, Each for
C
Consumption 968 a Particular Purpose 991
27.6 What Regulates Our Eating Behavior? 968 The Common Architecture of DNA Polymerases 991
he Hormones That Control Eating Behavior
T 28.4 How Is DNA Replicated in Eukaryotic Cells? 992
Come from Many Different Tissues 969 he Cell Cycle Controls the Timing of DNA Replication 992
T
Ghrelin and Cholecystokinin Are Short-Term Proteins of the Prereplication Complex Are AAA1 ATPase
Regulators of Eating Behavior 970 Family Members 995
Insulin and Leptin Are Long-Term Regulators of Eating Geminin Provides Another Control Over Replication
Behavior 970 Initiation 995

ukaryotic Cells Also Contain a Number of Different DNA

E NA Rearrangements Assemble an H-Chain Gene by
D
Polymerases 995 Combining Four Separate Genes 1021
28.5 How Are the Ends of Chromosomes Replicated? 996 V–J and V–D–J Joining in Light- and Heavy-Chain Gene
Assembly Is Mediated by the RAG Proteins 1022
28.6 How Are RNA Genomes Replicated? 996
Imprecise Joining of Immunoglobulin Genes Creates New
A Deeper Look: RNA as Genetic Material 998
Coding Arrangements 1025
The Enzymatic Activities of Reverse Transcriptases 998
Antibody Diversity Is Due to Immunoglobulin Gene
28.7 How Is the Genetic Information Rearranged Rearrangements 1025
by Genetic Recombination? 999 Foundational Biochemistry 1026
eneral Recombination Requires Breakage and Reunion
G Problems 1027
of DNA Strands 999
Further Reading 1028
Homologous Recombination Proceeds According to the
Holliday Model 1000
The Enzymes of General Recombination Include RecA,
RecBCD, RuvA, RuvB, and RuvC 1000
The RecBCD Enzyme Complex Unwinds dsDNA and
29
Cleaves Its Single Strands 1002 Transcription and the Regulation of Gene
The RecA Protein Can Bind ssDNA and Then Interact with Expression 1033
Duplex DNA 1002
29.1 How Are Genes Transcribed in Bacteria? 1033
RuvA, RuvB, and RuvC Proteins Resolve the Holliday
A Deeper Look: Conventions Used in Expressing the
Junction to Form the Recombination Products 1004
Sequences of Nucleic Acids and Proteins 1034
The Three Rs of Genomic Manipulation: Replication,
Bacterial RNA Polymerases Use Their Sigma Subunits to
Recombination, and Repair 1005
Identify Sites Where Transcription Begins 1034
A Deeper Look: Knockout Mice: A Method to Investigate
The Process of Transcription Has Four Stages 1034
the Biological Role of a Gene 1006
A Deeper Look: DNA Footprinting—Identifying
Homologous Recombination in Eukaryotes Helps to
the Nucleotide Sequence in DNA Where a Protein
Prevent Cancer 1007
Binds 1037
Transposons Are DNA Sequences That Can Move from
Place to Place in the Genome 1007 29.2 How Is Transcription Regulated in Bacteria? 1041
Human Biochemistry: The Breast Cancer Susceptibility ranscription of Operons Is Controlled by
T
Genes BRCA1 and BRCA2 Are Involved in DNA Damage Induction and Repression 1041
Control and DNA Repair 1008 The lac Operon Is a Paradigm of Operons 1042
28.8 Can DNA Be Repaired? 1008 lac Repressor Is a Negative Regulator of the lac
Operon 1043
ouble-Strand DNA Breaks 1009
D
C AP Is a Positive Regulator of the lac Operon 1044
Mismatch Repair Corrects Errors Introduced During DNA
Replication 1012 A Deeper Look: Quantitative Evaluation of lac
Repressor;DNA Interactions 1045
Damage to DNA by UV Light or Chemical Modification
Can Also Be Repaired 1012 Negative and Positive Control Systems
Are Fundamentally Different 1046
A Deeper Look: Transgenic Animals Are Animals
Carrying Foreign Genes 1013 The araBAD Operon Is Both Positively
and Negatively Controlled by AraC 1046
28.9 What Is the Molecular Basis of Mutation? 1014
The trp Operon Is Regulated Through a Co-Repressor–
oint Mutations Arise by Inappropriate Base-Pairing 1015
P Mediated Negative Control Circuit 1048
Mutations Can Be Induced by Base Analogs 1016 Attenuation Is a Prokaryotic Mechanism for Post-
Chemical Mutagens React with the Bases in DNA 1016 Transcriptional Regulation of Gene Expression 1049
Insertions and Deletions 1016 DNA: Protein Interactions and Protein;Protein
28.10 Can Genetic Recombination Create Interactions Are Essential to Transcription
Protein Diversity? 1018 Regulation 1050
ells Active in the Immune Response Are Capable of
C Proteins That Activate Transcription Work Through
Gene Rearrangement 1018 Protein;Protein Contacts with RNA Polymerase 1050
Immunoglobulin G Molecules Contain Regions DNA Looping Allows Multiple DNA-Binding
of Variable Amino Acid Sequence 1018 Proteins to Interact with One Another 1051
The Immunoglobulin Genes Undergo Gene 29.3 How Are Genes Transcribed in Eukaryotes? 1052
Rearrangement 1019 ukaryotes Have Three Classes of RNA Polymerases 1053
E
DNA Rearrangements Assemble an L-Chain Gene by RNA Polymerase II Transcribes Protein-Coding
Combining Three Separate Genes 1021 Genes 1053

he Regulation of Gene Expression Is More Complex in

T 29.6 Can Gene Expression Be Regulated Once the
Eukaryotes 1055 Transcript Has Been Synthesized? 1077
Gene Regulatory Sequences in Eukaryotes Include iRNAs Are Key Regulators in Post-Transcriptional Gene
m
Promoters, Enhancers, Insulators, and Silencers 1055 Regulation 1077
Transcription Initiation by RNA Polymerase II Requires Targeted RNA Degradation by Exosomes 1079
TBP and the GTFs 1057
29.7 Can We Propose a Unified Theory of Gene
The Role of Mediator in Transcription Activation and Expression? 1080
Repression 1058
Foundational Biochemistry 1081
Mediator as a Repressor of Transcription 1060
Problems 1082
Chromatin-Remodeling Complexes and Histone-
Modifying Enzymes Alleviate the Repression Due to Further Reading 1084
Nucleosomes 1060
Chromatin-Remodeling Complexes Are Nucleic
Acid–Stimulated Multisubunit ATPases 1061
Covalent Modification of Histones 1061
30
Covalent Modification of Histones Suggests Protein Synthesis 1089
the Existence of a Histone Code 1062
30.1 What Is the Genetic Code? 1090
Methylation and Phosphorylation Act as a Binary
The Genetic Code Is a Triplet Code 1090
Switch that Regulates Chromatin Dynamics 1062
Codons Specify Amino Acids 1090
Chromatin Deacetylation Leads to Transcription
A Deeper Look: Natural and Unnatural Variations in the
Repression 1063
Standard Genetic Code 1092
Nucleosome Alteration and Interaction of RNA
Polymerase II with the Promoter Are Essential Features in 30.2 How Is an Amino Acid Matched
Eukaryotic Gene Activation 1063 with Its Proper tRNA? 1092
29.4 How Do Gene Regulatory Proteins Recognize Specific minoacyl-tRNA Synthetases Interpret the Second
A
Genetic Code 1093
DNA Sequences? 1064
Evolution Has Provided Two Distinct Classes of
Human Biochemistry: Storage of Long-Term Memory
Aminoacyl-tRNA Synthetases 1093
Depends on Gene Expression Activated by
CREB-Type Transcription Factors 1065 Aminoacyl-tRNA Synthetases Can Discriminate Between
the Various tRNAs 1095
a-Helices Fit Snugly into the Major Groove of
B-DNA 1065 Escherichia coli Glutaminyl-tRNAGln Synthetase
Recognizes Specific Sites on tRNAGln 1096
Proteins with the Helix-Turn-Helix Motif Use One Helix
to Recognize DNA 1065 The Identity Elements Recognized by Some Aminoacyl-
tRNA Synthetases Reside in the Anticodon 1097
Some Proteins Bind to DNA via Zn-Finger Motifs 1066
A Single G;U Base Pair Defines tRNA Alas 1097
Some DNA-Binding Proteins Use a Basic
Region-Leucine Zipper (bZIP) Motif 1067 30.3 What Are the Rules in Codon–Anticodon Pairing? 1098
29.5 How Are Eukaryotic Transcripts Processed and rancis Crick Proposed the Wobble Hypothesis for
F
Delivered to the Ribosomes for Translation? 1068 Codon–Anticodon Pairing 1098
ukaryotic Genes Are Split Genes 1068
E Some Codons Are Used More Than Others 1098
The Organization of Exons and Introns in Split Nonsense Suppression Occurs When Suppressor tRNAs
Genes Is Both Diverse and Conserved 1069 Read Nonsense Codons 1100
Post-Transcriptional Processing of Messenger RNA 30.4 What Is the Structure of Ribosomes,
Precursors Involves Capping, Methylation, and How Are They Assembled? 1100
Polyadenylylation, and Splicing 1069 rokaryotic Ribosomes Are Composed of 30S and 50S
P
Nuclear Pre-mRNA Splicing 1072 Subunits 1100
The Splicing Reaction Proceeds via Formation of a Lariat Ribosomes Spontaneously Self-Assemble In Vitro 1102
Intermediate 1072 Ribosomes Have a Characteristic Anatomy 1102
Splicing Depends on snRNPs 1073 The Cytosolic Ribosomes of Eukaryotes Are Larger Than
snRNPs Form the Spliceosome 1073 Prokaryotic Ribosomes 1103
Alternative RNA Splicing Creates Protein Isoforms 1074 30.5 What Are the Mechanics of mRNA Translation? 1104
A Deeper Look: Inteins—Bizarre Parasitic Genetic ranslation Can be Organized into Three Steps: Initiation,
T
Elements Encoding a Protein-Splicing Activity 1075 Elongation, and Termination 1104
RNA Editing: Another Mechanism That Increases Peptide Chain Initiation in Bacteria Requires a G-Protein
the Diversity of Genomic Information 1076 Family Member 1105

eptide Chain Elongation Requires Two G-Protein Family

P A Deeper Look: Chaperone Proteins That Function by
Members 1107 Stress-Induced Unfolding 1138
The Elongation Cycle 1107 A Deeper Look: Small Heat Shock Proteins: Nature’s
Aminoacyl-tRNA Binding and the Peptidyl Transferase Molecular Sponges 1140
Reaction 1108 31.2 How Are Proteins Processed Following
GTP Hydrolysis Fuels the Conformational Changes That Translation? 1141
Drive Ribosomal Functions 1112
31.3 How Do Protein Translocation Pathways Target Pro-
A Deeper Look: Molecular Mimicry—The Structures of teins to Subcellular Compartments? 1142
EF-Tu: Aminoacyl-tRNA, EF-G, and RF-3 1112
roteins Are Delivered to the Proper Cellular
P
Peptide Chain Termination Requires Yet Another Compartment by Translocation 1142
G-Protein Family Member 1113
The SecYEG Translocon Mediates Translocation of Newly
The Ribosomal Subunits Cycle Between 70S Complexes Synthesized Prokaryotic Proteins 1143
and a Pool of Free Subunits 1113
The Sec61 Translocon Mediates Translocation of Newly
A Deeper Look: Tethered Ribosomes Open New Synthesized Eukaryotic Proteins 1144
Possibilities in Synthetic Biology 1115
Human Biochemistry: Autophagy—How Cells Recycle
Polyribosomes Are the Active Structures of Protein Their Materials 1146
Synthesis 1116
31.4 How Does Protein Degradation Regulate Cellular
30.6 How Are Proteins Synthesized in Eukaryotic
Levels of Specific Proteins? 1147
Cells? 1116
ukaryotic Proteins Are Targeted for Proteasome
E
Peptide Chain Initiation in Eukaryotes 1116 Destruction by the Ubiquitin Pathway 1147
Control of Eukaryotic Peptide Chain Initiation Is One Proteins Targeted for Destruction Are Degraded by
Mechanism for Post-Transcriptional Regulation of Gene Proteasomes 1149
Expression 1118
Small Ubiquitin-like Protein Modifiers Are Post-
Peptide Chain Elongation in Eukaryotes Resembles the transcriptional Regulators 1151
Prokaryotic Process 1120
HtrA Proteases Also Function in Protein Quality
Human Biochemistry: Diphtheria Toxin ADP-Ribosylates Control 1153
eEF2 1120
Human Biochemistry: Proteasome Inhibitors in Cancer
Eukaryotic Peptide Chain Termination Requires eRF1, Chemotherapy 1154
eRF3, and GTP 1121
Protein Triage—A Model for Quality Control 1155
30.7 Do Protein Synthesis Inhibitors Have Clinical
Foundational Biochemistry 1155
Applications? 1121
Problems 1156
The Decoding Site Is a Target of Aminoglycoside
Antibiotics 1121 Further Reading 1157
Many Antibiotics Target the PTC and the Peptide Exit
Tunnel 1122
Eukaryotic-Specific Protein Synthesis Inhibitors 1124
Foundational Biochemistry 1124
32
Problems 1125 The Reception and Transmission of Extracellular
Further Reading 1127 Information 1161
32.1 What Are Hormones? 1163

31 teroid Hormones Act in the Nucleus or at the

S
Plasma Membrane 1163
Polypeptide Hormones Share Similarities
Completing the Protein Life Cycle: Folding, of Synthesis and Processing 1163

Processing, and Degradation 1131 32.2 What Is Signal Transduction? 1164

Many Signaling Pathways Involve Enzyme Cascades 1165
31.1 How Do Newly Synthesized Proteins Fold? 1132
Signaling Pathways Connect Membrane Interactions
Human Biochemistry: Neurodegenerative Disorders are
with Events in the Nucleus 1165
Caused by the Accumulation of Protein Deposits 1133
Signaling Pathways Depend on Multiple Molecular
Chaperones Help Some Proteins Fold 1134
Interactions 1165
Hsp70 Chaperones Bind to Hydrophobic Regions of
Extended Polypeptides 1134 32.3 How Do Signal-Transducing Receptors Respond
to the Hormonal Message? 1168
Hsp90 Partners With Hsp70 in Hsp70-Hsp90 Folding
Cascades 1136 he G-Protein–Coupled Receptors Are 7-TMS Integral
T
Membrane Proteins 1168
The GroES–GroEL Complex of E. coli Is an Hsp60
Chaperonin 1137 The Single TMS Receptors Are Guanylyl Cyclases
or Tyrosine Kinases 1170

RTKs and RGCs Are Membrane-Associated Allosteric G-Protein Signaling Is Modulated by RGS/GAPs 1192
Enzymes 1170 GPCR Desensitization Leads to New Signaling
The EGF Receptor Is Activated by Ligand-Induced Pathways 1192
Dimerization 1170 A Deeper Look: Whimsical Names for Proteins and
The Insulin Receptor Mediates Several Signaling Genes 1196
Pathways 1173 Receptor Responses Can Be Coordinated by
Receptor Guanylyl Cyclases Mediate Effects Transactivation 1196
of Natriuretic Hormones 1175 Signals from Multiple Pathways Can Be Integrated 1196
Nonreceptor Tyrosine Kinases Are Typified by 32.7 How Do Neurotransmission Pathways Control
pp60src 1177
the Function of Sensory Systems? 1198
A Deeper Look: Nitric Oxide, Nitroglycerin, and Alfred
Nerve Impulses Are Carried by Neurons 1198
Nobel 1178
Ion Gradients Are the Source of Electrical Potentials in
Soluble Guanylyl Cyclases Are Receptors for Nitric
Neurons 1198
Oxide 1179
Action Potentials Carry the Neural Message 1199
32.4 How Are Receptor Signals Transduced? 1179
The Action Potential Is Mediated by the Flow of Na1 and
GPCR Signals Are Transduced by G Proteins 1179 K1 Ions 1200
Cyclic AMP Is a Second Messenger 1180 Neurons Communicate at the Synapse 1201
Ras and Other Small GTP-Binding Proteins Are Communication at Cholinergic Synapses Depends upon
Proto-Oncogene Products 1181 Acetylcholine 1202
G Proteins Are Universal Signal Transducers 1182 There Are Two Classes of Acetylcholine Receptors 1202
Specific Phospholipases Release Second Amino Acids, Catecholamines, and Peptides Can Act as
Messengers 1183 Neurotransmitters within Synaptic Junctions 1204
Human Biochemistry: Cancer, Oncogenes, and Tumor Glutamate and Aspartate Are Excitatory Amino Acid
Suppressor Genes 1185 Neurotransmitters 1205
Lipids Such as Phosphatidylcholine, Sphingomyelin, A Deeper Look: Tetrodotoxin and Saxitoxin Are Na1
Glycosphingolipids, and Arachidonic Acid Also Generate Channel Toxins 1206
Second Messengers 1185
Human Biochemistry: Neurexins and Neuroligins—the
Calcium Is a Second Messenger 1186 Scaffolding of Learning and Memory 1207
Calmodulin Target Proteins Possess a Basic Amphiphilic g-Aminobutyric Acid and Glycine Are Inhibitory
Helix 1186 Neurotransmitters 1208
Human Biochemistry: PI Metabolism and the Human Biochemistry: The Biochemistry of Neurological
Pharmacology of Li1 1186 Disorders 1210
32.5 How Do Effectors Convert the Signals to Actions The Catecholamine Neurotransmitters Are Derived from
in the Cell? 1188 Tyrosine 1212
Protein Kinase A Is a Paradigm of Kinases 1188 Various Peptides Also Act as Neurotransmitters 1212
A Deeper Look: Mitogen-Activated Protein Kinases and Some Ion Channels Respond to Physical Stimuli Rather
Phosphorelay Systems 1189 Than Chemicals 1213
Protein Kinase C Is a Family of Isozymes 1189 Foundational Biochemistry 1214
Protein Tyrosine Kinase pp60 c-src Is Regulated Problems 1214
by Phosphorylation/Dephosphorylation 1190
Further Reading 1216
Protein Tyrosine Phosphatase SHP-2 Is a Nonreceptor
Tyrosine Phosphatase 1190 Abbreviated Answers to Problems A-1
32.6 How Are Signaling Pathways Organized and
Index I-1
Integrated? 1191
GPCRs Can Signal Through G-Protein–Independent
Pathways 1191

Chapter 1: Michelle Nguyen, Compliance and Integrity Officer at Nationwide Children’s Hospital 9
Chapter 2: Kilan C. Ashad-Bishop, Biomedical Scientist and Advocate at Sylvester Comprehensive Cancer Center 32
Chapter 3: (Chemistry in History) Satoshi Ōmura, 2015 Nobel Prize Winner in Physiology or Medicine for his studies on novel
therapies against infections caused by roundworm parasites 53
Chapter 4: Vanessa A. Nadal, Professor of Law at Fordham University and co-creator of first U.S. Cosmetics Regulation course 78
Chapter 5: Lilla Morton, Biochemistry Teacher at Zayed Private Academy 106
Chapter 6: (Chemistry in History) César Milstein, 1984 Novel Prize Winner for Physiology or Medicine for his studies on monoclonal
antibodies 147
Chapter 7: Dr. Shannon Timmons, Professor and Chair of the Natural Sciences Department at Lawrence Technological University 194
Chapter 8: (Chemistry in History) Alice Ball, creator of the “Ball Method” as a treatment for leprosy in the early 20th century 240
Chapter 9: Dr. Audie Thompson, Assistant Professor of Chemical Engineering at the University of Arkansas 267
Chapter 10: Phillip Nega, researcher in solid-state battery technology at A123 Systems 325
Chapter 11: Sabrina Farais, lab director with the Oklahoma Medical Marijuana Authority (OMMA) 348
Chapter 12: (Chemistry in History) Tu Youyou, 2015 Nobel Prize winner in Physiology or Medicine for her discoveries of novel therapies
against malaria 394
Chapter 13: (Chemistry in History) Maud Menten, co-creator of the Michaelis-Menten equation which relates the rate of an enzyme-
catalyzed reaction to the enzyme’s affinity for its substrate 434
Chapter 14: (Chemistry in History) Dr. John Cornforth, 1975 Nobel Prize Winner in Chemistry for his studies of the stereochemistry of
enzymes involved in cholesterol biosynthesis 483
Chapter 15: Dr. Cierra Smith, Manager of Diversity, Equity, and Inclusion (DEI) Programs for the American Society of Biochemistry and
Molecular Biology (ASBMB) 512
Chapter 16: Dr. Enrique M. De La Cruz, Professor and Chair of Molecular Biophysics and Biochemistry at Yale University 548
Chapter 17: (Chemistry in History) Dr. Marie Maynard Daly, responsible for the earliest research on the relationship between diet,
blood cholesterol, and heart health 580
Chapter 18: Neem J. Patel, Ph.D. candidate at the University of California studying soil recovery after forest fires. 606
Chapter 19: Rochelle Diamond, Manager of the Flow Cytometry/Cell Sorting Facility at the California Institute of Technology and
founder of Out to Innovate 637
Chapter 20: Dr. Vincent Wu, research scientist at Triplebar engineering fungi to produce bovine milk proteins 674
Chapter 21: (Chemistry in History) Dr. Emmett Chapelle, inventor of method for the detection of ATP used today for detection of
microbes in food and water 720
Chapter 22: Dr. Kayunta Johnson-Winters, Associate Professor at the University of Texas at Arlington with research focused on F420-
dependent enzymes. 753
Chapter 23: Dr. Katherine Scheibel, subject matter expert for Cengage Academic Publishing
Chapter 24: (Chemistry in History) Dr. Konard Emil Bloch, 1964 Nobel Prize winner in Physiology or Medicine for his studies of
cholesterol and fatty acid metabolism
Chapter 25: Dr. Squire J. Booker, Evan Push Professor of Chemistry, Biochemistry, and Molecular Biology as well as the Eberly
Distinguished Chair in Science at Pennsylvania State University 876
Chapter 26: Dr. Allison C. Augustus-Wallace, Associate Professor and Director of Undergraduate Academic Pathway Programs for
Diversity at LSU Health Sciences Center-New Orleans 927
Chapter 27: Dr. James M. Ntambi, Professor at the University of Wisconsin-Madison and winner of the American Society for
Biochemistry and Molecular Biology Award for Exemplary Contributions to Education

xxviii

Chapter 28: (Chemistry in History) Dr. Slayton A. Evans, Jr., First African-American Assistant Professor of Chemistry at University of
North Carolina-Chapel Hill and committee chair for the American Chemistry Society, the National Institutes of Health, and
the National Science Foundation 983
Chapter 29: Dr. Elsa Pao, Optometrist with her own private practice 1038
Chapter 30: Dr. Alison Brown, Program Director for the National Institutes of Health’s National Heart, Blood, and Lung Institute 1091
Chapter 31: Dr. Odutayo (Tayo) Odunuga, Professor of Biochemistry at Stephen F. Austin State University 1135
Chapter 32: Dr. Shantá D. Hinton, Associate Professor and Chair of Biology at the College of William and Mary 1164

*Magnotti, E., Moy, J., Sleppy, R., Carey, A., Firdyiwek, Y., Garrett, R. H., and Grisham,
C., 2019. ‘‘Developing and Implementing a Free Online Protein Structure and Function
Exploration Project to Teach Undergraduate Students Macromolecular Structure−Function
Relationships.’’ Journal of Chemical Education 96:729–733.

xxx

Recombinant DNA Techniques Fluxomics Section 17.5

Restriction endonuclease digestion of DNA Section 10.6d Tumor diagnosis with positron emission tomography (PET) Section 18.7
Restriction mapping Section 10.6e–f Glucose monitoring devices Section 22.1
DNA sequencing Section 11.1 Fluoro-substituted analogs as therapeutic agents Section 26.8
Nucleic acid hybridization Section 11.3 “Knockout” mice Section 28.7
Chemical synthesis of nucleic acids Section 11.6
Isolation/Purification of Macromolecules
Cloning; recombinant DNA constructions Section 12.1
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
PCR (polymerase chain reaction) Section 12.2d Size exclusion chromatography Section 5.2
mRNA isolation Section 12.2e SDS-polyacrylamide gel electrophoresis Section 5.2
Construction of cDNA libraries Section 12.2e Isoelectric focusing Section 5.2
Expressed sequence tags (ESTs) Section 12.2e Two-dimensional gel electrophoresis Section 5.2
Southern blotting Section 12.2d Hydrophobic interaction chromatography Section 5.2
Gene chips (DNA microarrays) Section 12.2f High-performance liquid chromatography Section 5.2
Protein expression from cDNA inserts Section 12.3 Affinity chromatography Section 5.2
Screening protein expression libraries with antibodies Section 12.3a Ultracentrifugation Section 5.2
Two-hybrid systems to identify protein-protein interactions Section 12.3c Fractionation of cell extracts by centrifugation Section 5.2
Reporter gene constructs Section 12.3b Proteomic analysis by multidimensional protein identification
RT-qPCR (real-time quantitative PCR) Section 12.3a technology Section 5.8b
In vitro mutagenesis Section 12.3d
ChIP-Seq (chromatin immunoprecipitation-DNA sequencing) Section 12.3c Analyzing the Physical and Chemical Properties
RNAi Section 12.4 of Biomolecules
Genome editing with CRISPR-Cas9 Section 12.5d Titration of weak acids Section 2.2b
Base editing with CRISPR-Cas9 Section 12.5e Preparation of buffers Section 2.3
Prime editing with CRISPR-Cas9 Section 12.5f Measurement of standard reduction potentials Section 3.6
Gene silencing with CRISPR-Cas9 Section 12.5g
Edman degradation Section 4.3
High-throughput screening Section 12.6
Nuclear magnetic resonance (NMR) Sections 4.5 and 6.4
BioBricks Section 12.7a
Estimation of protein concentration Section 5.2
CRISPR/Cas9 Section 12.5
Amino acid analysis Section 4.6
Probing the Function of Biomolecules Amino acid sequence determination Section 5.3
Green fluorescent protein Section 4.4 Mass spectrometry of proteins Section 5.3i
Plotting enzyme kinetic data Section 13.3j Solid-phase peptide synthesis Section 5.5
Enzyme inhibition Section 13.4 Cryo-Electron Microscopy Section 6.4
Isotopic tracers as molecular probes Section 17.4c Membrane lipid phase transitions Section 9.4b
RNAi Section 12.4 Nucleic acid hydrolysis Section 10.6
NMR spectroscopy Section 17.4d DNA sequencing Section 11.1
Transgenic animals Section 28.8 Single-molecule DNA sequencing Section 11.1e,f
DNA footprinting Section 29.1 Density gradient (isopycnic) centrifugation Section 11.3
Techniques Relevant to Clinical Biochemistry
Human gene therapy Section 12.5
Metabolomic analysis Section 17.5 xxxi

Biochemistry
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 devel-
opment 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, 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 seventh edition of Biochemistry embodies and reflects
the expanse of this knowledge. 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 sci-
ences 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 sys-
tems with the character of their constituent molecules. As a consequence, these general-
izations, validated by numerous 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 bio-
chemical 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 spent his career in a biology department, and
the other 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
appreciation and understanding for all students.

xxxii

Our Audience
This biochemistry textbook is designed to communicate the fundamental principles
upon which all life is based to students encountering biochemistry for the first time. We
aim to bring an appreciation of biochemistry to a broad audience that includes under-
graduates majoring in the life sciences, physical sciences, or premedical programs as well
as medical students and graduate students in the various health sciences for whom bio-
chemistry is an important route to understanding human physiology. To make this sub-
ject matter more relevant and interesting 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.

New Features
New Textbook Features
●● Think-Pair-Share Problems in every chapter encourage students to work collabora-
tively to further their understanding of biochemistry concepts.
●● Careers in Chemistry showcase various career paths that students can take after study-
ing biochemistry. By seeing a diverse, inclusive, and equitable chemical community, all
students know that they have a future in chemistry-related careers.
●● Over 160 New and Revised Exercises were added to the book and online course to
keep the content current.
●● Step-by-Step Solutions were added to examples to help students master the approach
to complicated problems.
●● Recent Developments in Biochemistry: A number of Deeper Look and Critical Develop-
ments in Biochemistry boxes were added to address the latest developments in biochem-
istry such as the human proteome, NMR and Cryo-EM, AlfaFold, and CRISPR-Cas9.

New to the Online Course and Resources

●● MCAT Essays and Practice Problems accompanied by detailed answer explanations,
written by members of medical school admissions and advisors, have been added to
the online course in OWLv2 to prepare students for the biochemistry section of the
MCAT exam.
●● Hints and Targeted Feedback. Over fifty percent of problems in OWLv2 now come
with targeted feedback on common errors that students make. The targeted feed-
back explains why the student's answer is incorrect and guides them toward a correct
solution.
●● Laddered Assessments. Conceptual mastery modules are combined with more tradi-
tional homework questions into one structured learning path, organized by topic at
the chapter level.
●● Over 300 New Problems were added to the online course.
●● PSAFE: Protein Structure and Function Exploration Project. Students research a protein
and use protein-modeling software to practice biochemistry actively in this research
and writing semester-long project.
●● Protein Structure and Function Exploration Library of Proteins and Nucleic Acids is an
online resource ([Link] of over 1300 protein and nucleic acid
animations and interactive views, sorted by proteins and chapters in this textbook.

New to this Edition

Chapter 3 A new Deeper Look box called “Why Nature Chose Phosphates.”
Chapter 4 A new Deeper Look box called “Why Nature Chose Selenium,” and a revised
Critical Developments in Biochemistry box on the incorporation of unnatural amino
acids into proteins.
Chapter 5 A new exercise on determining amino-acid sequence from mass spectrometry
data. Efforts to describe the human proteome are introduced in a new Deeper Look box:
“The Human Proteome Project and the Human Protein Atlas.”
Chapter 6 A new Critical Developments in Biochemistry box on the X-ray crystallography
of proteins and a revised Deeper Look feature on metamorphic proteins, which exist as
an ensemble of structures of similar energies and stabilities. New Critical Developments
in Biochemistry boxes on the Protein Data Bank (PDB) and “NMR and Cryo-EM —
Revolutionary Methods that Probe Protein Structure and Dynamics” (including
cryo-EM structure of the 2P spike protein mutant related to development of COVID-
19 vaccines). New coverage of AlphaFold, artificial intelligence software that accurately
predicts the three-dimensional structures of proteins based solely on their amino acid
sequences.
Chapter 8 A new Human Biochemistry box on the development of vaccines for
COVID-19 that employ lipid nanoparticles and make RNA vaccines practical and
effective.
Chapter 9 New coverage of monotopic, bitopic, and polytopic membrane proteins and
a section called “Dynamic Exchange of Lipids and Proteins with Membrane Domains.”
Chapter 10 An updated introduction to the many roles of small RNAs in the regulation
of gene expression: miRNAs and the long, noncoding RNAs (lincRNAs).
Chapter 11 Completion of the complete nucleotide sequence determination for the human
genome in 2022. Focus on the rapidly growing science of bioinformatics: the study of the
nature and organization of biological information, including functional genomics and
proteomics. New principles emerging about the higher order structural organization of
chromosomes, chromosome territories, and chromosome dynamics. Synthetic chromo-
somes, DNA as a data storage medium.
Chapter 12 Genome engineering with CRISPR-Cas9, CRISPR-Cas9 in gene-editing and
base-editing. A new section on human gene therapy, rewriting the human genome.
Chapter 14 A new Critical Developments in Biochemistry box on Nobel laureate Frances
Arnold and her pioneering work on the directed evolution of enzymes.
Chapter 17 Metabolites at the center of life, metabolomics as the driver of all the
other –omics.
Chapter 18 The newly-discovered protein kinase activity of protein kinase M2 (PK M2),
its stimulation by SAICAR (an intermediate in the purine biosynthetic pathway), and its
role in tumor proliferation.
Chapter 20 The new molecular structures of the supercomplexes that carry out electron
transport and oxidative phosphorylation, including the new structure of Complex I and
insights regarding its mechanism of action.
Chapter 22 A new Human Biochemistry box called “Metformin — A Diabetes Drug
with Multiple Actions,” and a Critical Developments in Biochemistry feature describing
how the consumption of ATP promotes and supports the metabolism of cancer cells.
Chapter 25 Synthesis of cysteine in humans by a reverse transsulfurylation pathway.
A new Human Biochemistry box on amino acid metabolism and cancer.
Chapter 26 Figure describing the purinosome metabolon that synthesizes purines on a
PRPP platform.

Chapter 27 New molecular graphic of mTORC1, the master integrator of information

about nutrient status and a global regulator of biosynthesis. A new section on AMPK
inhibition of mTORC1 through reversible phosphorylation. A new section on SIRT1,
mTORC1, AMPK, caloric restriction, and metabolic syndrome.
Chapter 28 New discussion and figure illustrating that DNA polymerases are immo-
bilized within replication factories. New figure showing the structural organization of
eukaryotic DNA replicons.
Chapter 29 Updated discussion of eukaryotic gene regulatory sequences such as promot-
ers, enhancers, insulators, and silencers.
Chapter 30 Pyrrolysine as the twenty-second amino acid. New art illustrating the richly
detailed events in eukaryotic translation initiation.
Chapter 31 New structures of the SecY channel and the SecA ATPase, and cryo-EM
structures of co-translational and post-translational states of the Sec61 translocon com-
plex. New cryo-EM structures of a cullin-RING-UBE2D ubiquitin ligation assembly.
Chapter 32 New cryo-EM structure of the neurotensin receptor-arrestin2 complex. New
section on ion channels that respond to physical stimuli (including temperature, voltage,
pH, redox status, and mechanical phenomena) rather than chemical signals.

Features
●● Clarity of Instruction This edition was re-organized for increased clarity and readability.
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 ([Link]) and avail-
ability of molecular graphics software has been exploited to enliven this text. Over
1100 images of prominent proteins and nucleic acids involved with essential biologi-
cal 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 thermody-
namics that allow us to describe the flows and interchanges of heat, energy, and mat-
ter 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.
●● Foundational Biochemistry At the end of each chapter, this feature provides a com-
prehensive list of the principal facts and concepts that a student should understand
after reading each chapter. Presented as short statements or descriptive phrases, the
items in the Foundational Biochemistry list serve as guides to students of the knowl-
edge they have acquired from the chapter and as checklists the students can review in
assessing their learning.
●● End-of-Chapter Problems More than 700 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 calculations to find mathematical answers to relevant structural or functional
questions. Other questions address conceptual problems whose answers require appli-
cation and integration of ideas and concepts introduced in the chapter.
●● Think-Pair-Share problems encourage students to work collaboratively to further their
understanding.
●● Further Readings sections at the end of each chapter make it easy for students to find
up-to-date additional information about each topic.

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

in the field.
●● Human Biochemistry essays emphasize the central role of basic biochemistry in med-
icine 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 xxxi.

Instructor and Student Resources

Instructor and student resources are available online.
Instructor resources include:
●● Solution and Answer Guide
●● Test Bank
●● Transition Guide from the Sixth Edition to the Seventh Edition
●● Lecture Note PowerPoint slides
●● Image Library slides
●● Guide to Teaching Online
●● Educator’s Guide

Acknowledgments
We are indebted to the many experts in biochemistry and molecular biology who care-
fully reviewed this book at several stages for their outstanding and invaluable advice
on how to construct an effective textbook.

Reviewers for the 7th edition

Bobby Burkes, Grambling State University
Natasha DeVore, Missouri State University
Todd Eckroat, Penn State Behrend
Michael Guy, Northern Kentucky University
Steven Herron, Utah Valley University
Amber Howerton, Nevada State College
Kyoung Nan Kim, University of Colorado, Denver
Steven LaiHing, Oakwood University
Timothy Reichart, Hampden-Sydney College
Stephen Spiro, University of Texas at Dallas
Brent Znosko, Saint Louis University
Lisa Zuraw, The Citadel

We also wish to gratefully acknowledge many other people who assisted and encour-
aged us in this endeavor. Roxanne Wang, our Product Manager for Upper-Level
Chemistry, has brought enthusiasm and an unwavering emphasis on student learning
as the fundamental purpose of our collective enterprise. Meaghan Ford, the Senior
Content Manager 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, as is Mona Zeftel, our Learning Designer, whose focus on student
learning and student perceptions provided crucial guiderails for us in keeping the educa-
tion of students uppermost as we created this new edition. We also applaud the unsung
but absolutely indispensable contributions by Maria Lokshin, Ph.D., our Development
Editor. Maria’s editorial grace was precise and immensely helpful. Her writing skills
and scientific acumen made this textbook eminently more readable. The contribution
of new supplementary end-of-chapter problems by Koen Vercruysse of East Tennessee
State University is gratefully acknowledged and appreciated. This book’s design and
layout is the creative result of work by Chris Doughman. If this book has visual
appeal, it is due to Katy Gabel and John Rich, Project Managers at Lumina Datamatics
and their colleagues. The beautiful illustrations that not only decorate this text but also
explain its contents are a testament to a number of important collaborators. Many
colleagues provided original art and graphic images for this book, particularly Professor
Jane Richardson of Duke University. We acknowledge with pleasure the scientific and
artistic contributions of Michal Sabat of 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. Tina Chai, B.S. (Chemistry) graduate of
the University of Virginia, his successor and our Molecular Graphics Design specialist,
carried his work further. Elizabeth Magnotti, B.S. (Chemistry) graduate of the University
of Virginia, and Ph.D., Emory University, pioneered the development of the PSAFE
project, a multi-faceted task requiring scientific knowledge and a sense of its importance.
Yitna Firdyiwek was instrumental in the creation of the PSAFE archive site. Celeste
Costa, a current University of Virginia student, prepared content and tutorial videos
for the current PSAFE course. We want to acknowledge P. Kelley, of Philander Smith
College who audited the content for accuracy, Michael Cascio, of Duquesne University
who is writing hints and targeted feedback for new questions for the online course, and
Rochelle Williams, of the ARC Network, who advised on inclusivity and diversity for this
edition. 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, David and Andrew Grisham, and Emily Grisham Cooke.
We hope this seventh edition of our textbook has captured the growing sense of won-
der and imagination that researchers, teachers, and students 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
December 2022

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

 A 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 1.4 How Do the Properties of
Biomolecules Reflect Their Fitness to
compose living things. These living systems are distinct from the inanimate
the Living Condition?
world because they have certain extraordinary properties. They can grow, move,
1.5 What Are the Organization and
p erform the incredible chemistry of metabolism, respond to stimuli from the
Structure of Cells?
environment, and, most significantly, replicate themselves with exceptional fidelity.
1.6 What Are Viruses?
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 i ntricacy
of biological structures, and the complexity of vital mechanisms, life functions are
interpretable in chemical terms. Chemistry is the logic of biological phenomena. Living
organisms are self-sustaining systems of chemical reactions.

1.1
What Are the Distinctive Properties
of Living Systems?
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
polymeric molecules, called macromolecules. These macromolecules show an exquisite

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.

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 macromolecule, known as
its conformation, is a consequence of interactions between the monomeric units,
according to their individual chemical properties.
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 intermedi-
ates, a biological purpose can be given for each component. 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.
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. The biosphere is thus a system
through which energy flows. Organisms capture some of this energy, be it from photo-
synthesis or the metabolism of food, by forming special energized biomolecules. ATP
and NADPH are the two most prominent examples (Figure 1.2). (Commonly 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 represent chemically
useful forms of stored energy. When these molecules react with other molecules in the
cell, the energy released can be used to drive energetically unfavorable processes. That is,
ATP, NADPH, and related compounds are the power sources that drive the energy-
requiring activities of the cell, including biosynthesis, movement, osmotic work against
concentration gradients, and, in special instances, light emission (bioluminescence). The
living state is characterized by the flow of energy through the organism. Only upon death
does an organism reach equilibrium with its inanimate environment. At the expense of
energy flow, the organism can maintain its intricate order and activity far removed from
equilibrium with its surroundings, yet exist in a state of apparent constancy over time.
This state of apparent constancy, or so-called steady state, is actually a very dynamic
condition: Energy and material are consumed by the organism to maintain its stability
Entropy A thermodynamic term used to designate that
and order. In contrast, inanimate matter, as exemplified by the universe in totality, is
amount of energy in a system that is unavailable to do moving to a condition of increasing disorder or, in thermodynamic terms, maximum
work. entropy.

NH2 O
H H
N N C NH2
O– O– O–
–O N N
P O P O P OCH2
N
O O CH2
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 1.2 ATP and NADPH, two biochemically important O

energy-rich compounds. NADPH

Living systems have a remarkable capacity for self-replication. Generation after

g eneration, organisms reproduce virtually identical copies of themselves. This self-
replication can proceed by a variety of mechanisms, ranging from simple division in
bacteria to sexual reproduction in plants and animals; but in every case, it is characterized
by an astounding degree of fidelity (Figure 1.3). Indeed, if the accuracy of self-replication

Randal H. Garrett

Figure 1.3 Organisms resemble their parents. Orangutan with infant.

Figure 1.4 The DNA double helix. Two complementary polynucleotide chains run in opposite direc-
tions and pair through hydrogen bonding between their nitrogenous bases, A with T and C with G.
Note that everywhere there is an A in one strand, the other has a T; everywhere there is a C in one
strand, there is a G in the other. These complementary nucleotide sequences give rise to structural
complementarity.

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 is
deoxyribonucleic acid, abbreviated as DNA. It consists of a pair of polymeric chains
built using four different monomers known as deoxynucleotides. These four deoxynu-
cleotide building blocks are symbolized by the letters A, C, G, and T. Information is
encoded in each polynucleotide strand in the form of the precise sequence of A, C, G,
and T deoxynucleotides along its length, much as this sentence contains information as
encoded in the letters of the words that compose it. The two deoxynucleotide chains are
In biochemistry and molecular biology, structurally structurally complementary to one another (Figure 1.4) in that everywhere there is an A
complementary means that two structures align and fit in one strand, the other has a T, and everywhere there is a C in one strand, there is a G
together like pieces of a puzzle.
in the other. DNA can generate two identical copies of itself in a rigorously executed
polymerization process whereby each chain is copied precisely, using the information
provided by its complementary strand. This process ensures a faithful reproduction of
the information written by the original polynucleotide strands. In contrast, the mole-
cules of the inanimate world lack this capacity to r eplicate. A crude mechanism of rep-
lication 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
abundance of elements in the earth’s crust. Hydrogen (H), oxygen (O), carbon (C),
and nitrogen (N) constitute more than 99% of the atoms in the human body, with
most of the H and O occurring as water, H2O. Oxygen, silicon (Si), aluminum (Al),
and iron (Fe) are the most abundant atoms in the earth’s crust, with hydrogen, car-
bon, and nitrogen being relatively rare (less than 0.2% each). Nitrogen as d initrogen
(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. What property unites hydrogen,
oxygen, carbon, and nitrogen and renders these atoms so suitable to the chemistry
of life? It is their ability to form covalent bonds by electron-pair sharing. Further-
more, hydrogen, c arbon, nitrogen, and oxygen are among the lightest elements of

the periodic table capable of forming such bonds (Figure 1.5). Because the strength Bond
of covalent bonds is inversely proportional to the atomic weights of the atoms Covalent energy
Atoms e– pairing bond (kJ/mol)
involved, hydrogen, carbon, nitrogen, and oxygen form the strongest covalent
bonds. Two other covalent bond-forming elements, phosphorus (as p hosphate H + H H H H H 436

[2OPO322] derivatives) and sulfur, also play important roles in biomolecules.

C + H C H C H 414

1.2a Biomolecules Are Carbon Compounds

C + C C C C C 343
All biomolecules contain carbon. The prevalence of carbon is due to its unparalleled
versatility in forming stable covalent bonds through electron-pair sharing. Carbon
can form up to four such bonds by sharing each of the four electrons in its outer shell C + N C N C N 292
with electrons contributed by other atoms. Atoms commonly found in covalent link-
age to carbon are carbon itself, hydrogen, oxygen, and nitrogen. Hydrogen can form
one such bond by contributing its single electron to the formation of an electron pair. C + O C O C O 351
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 cova-
lent bonds. Furthermore, carbon, nitrogen, and oxygen can share two electron pairs C + C C C C C 615
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 C + N C N C N 615
form triple bonds.
Two properties of carbon covalent bonds merit particular attention. One is the ability
of carbon to form covalent bonds with itself. The other is the tetrahedral nature of the
C + O C O C O 686

four covalent bonds when carbon atoms form only single bonds. Together these proper- O + O O O O O 142
ties hold the potential for an incredible variety of linear, branched, and cyclic carbon
compounds. This diversity is multiplied further by the possibilities for including nitro- O + O O O O O 402
gen, oxygen, and hydrogen atoms in these compounds (Figure 1.6). We can therefore
envision the ability of carbon to generate complex structures in three dimensions. These N + N N N N N 946
structures, by virtue of appropriately included nitrogen, oxygen, and hydrogen atoms,
can display unique chemistries suitable to the living state. Thus, we may ask, is there any N + H N H N H 393
pattern or underlying organization that brings order to this astounding potentiality?
O + H O H O H 460

Figure 1.5 Covalent bond formation by e2 pair

s haring. The energy necessary to break a bond is given
1.3
What Is the Structural Organization of Complex in kJ/mol.
Biomolecules?
Examination of the chemical composition of cells reveals a dazzling variety of
organic compounds covering chemical dimensions such as length and mass
(Table 1.1). When biomolecules are classified based on size and chemical properties,
an organizational pattern emerges. The biomolecules are built according to a struc-
tural hierarchy: S imple molecules are the units for building complex structures.
The molecular constituents of living matter do not reflect randomly the infinite
possibilities for combining carbon, hydrogen, oxygen, and nitrogen atoms. Instead, only
a limited set of the many possibilities is found, and these collections share certain
properties essential to the living state. The most prominent aspect of biomolecular
organization is that simple molecules are the building blocks for polymers that contain
thousands or even millions of atoms, structures so large that we refer to them as
macromolecules. What properties do these biomolecules possess that make them so Macro - prefix from the Greek “makros” meaning large
appropriate for the condition of life? or long.

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 transform these inorganic precursors through ever

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Deschenes, a splendid sheet of water not far from the city of
Ottawa.
The invitation mentioned, as one of the attractions of the place,
that he would be able to have all the sailing that his heart could
wish.
"Hurrah! hurrah!" shouted Mort, capering about the room with a
face beaming like the sun. "All the sailing I want! Just think of it!
Won't that be grand? The very thing I've been looking for."
"It will be grand, Mort dear," said his mother, "provided you take
good care not to run any unnecessary risks. You must do exactly
what your uncle tells you, just as if he were your father."
"Oh yes, mother, I'll do that," quickly responded Mort, ready to
promise anything in the exuberance of his joy. "I'll be his crew, you
know, and obey orders just as if I were at sea with him."
Very impatiently did Mort await the coming of the day when he
should set forth for Deschenes. His uncle was principal of the
Collegiate Institute at Ottawa, and had three months' vacation,
which he usually spent at the lake in sailing, rowing, bathing, and
fishing, until the return of autumn recalled him to his duties.
It was the last week in June when Mort arrived at Lake
Deschenes, and his first question, after exchanging greetings with
his uncle and aunt, was,—
"Will you show me your boat, please, uncle?"
Smiling at his eagerness, Mr. Turner took him over to the
boathouse, where a number of boats and canoes lay upon the floor,
or were suspended upon racks against the wall.
Mort had never seen so many or such fine boats in his life
before. They were nearly all built of cedar, and were varnished
instead of being painted, the copper fastenings dotting their shining
sides with regular lines. The boy gave a great gasp of admiration,
and it was some time before he recovered himself sufficiently to ask,
—
"And which is your boat, uncle?"
Mr. Turner pointed to one lying just in front of them.
"Oh, what a beauty!" cried Mort. "She's the best of them all."
His uncle smiled a complacent assent, for that was precisely his
own opinion. As to beauty of lines, perfection of finish, completeness
of outfit, and speed on any tack, he considered the Gleam without a
superior on Lake Deschenes, and Mort's prompt recognition of the
fact pleased him as much as the cordial praise of her baby does a
young mother.
"You are not far from right, my boy," said he. "The Gleam is
both a beauty to look at and a good one to go, as you shall see for
yourself very soon."
The Gleam belonged to the class of boat known as the "St.
Lawrence skiff," the swiftest and safest boats of their size—when not
over-canvassed—that carry sails. She was about twenty-two feet
long, and had a half-deck all round, with a six-inch combing to keep
out the water. Two tall masts carried big bat-wing sails, which would
have soon toppled her over but for the heavy iron centre-board that
kept her stiff in an ordinary breeze. Everything about her was of the
best, and Mort thought her the most beautiful object his eyes ever
beheld.
That afternoon he had his first sail in the Gleam, and as,
responding perfectly to every puff of the wind and turn of the tiller,
she went flying across the lake, his heart thrilled with delight, and
became filled with a passionate desire to master the art of handling
such a craft.
"O uncle, won't you teach me how to steer and to manage the
sails before I go back home?" he pleaded, looking earnestly into Mr.
Turner's face.
"Certainly, Mort, certainly," was the kindly reply; "and I think
you ought to make a very apt pupil, too."
Mr. Turner was altogether as good as his word. He took much
pains in initiating Mort into the mysteries of sailing, teaching him the
way to tack, when it was permissible to jibe, how to run before the
wind, and so forth, until, by the end of the first month, Mort had
become tolerably proficient, and could be trusted to manage the
Gleam alone in an ordinary breeze.
This special privilege he was then allowed to exercise, provided
he did not go outside the "boom"—that is, the long line of shackled
logs which enclosed the bay where the boathouse stood, and which
was intended to keep the saw-logs from stranding on the beach.
Inside the boom was a stretch of shallow water nearly a mile
long by a quarter of a mile wide, on which plenty of sailing might be
had without going out through the gap into the body of the lake.
For a time Mort was content with this enclosed space, and,
whenever his uncle permitted him, would get the boat out, and go
tacking up and down from end to end, feeling almost as proud of his
newly-acquired skill as if he had been discoverer of the science of
sailing.
But of course it was not many days before he began to cast
longing eyes beyond the line of swaying logs, and to feel that the
thing he most desired in the world was to be allowed to sail the
Gleam across the lake and back.
But when he hinted as much to his uncle he met with no
encouragement.
"No, no, Mort. You must be content with staying inside the
boom; for, besides the chance of a squall, there is the danger of
being caught in the current and carried into the rapids, which would
soon make an end of both you and the boat."
Now it happened that one morning both Mr. and Mrs. Turner
had to go into the city, not to return until by the night train, and
Mort was left entirely to his own resources. Of course he turned to
the Gleam for company, and as soon as the morning breeze came
up, taking with him two other lads about his own age, he launched
the boat, and went skimming from end to end of the bay.
"This is good fun," said Ted Day, "but it would be better still
outside the boom."
"Oh yes!" cried Charlie Lister. "Do go outside; just a little bit,
Mort."
Mort shook his head, and tried to look very decided. His own
heart was beating a lively response to the suggestions of his
companions, but his answer was,—
"No, Charlie; uncle does not allow me to go outside, you know."
Once the idea had been mooted, however, it refused to go to
rest again. The morning seemed a perfect one. There was a steady
breeze from the north-west, just the direction best suited for a slant
across the lake and back without having to tack at all.
"MORT CRAWLED UPON THE STAGE AND
FASTENED TO IT THE BOAT'S PAINTER."

Ted and Charlie begged and coaxed Mort to make one trip out,
any way. Mr. Turner would never know anything about it, and they
could easily be back before mid-day.
Mort's resolution, which had been rapidly weakening, finally
gave way altogether.
"All right," said he, allowing a sudden spirit of reckless ambition
to submerge his compunctions at doing what he knew well enough
was a mean betrayal of his uncle's confidence in him. "We'll just
make one trip across. It does seem a pity to lose the chance this
glorious morning."
So out through the gap the Gleam darted, as if glad of her
freedom, and went flying over the blue water toward Blueberry
Point.
"My, but this is grand!" exclaimed Charlie rapturously, as the
boat careened before the freshening breeze, so that the water
lapped the lee-combing.
"You are right; it is—eh, Mort?" echoed Ted, turning to Mort,
who, holding the tiller in one hand and the end of the main sheet in
the other, watched every move of the boat with feelings strangely
divided between anxiety and proud delight.
The passage across was quickly made, and then, being thirsty,
Charlie proposed that they land for a few minutes to get a drink at a
spring near the shore. After the drink Ted suggested a bathe; and
thus an hour slipped by, during which an ominous change took place
in the weather. The sky clouded over, the wind, which had been
steady, began to come in fitful gusts.
"I don't like the look of things," said Mort, in a tone of concern.
"I wish we were inside the boom."
"Well, let's hurry and get there as quickly as we can," responded
Ted.
It was all well enough to say this, but with the change of
weather had come a change of wind, which was now against them,
so that they would have to tack all the way home.
By dint of careful sailing they had got about a third of the
distance, when suddenly the sky darkened, some large drops of rain,
pattered upon them, and the next moment a sharp squall struck the
Gleam full upon her quarter.
In order to give his whole attention to the steering, Mort had
asked Charlie to hold the main-sheet, impressing upon him to take
only one turn around the cleat. But Charlie, who was of the lazy
sort, finding the sheet hard to hold, had taken two turns, and done it
in such a way that the rope had jammed. Consequently, when Mort
shouted to him, as he put the tiller hard a-port, "Let go the main-
sheet instantly, Charlie!" and he attempted to obey the order, he
could not do so in time to meet the emergency, and the next instant,
amid simultaneous shrieks from all three boys, the Gleam went over
on her beam ends.
Fortunately they were all good swimmers, and did not get
entangled in any of the ropes, so that, without much difficulty, they
succeeded in climbing up on the side of the boat, where it was easy
enough to hold on for a while.
There was no fear of the Gleam sinking, as she bore no ballast
to carry her down, and had air-tight compartments in both bow and
stern. Nevertheless, the position of the boys was one of great peril,
for the boat was right in the channel leading to the rapids at the
lower end of the lake, in the direction of which the wind was now
blowing. To get into these rapids meant utter destruction for both
boys and boat, yet to keep out of them was impossible without help,
while to swim ashore was far beyond their powers.
They shouted and shrieked for aid, but there was no one in
sight to hear them, and soon the storm burst upon them in full fury,
blotting out the shore on both sides, and threatening to beat them
off the boat as it tossed up and down in the white-caps.
How bitterly Mort regretted having ventured beyond the boom,
and how fervently he vowed never to do so again if he could only be
saved this time!
When the squall passed and the air cleared, he saw that they
were fast drawing near the rapids.
"O Charlie," he groaned, "why did you make me go outside the
boom?"
Charlie made no reply. He could think of nothing else but his
imminent danger.
Steadily and surely the Gleam drifted downward. In another
fifteen minutes she would be in the remorseless grasp of the rapids.
The wind went down almost to a calm, but the current grew
stronger, so that there was no slacking of her speeding toward
destruction.
The boys held desperately on to the keel, saying nothing to
each other, but praying as best each could.
On, on the boat moved. Oh, was there no chance of help? Must
they go down, to death in sight of so many homes?
A couple of hundred yards above the rapids was a floating
stage, strongly moored, which was used by the men looking after
the saw-logs that came down the river in great droves from time to
time. As they neared this a bright thought flashed into Mort's mind.
"Say, boys," he cried, "I've got it! Do you see that float? Let's
push the Gleam over to it."
The others caught the idea at once. All getting on the same side
of the boat, they proceeded to push her toward the stage by
swimming with their legs.
It was exhausting work, but they were encouraged by seeing
that they were making headway, and they persevered until at last
success crowned their efforts, and with a glad cry of relief Mort
crawled upon the stage and fastened to it the boat's painter.
All actual danger was now over, and at once Mort regained his
self-possession. Under his directions the masts were taken out, the
boat righted and bailed dry, and everything stowed snugly aboard.
Then with the oars she was rowed back to Deschenes, not a whit
the worse for her wetting.
As soon as his uncle returned, Mort told him the whole story.
Mr. Turner was very sorry to learn of his nephew's breach of
trust, and, as a penalty therefor, withdrew from him for the rest of
the summer the privilege of taking the boat out alone, which was a
sore deprivation; but Mort felt that it was richly deserved, and it only
strengthened his resolution to be more obedient to orders in the
future.

FOUND AFTER MANY DAYS.

"Edie! Edie!" rang out in a clear, strong voice from the door of a
farmhouse, where stood a comely, brown-faced woman, shading her
eyes with her right hand, as she swept the sunny space around in
search of her daughter.
"I'm coming, mother," was the prompt response.
And the next instant there appeared from behind the barn a
little girl not more than eight years old, who looked the very picture
of health and happiness.
"You know where your father's chopping to-day, don't you,
Edie?" asked Mrs. Hazen, with a glance of affectionate pride at the
sturdy little figure before her.
"Oh yes, mother," replied Edie, swinging around and pointing
with her plump forefinger, stained by the juice of the raspberries she
had just been picking, to the top of the hill that sloped upwards from
the other side of the road. "Father's over there in the back pasture,
near the blackberry patch."
"That's right, pet," said Mrs. Hazen, lifting up the bright face for
a hearty kiss. "And now wouldn't you like to take him his dinner?"
"Indeed I would," cried Edie, dancing around and clapping her
hands. "And may I stay with him until he comes home?"
"I suppose so—if he wants you," assented Mrs. Hazen. "But in
that case you must come in and have your own dinner first."
A half-hour later, with a well-filled basket on her arm, and her
mother's parting injunction not to loiter on the way in her ears, Edie
set forth full of joy on her mission.
"She's a little thing to send so far," mused the mother, following
the retreating figure with eyes full of tender concern. "But she does
so love the woods, and seems to make her way through them like an
Indian."
With heart as light as any bird chirping by the wayside, Edie
hastened through the gate, across the road, between the lower bars
of the pasture gate, and then, climbing the hill behind which lay the
back pasture, entered the bush, in which her pink calico sun-bonnet
soon vanished from view.
Mr. Hazen's farm stood on the very edge of civilization, in the
northern part of New Brunswick. The most of his acres he had
cleared himself, and he never lost an opportunity of hewing his way
further and further into the mighty forest, whose billows of birch,
pine, and hemlock rolled away northward, eastward, and westward
for uncounted leagues.
This day he was working at a bunch of timber a little beyond
the eastern edge of the clearing, called the "back pasture."
As mid-day drew near he began to feel hungry, and more than
once paused in his work to go to the edge of the clearing, to see if
there were any signs of an approaching dinner.
"I hope Esther hasn't forgotten me to-day," he thought, after
doing this for the third time to no result. "It's not like her to do it."
The great golden sun moved steadily on to the zenith, and then
inclined westward, but still no messenger appeared bearing the
needed refreshment.
Mr. Hazen felt strongly tempted to shoulder his axe and go
home. But the day was so favourable to his work that, after a good
deal of grumbling at what he supposed to be his wife's neglect, he
decided not to quit it. So, tightening his belt, he grasped his axe
anew and strove to forget his hunger in the ardour of his toil.
He did not, however, work as late as common that day, for in
addition to his hunger, there grew upon him a feeling of uneasiness,
which at length became so disturbing that he could not endure it.
Accordingly, fully an hour before his usual time, he shouldered his
axe and strode off homeward, saying to himself,—
"I hope nothing's gone wrong; but I don't know what gives me
such an apprehensive feeling."
When he approached the farmhouse, he caught sight of his wife
coming up the road that led to the nearest neighbour, about half-a-
mile away.
Hurrying on to meet her, he asked in a tone not altogether free
from irritation at his needless fears,—
"Why, Esther, where have you been? And where is Edie?"
"I ran over to neighbour Hewett's for the paper," Mrs. Hazen
responded. "But"—and her face filled with sudden alarm—"Edie?
Wasn't Edie with you?"
"Why, no!" replied Mr. Hazen, while in his face was reflected the
expression of his wife's; "I haven't seen her since breakfast."
"Not seen her!" repeated Mrs. Hazen. "O Henry, what has
happened? I sent her with your dinner just before mid-day, and she
asked me if she might stay with you until you came home."
Mr. Hazen was a man prompt to action. Taking his wife's arm
and fairly pushing her along the road, he said,—
"There's not a moment to lose, Esther. Edie's lost her way, and
we must go after her."
Without returning to the farmhouse, they pressed up the hill
and through the back pasture into the forest.
Hither and thither they hunted, now one and now the other
raising the echoes of the leafy fastness by calls of "Edie! Edie!" but
getting no response save the cries of startled birds or the mocking
chatter of a squirrel.
As night drew on Mr. Hazen realized that a more organized
effort was necessary; and hastening home with harrowed hearts, his
wife got ready some food, while he rode over to Hewett's to obtain
assistance.
Both Mr. Hewett and his eldest son returned with him. They
hurriedly snatched a meal, and then, provided with guns and
lanterns, set off to renew the search.
All that night they tramped through the gloom of the forest,
meeting from time to time to take counsel together, and then
separating, to cover as much ground as possible.
But the day dawned without bringing any comforting news for
the haggard woman who anxiously waited their return at the gate,
and, when they came without her daughter, sank down on the
ground, half fainting with uncontrollable grief.
As soon as possible the eager search was renewed, and
continued from day to day, until at last even the heart-broken
parents had to give up all hope, and strove to resign themselves to
the awful conviction that their darling Edith—their only one—had
met her death all alone in the depths of the great forest, having
either died of hunger and exposure or fallen a victim to the bears
and wolves with which its solitudes abounded.
In the meantime, how had it fared with Edie, who had gone
forth so joyously to carry her father's dinner to him?
Her intention at the start was certainly to make a straight
course to her destination. But the attention of little folks is easily
attracted, and in this instance, just as she entered the edge of the
forest, and should have turned off to the left, a saucy little squirrel
challenged her on the right, and in trying to get near him Edie
pushed further and further into the forest, until presently she began
to wonder if she had not lost her way.
At once losing interest in the squirrel, she put down her basket
to look about her. With a pang of sharp dismay, the child realized
that she had lost her bearings, and did not know which way to turn.
Just at that moment her keen ear caught a sound that she
immediately recognized. It was the regular blows of an axe falling
upon a tree-trunk.
Her face lit up, and she clapped her hands for joy.
"That's father chopping!" she exclaimed. "Now I know which
way to go!"
And picking up her basket, Edie trotted off in what she took to
be the direction from which the sound came.
On she trudged bravely for some distance, hoping each minute
to come upon her father, until, growing weary of her burden, she put
it down to rest a moment.
As she rested it seemed to her that the sound of chopping had
grown fainter—so much so, indeed, she could hardly make out which
way it came to her ears.
"Oh dear!" she sighed; "where can father be? I'll call for him."
And she made the place ring with shrill cries of "Father! father!
Where are you?"
But they evoked no response, and then, more alarmed than
ever, Edie picked up her basket again, and pushed on with all her
little strength.
Unhappily every step increased the distance between Mr. Hazen
and herself; for it was not the real sound of the chopping Edie had
followed but the echo, and instead of making toward him, she had
been going in directly the opposite direction.
At the end of an hour she felt very tired, and throwing herself
down on a bank of moss at the foot of a forest monarch, gave way
to the tears that hitherto she had resolutely restrained.
"Oh dear!" she said, "I'm lost, I'm lost! and how ever will father
find me?"
After the first passion of tears had passed, Edie began to be
conscious of the pangs of hunger, and the thought came that she
might as well eat something out of the basket, as she could not find
her father to give it to him.
So she ate a little of the bread and meat, and took a sup out of
the bottle of milk, and then, feeling refreshed, renewed her tramp,
first listening eagerly, but in vain, for the sound of her father's axe.
All that afternoon the lost child alternately walked and rested,
often crying softly to herself, then drying her tears and seeking to
take heart from the hope of yet finding her father before darkness
came on.
She was a brave little thing, accustomed to a good deal of
outdoor life, and to running through the woods; but when night
closed around her and the forest shade deepened into impenetrable
gloom, poor Edie gave up the struggle, and sank down in a mossy
hollow, shivering with terror.
Yet so weary was she that presently she fell asleep, and did not
awake until dawn, when, though feeling very stiff and sore from the
unwonted exertions of the day before, she ate her breakfast out of
the basket and renewed her progress.
The following day she wandered about, only getting deeper and
deeper into the forest. Her basket was empty before evening, and
she was fain to make her supper of the berries, which fortunately
were very plentiful. They were not altogether satisfying, but they
were better than nothing.
Another day passed, the weather providentially continuing
bright, clear, and warm, and the little wanderer still kept on, not
knowing whither she was going. That night strange things began to
happen. She was more wakeful than usual, and as she lay at the
foot of a tree, she saw some large animals moving about in the dim
light, and her bosom thrilled with joy, for she thought they must be
her father's oxen. So she called out,—
"Buck! Bright! Come here!"

"HE LEVELLED HIS RIFLE IN READINESS

TO FIRE."

But at the sound of her voice they started as if greatly

frightened, and at once dashed off through the woods at the top of
their speed; which showed her that they must have been moose,
such as her father sometimes shot.
The following night two great, black, shaggy dogs, which she
supposed must be neighbour Hewett's, came near her; but when
she called them by their names they seemed more surprised than
the moose, for they stood up on their hind legs, looked very hard at
her for a few moments, and then, dropping down on all fours,
hastened away into the darkness again, where, as Edie thought, she
heard them howling. In this, however, she must have been doubly
mistaken.
What she took to be dogs were no doubt black bears, then quite
numerous in that district, being, attracted by the berries; and the
howling, of course, was done by wolves, which, luckily, seemed
afraid to attack her.
On the fourth afternoon, Edie, by happy chance, came across
the deserted shanty of an early pioneer, standing in the middle of a
clearing that was thickly overgrown with raspberry bushes.
Here she remained for three days, feeding upon the berries
during the daytime, and sleeping in the shanty at night. The nights
were so warm that she needed no fire, and inside the shanty she
was safe from the attacks of bears or wolves. It was dreadfully
lonely, yet still she hoped that her father would come and find her.
A whole week thus passed away. Edie had been given up for
lost by her heart-broken parents, and the neighbours who were
assisting in the search had returned to their homes, when a
gentleman—Mr. Barker by name—had an experience such as no
sportsman surely ever had before.
He had been out on a hunting expedition for a fortnight, and
that day came to the banks of Bear Creek.
He was preparing to cross on a fallen log almost spanning the
stream, when his keen ear caught the sound of soft footsteps,
accompanied by a continuous rustling movement in the thicket of
wild raspberries that covered the opposite bank.
At once with a tremor of delight he suspected the approach of a
deer, or possibly a bear, and dropping behind a bush, he levelled his
rifle in readiness to fire.
The next moment, as his eager eyes intently scanned the
raspberry bushes, his sportsman's feeling of delight suddenly
changed to a thrill of horror when a tiny brown, berry-stained hand
was quietly raised to pull down a loaded branch of fruit.
"Well, of all things!" cried the hunter, as his finger fell from the
trigger that had so nearly sent the bullet upon its fatal mission.
"What an awful mistake I almost made!"
Throwing down his rifle he sprang across the log, to catch in his
arms a little girl not more than eight years old, whose torn
garments, tangled locks, soiled hands, and thin, pale face, told in a
glance the story of many days' hapless wanderings.
Oh, how glad poor Edie was to see him, and how artlessly she
told the story of her wonderful adventures! And how thankful to
Providence the hunter was that he had chanced to find her ere it
was too late!
Forgetting all about his hunting, her rescuer now applied himself
to the task of getting her home. They were far from the nearest
house, and the poor child was so weak from lack of proper food that
he had to lift her up on his broad shoulders.
But Mr. Barker was as strong as he was kind-hearted, and he
pushed resolutely on, guiding himself by his compass, until at last,
just as dusk was closing around them, and he began to fear they
would have to pass another night in the forest, they came upon a
clearing, at the far side of which stood a neat log house.
Edie shouted her joy at the sight. It meant that all her perils
were over; and the hunter, putting on a big spurt, dashed across the
clearing at a run and deposited her on the doorstep, exclaiming in a
tone of vast relief,—
"There now, my child, that's the end of your wanderings!"
The good people of the house gave them both a warm
welcome. Edie received every attention; and the following morning,
looking altogether a different girl, with dress mended, hair neatly
brushed, hands free from berry-stains, and face radiant at the
prospect of returning to her parents, she took her seat in the
farmer's waggon to be driven home.
How shall the joy of the Hazens be described when the little
daughter they had mourned for as dead came back to them, looking
thin and worn, it is true, but otherwise not a whit the worse for her
thrilling experience!
Mr. Barker watched them with brimming eyes, murmuring, as he
fondly patted the stock of his Remington,—
"The best day's work you ever did was when you didn't go off at
all. A lucky chance, indeed!"

MRS. GRUNDY'S GOBBLERS.

Mrs. Grundy (or, as the boys disrespectfully called her, Mrs. Grumpy)
was certainly not a favourite with the young people of Westville. In
the first place, she did not like children. The fact that she had never
been blessed with any of her own no doubt had a great deal to do
with this dislike for other people's, which she manifested by vigorous
use of hand and tongue at the slightest provocation.
Many a sharp speech and stinging slap did Mrs. Grundy inflict—
and not always upon those who deserved it most, either; for so hot
was her temper, so hasty her action when irritated, that she would
visit her wrath upon the first youngster she could reach, without
waiting to investigate the extent of her luckless captive's guilt.
Another reason why Mrs. Grundy was not popular was that,
although she owned the finest orchard and garden in all Westville,
not one crimson strawberry, purple plum, or golden apple was she
ever known to bestow upon boy or girl; and woe betide the
adventurous urchin that dared to take one unbidden, even though it
be a half-spoiled windfall, if he fell into her strong hands! Forthwith
he was marched off, amid a storm of slaps and scolding, despite his
sobs and vows of penitence, into the awful presence of Squire
Hardgrit, and, his alarmed parents having been duly summoned, was
in their presence condemned to that most appalling of punishments
—a whole day in the house of detention!
This method of dealing with the would-be or actual fruit-filchers
had one advantage, so far as Mrs. Grundy was concerned—it gave
her a sharer in the burden of her unpopularity, which perhaps might
otherwise have proved insupportable; for so hard, cold, and
unsympathetic was Squire Hardgrit, and such evident pleasure did
he take in imposing his penalties, that if the Westville boys hated
anybody as cordially as they did Mrs. Grundy, it was certainly the
stern, severe squire.
For some time past the relations between these two worthies
and the boys had, as the newspapers say about the great Powers,
been more than usually strained. Not content with fiercely defending
her garden and orchard from juvenile depredation, Mrs. Grundy had
asserted her right to keep everybody off the broad, smooth plot of
grass that lay between her cottage and the road, and had been
upheld in her claim by the squire, to the profound disgust of the
boys, who had long made it their gathering-place in the summer
evenings; for although too small to play a game of baseball upon, it
was big enough for pitching and catching, chase, leap-frog, and that
sort of thing.
This appropriation of the grass plot, which had hitherto been
regarded as public property, was quite too much for the boys. It was
the last drop in the cup of bitterness, and in desperation they called
a meeting to be held in Thompson's barn on Saturday night to
consider the situation.
Saturday night came, and a dozen of the brightest boys of
Westville gathered in solemn conclave around a lantern to see if
some way could not be devised of getting even with Mrs. Grumpy
and the squire.
As the barn belonged to his father, Charlie Thompson was
chosen chairman, and he promptly opened the meeting as follows:—
"Now, fellows, we can't stand this sort of thing any longer.
Something must be done, if we perish in the attempt. The honour of
the country demands" (Charlie, whose memory was particularly
good, had not yet forgotten the last 4th of July oration) "that
measures should be taken to show to our oppressors that we are not
slaves and cowards. The meeting is now open, and the chair will be
pleased to receive suggestions."
And amid a vigorous round of boot-heel applause Charlie sat
down, feeling that he had proved himself quite equal to the
occasion.
For a few moments there was a dead pause, all having some
sort of a scheme, more or less hazy, in their heads, but none wishing
to speak first.
At last little Tommy Short, the youngest in the group, piped out,
—
"Let's tar and feather 'em. Father has lots of tar in his back
shop, and I know where there's a big pot."
A roar of laughter greeted this suggestion, the impracticability of
which was exceeded only by its absurdity, could it have been carried
out.
Dame Grundy and Squire Hardgrit would certainly have made a
most mirth-provoking sight, done up in suits of tar and feathers.
The speech served its purpose, however, in loosening the other
tongues, and plans and projects now poured in thick and fast.
"S'pose we burn their barns down," said Dick Wilding, who was
a great reader of cheap-novel literature.
But all the rest shouted "No" at once.
"What do you say to ham-stringing their horses?" asked Bob
Henderson, in rather a dubious tone, as if he had not much
confidence in the wisdom of his scheme, which, in fact, just occurred
to him because he had read that that was the way the Arabs treat
their enemies' horses when they get the chance.
"Stuff and nonsense!" cried the chairman. "That's not the sort of
thing we mean at all. We're not hankering after the penitentiary."
"Give us your plan, then, Mr. Chairman," said Dick Wilding.
"Well, fellows, I'll tell you what I was thinking of. Let us hook
the old lady's gobblers, and hide them until she thinks they're gone
for good. You know what a heap she thinks of them, and it will
worry her awfully to lose them."
"Capital! capital!" shouted the rest of the boys "The very thing!"
"But where shall we hide them?" asked Sam Lawson. "It'll have
to be a pretty safe place, for Mrs. Grumpy will turn the town upside
down hunting for her precious turkeys, you may be sure."
While all this talk was going on, Harold Kent had been sitting on
an upturned box which served him as a chair, without opening his
mouth. Now, however, taking advantage of the pause which followed
Sam's question, he said quietly,—
"Why not hide the gobblers in one of the empty rooms in Squire
Hardgrit's building? You know, the squire's been trying to get these
Bronze Gobblers from Mrs. Grumpy for ever so long, and she won't
let him have them; and if they're found on his premises, she'll be
sure to think that he had something to do with hooking them."
It was just like Harold to propose something so original and
daring in its conception as to fairly take his companions' breath
away, and they now looked at him with feelings divided between
admiration and amazement.
The chairman was the first to speak. Bringing his hand down
upon his knee with a crack that made the others jump, he cried,—
"Magnificent! Boys, we'll do it, or perish in the attempt."
Whereat the others shouted in chorus,—
"Hoorah! We'll do it!"
"Since we're all agreed, then," said Charlie, "the next business
before the meeting is to plan how to do it."
As before, all sorts of wild suggestions were put forward, and
again it was left for Harold Kent to advance the most practicable
scheme.
This was it: the shed in which Mrs. Grundy's famous flock of
turkeys was carefully secured at night stood at some distance to the
back of her house, and as she slept in one of the front rooms, there
was slight risk of her seeing or hearing anything. What Harold
proposed was, that, slipping out of their rooms after everybody was
asleep, they should meet behind the turkey-shed, bringing with
them three gunny sacks and a dark lantern. Having got the gobblers
safely into the sacks, they would then creep round the back way to
the building in which the squire's office was situated, climb in
through a lower window, and so upstairs to the room in which the
turkeys were to be left.
"You've a great head, Hal," said Jack Wilding admiringly, when
all this had been detailed, "and you can count on us every time—
can't he, boys?"
"You bet he can," chorused the crowd.
A satisfactory plan of campaign having thus been settled upon,
the meeting was adjourned until Monday midnight, then to assemble
behind Mrs. Grundy's turkey-shed. The eventful night came; and as
midnight drew near, one by one the boys gathered with throbbing
hearts at the rendezvous.
At length all but Tommy Short, whose courage had failed him,
and Bob Henderson, whose father had nabbed him in the act of
slipping out, and sent him back to bed with a spank, turned up.
"THEY WERE TOO BEWILDERED BY THE
BLAZE TO MAKE ANY NOISE. Page 227"

It was an intensely dark night and blowing half a gale. all of

which was in favour of the enterprise. The shed door was found to
be simply secured with a wooden latch, and lifting this the
conspirators tip-toed inside; and then Charlie Thompson, who
carried the dark lantern, suddenly turned its glare full upon the
startled gobblers as they nodded solemnly side by side upon their
roost.
They were too bewildered by the blaze to make any noise, and
before they could recover their self-possession sufficiently to exclaim
at so extraordinary an apparition, the other boys had stepped behind
them, and with quick, deft movements slipped the big sacks over
their heads, thus reducing them at one bold stroke to helpless
captives.
The poor turkeys struggled and "gobbled" a good deal in their
narrow quarters, but all to no purpose; and full of terror, no doubt,
at their strange treatment, were hurried out of the shed into the
lane, and thence through dark and silent ways to the rear of the
squire's building. Here the conspirators paused for breath and
consultation.
"Now, fellows," whispered Harold Kent, "we needn't all go
inside, you know. I'll take the lantern, while the three biggest of you
carry the gobblers, and the rest will stay here until we come back."
Somewhat reluctantly this was assented to, for all wanted to
share the danger as well as the fun; and then Harold, lantern in
hand, followed by Dick Wilding, Sam Shaw, and Frank Cushing, each
bending beneath a bag of struggling, "gobbling" turkey, climbed in
through the low window, crept softly in stocking feet along the
narrow hall and up the creaking stairs; while their companions, with
hearts beating like trip-hammers, shrank close together in the
darkest corner outside and anxiously awaited their return.
It was no easy task that the four boys had in hand. True enough
that the building was uninhabited at night, but there were people
living next door, and any unusual noise could hardly fail to be heard
through those thin wooden walls; while, late as the hour was, the
sound of footsteps on the plank side-walks would ever and anon
send a chill of terror through the anxious watchers below.
Moreover, to carry three big turkeys up a flight of stairs and
deposit them in an empty room without filling the whole place with
their noise was the hardest part of all. Nevertheless they succeeded
admirably.
Five minutes after they disappeared they rejoined their
companions, trembling but triumphant, having left their captives in
good order and condition in the front room, just across the room
from Squire Hardgrit's office, where they would be certain to make
themselves seen and heard in the morning.
This done, the boys scattered to their homes, creeping back
noiselessly to their beds, in which, being thoroughly tired out, they
slept as soundly until morning as if they had not been up to any
mischief whatever.
The great gathering-place of the Westville boys was the
blacksmith's forge, which stood across the road from Mrs. Grundy's,
and thither the conspirators came one by one the following morning
in expectation of seeing the fun.
Nor were they disappointed. Their enemy thought too much of
her precious turkeys to intrust any person else with the duty of
feeding them, and so every morning carried them a big dish of corn-
meal mush after she had finished her own breakfast.
"There she goes!" exclaimed Dick Wilding presently, as the boys
were laughing and talking somewhat nervously together.
And, sure enough, Mrs. Grundy's portly figure emerged from the
house and went slowly toward the shed.
Soon after a sharp cry of "Susan! Susan!" cut the still morning
air, and the prim maid-servant was observed to hurry to her
mistress.
A moment later the two women could be observed running
hither and thither through the garden and orchard, calling, "Turkey!
turkey! turkey!" at the top of their voices.
Great indeed was Mrs. Grundy's concern, and soon the whole
neighbourhood was made aware of her loss.
"It's those rascally gipsies, sure's I'm alive," she cried. "Who
else would steal my beautiful gobblers, that I wouldn't sell even to
the squire? I'll have every one of them sent to jail, see if I don't. Just
wait till the squire comes!"
And so she stormed while awaiting the arrival of the squire at
his office.
The moment he appeared she poured her woful tale into his
ears, while a curious crowd gathered outside, eager to see what the
majesty of the law could effect.
Most prominent in the crowd were, of course, the boys, who
alone held the clue to the mystery, and were now eagerly expecting
the grand denouement.
It was not long in coming. Mrs. Grundy had only about half
finished her confused recital of facts, suspicions, and theories to the
gravely listening squire, when a vigorous "Gobble-gobble-gobble!"
was distinctly heard coming from somewhere near at hand, just as a
shout broke in from the street of,—
"There they are—up in Squire Hardgrit's room! Look at them!"
Before the squire could take in the situation, his excited client
sprang to her feet, rushed out of the office, across the hall, threw
open the door into the opposite room, and there, behold! as large as
life, and as cross as three gobblers could be, were her missing
turkeys, who, the instant the door was opened, charged straight
through it, almost upsetting their mistress, and went flapping
violently downstairs and out into the street, where they were
greeted with a shout of laughter from the surprised spectators.
It would be impossible with either pen or pencil to give an
adequate conception of the old lady's countenance as she returned
to the squire's office, and met that worthy magistrate just rising
from his chair.
Surprise, suspicion, indignation, and wrath chased one another
swiftly across her features, and, once her feelings found utterance,
there was poured upon the amazed squire such a torrent of reproach
and contumely that he was fairly stunned into silence; and before he
could recover himself sufficiently to make his defence, his accuser,
with a scornful swing of her ample skirts that was simply
magnificent, flounced out of the office, while he sank back into his
chair, the very picture of helpless bewilderment.
That he, Squire Hardgrit, the incorruptible guardian of the
people's rights, should be suspected of having stolen, or causing to
have stolen for him, the turkeys of a neighbour, whose situation as a
lone widow was such as to make the crime seem particularly heinous
—that any person should for one moment suspect anything so
abominable; and not only suspect it, but charge him to his face with
his supposed guilt before the whole village (for the squire was well
aware that Mrs. Grundy's shrill utterances had been audible clear
across the street), it was awful, perfectly awful, and not to be borne
for a moment! He must see Mrs. Grundy immediately, and compel
her to listen to him.
Accordingly, away he posted to the widow's cottage, where he
arrived just in time to check the poor dame from going off into a fit
of hysterics.
Her turkeys being once more safely in her yard, and her anger
pretty well abated, Mrs. Grundy was quite willing to listen believingly
to the squire's indignant denials, and graciously accept his assurance
that no pains would be spared to ferret out the real delinquents.
The former harmony was restored, and an alliance, offensive
and defensive, sealed with a glass of gooseberry wine, for both were
strongly of the opinion that "those wicked wretches of boys" were at
the bottom of the whole mischief.
Thanks to those same boys holding their tongues, however,
neither Mrs. Grundy nor the squire could ever get hold on any
evidence more solid than their own suspicions, and they both had
too much sense to take any action upon them.
But the nocturnal travels of the turkeys were not in vain; for
their mistress, realizing that the boys, if pressed too far, might do
something worse next time, thought it wise to mitigate her severity
toward them, and even softened to the extent of calling a lot of
them into her orchard that very autumn to fill their pockets with the
windfalls.
This stroke of diplomacy was not lost upon the boys, who
reciprocated after their own fashion: and thus matters went
smoothly on, until at length most harmonious relations were
established, and in all the countryside no creatures were safer from
the youngsters' mischief than Mrs. Grundy's gobblers.
ON THE WRONG SIDE OF THE SNOW-RIDGE.

One of the Fur Commissioners of the Hudson Bay Company at

Winnipeg was entertaining a number of the factors and other
officials at Christmas dinner, and after the successive courses had
received appreciative attention, the guests settled themselves at
ease about the table to enjoy the excellent cigars and one another's
conversation.
Made up as the gathering was of men who had for ten, twenty,
thirty years or longer, in the pursuance of their vocation, experienced
most moving adventures by flood and field, good stories followed
fast. One told of a thrilling trip through the dangerous rapids of the
Portage of the Drowned; another, of the narrow escape from
meeting death at the hands of a grizzly among the foot-hills of the
Rockies; while a third held the attention of all as he graphically
described the fearful struggle that he had with a wounded bull bison
in the valley of the Bow River.
Thus the story-telling went around until it reached Hugh
M'Kenzie, one of the oldest officials in the active service, who, in
response to a unanimous demand, spun the following interesting
yarn of mountain-sheep hunting.
"It was in the third year of my clerkship, and they had sent me
away out to Fort George, right in the heart of the Rockies. I would
rather have stayed on the plains, where the buffalo were in plenty;
but you're not asked as to what you'd like best in the company.
You're just told to go, and there's an end of it. I found it very dull at
Fort George, and to while away the time I did all the hunting I could.
To help me in this I had two fine dogs, of whom I was extremely
proud. They were half-bred collies, not particularly handsome
creatures, but full of pluck, and as knowing animals as ever wagged
tails.
"Having had pretty good luck with bear and other game to be
found in the neighbourhood of the fort, I became possessed of a
strong desire to secure the head of one of those Rocky Mountain
sheep which have their home high up among the peaks, and are as
difficult animals to hunt as there are in the world.
"Again and again I went out without success, although my dogs,
Bruce and Oscar, seemed as eager to get sheep as I was myself; but
instead of becoming disheartened, I grew all the more determined,
and longed for the winter to come, when the snow, by covering their
higher pasturing grounds, would drive the sheep lower down the
mountain, and thus make them more getatable.
"The winter began with a series of heavy snowfalls which shut
us all up in the fort for several weeks, and it was early in December
before I thought it safe to have another try after the sheep.
"Then one fine, bright morning I started off, feeling very hopeful
that I would return with my much-coveted prize. The dogs, of
course, went with me, but I had no other companion, nobody else
having sufficient sporting ardour to share in the risks of my
expedition; for it certainly was full of risks, and had I been older and
wiser I would never have undertaken it. But I was young and strong
and full of spirit, and my eagerness to obtain a set of horns had
become a bit of a joke against me with the fellows; so that I was not
in the mood to soberly weigh the pros and cons of the matter.
"Thinking it possible I might be out all night, I rolled up some
provisions and matches in my thick plaid, and strapped it on my
shoulders. With hatchet and hunting-knife in my belt, a full powder-
horn at my side, snowshoes on feet and rifle in hand, I set out amid
the good-humoured chaffing of my fellow-clerks.
"Up into the mountains I climbed, keeping a keen look-out for
signs of the game I was seeking, while Bruce and Oscar ranged right
and left, so that we covered a good deal of ground between us. By
mid-day the climbing became so steep and difficult that I had to
take off my snow-shoes, and strapped them on my back. They were
no longer necessary, at any rate, for the snow was covered with a
crust which bore me up admirably, and made easy going for my
moccasined feet.
"It was not until afternoon that the first sheep were sighted,
and, much to my delight, they seemed not far away, and easy to get
at. There were five in the flock: a huge ram with superb horns—just
the thing I hankered after—and four fine ewes, which, however, had
nothing to fear from me.
"Calling the dogs to heel, I proceeded to stalk the unsuspecting
creatures with all the skill I possessed. It proved a harder job than I
thought. They were on a kind of ledge several hundred feet above
me, and in order to get a proper shot without giving them warning,
it was necessary to make a wide circuit, so as to reach a point
opposite their ledge from which a capital chance might be had.
"By dint of great exertion, however, I reached the point all right,
and was just waiting a moment to catch my breath before taking
aim at the ram, when Oscar's impatience overcame him, and he
gave a sharp bark. Instantly the whole live animals started to flee. I
threw the rifle to my shoulder and pulled the trigger. It was nothing
better than a snap-shot, yet it did not miss; for with the report the
ram sprang into the air, stumbled as he came down, and then
dashed off again, leaving behind him a plain trail of blood-drops on
the white snow.
"With an exultant shout I sent the dogs forward, and followed
as fast as I could. I had to go down into a ravine and get up the
other side before reaching the bloody trail. Forgetting everything
else in my wild excitement, I pressed on, guided by my dogs' sharp
barking. It was terribly hard work, and I had many a slip and
stumble; but the red splashes in the snow grew larger the further I
went. Bleeding at the rate he was, the ram surely could not keep up
his flight for any great distance.
"Presently I came to a place that at any other time would have
brought me to a full stop. A ridge of hard frozen snow stretched
between two rocky ledges. On the one side it reached down to the
edge of a precipice, which then fell away abruptly into an unknown
depth. On the other side, in one unbroken sheet, it sloped down full
five hundred feet to a level upon, which the snow lay in great drifts.
The ram was already half-way across the ridge, although evidently in
distress, and the dogs were hard at his heel, barking fiercely, for
they knew that victory was not far off.
"Throwing all considerations of prudence to the winds, I set out
to follow them. So narrow was the ridge that I could not stand erect,
but had to sit astride it, and push myself forward by using both
hands and feet. I never glanced below me, lest I should lose my
head; and at length, almost completely exhausted, I succeeded in
making the other side.
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Biochemistry 7Th Edition Reginald H. Garrett - Ebook PDF Download

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(eBook PDF) Biochemistry 6th Edition by Reginald H.

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Lehninger Principles of Biochemistry 7th Edition

(eBook PDF) Biochemistry: The Molecular Basis of Life

(eBook PDF) Organic Chemistry 7th Edition by William H.

(eBook PDF) Principles of Economics 7th Edition by

Principles of Microeconomics 7th ed. Edition Robert H.

Atlas of Human Anatomy 7th Edition Frank H. Netter -

Reginald H. Garrett | Charles M. Grisham

With molecular graphic images

Australia • Brazil • Canada • Mexico • Singapore • United Kingdom • United States

Learning Designer: Mona Zeftel

Content Program Manager: Ivan Corriher

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Production Service: Lumina Datamatics, Ltd.

Cover Image: CRISPR-Cas9, by Tina Chai

Printed in the United States of America

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

Reginald H. Garrett and Charles M. Grisham

Part I Molecular Components of Cells 1

Part II Protein Dynamics 433

Part III Metabolism and Its Regulation 573

Part IV Information Transfer 981

Abbreviated Answers to Problems A-1

 itration Curves Illustrate the Progressive

5 in the Laboratory? 131

8 9.1 What Are the Chemical and Physical

 eripheral Membrane Proteins Associate Loosely

 ext-Generation Sequencing by Synthesis 348

14 15.1 What Factors Influence Enzymatic Activity? 511

 lagellar Filaments Are Composed of Protofilaments of

Metabolism: An Overview 573 Foundational Biochemistry 597

 tilization of Glucose-6-P Depends on the Cell’s Need

26.2 How Do Cells Synthesize Purines? 922 Foundational Biochemistry 945

 ukaryotic Cells Also Contain a Number of Different DNA

 he Regulation of Gene Expression Is More Complex in

 eptide Chain Elongation Requires Two G-Protein Family

31  teroid Hormones Act in the Nucleus or at the

Processing, and Degradation 1131 32.2 What Is Signal Transduction? 1164

Recombinant DNA Techniques Fluxomics Section 17.5

Objectives and Building on Previous Editions

New to the Online Course and Resources

New to this Edition

Chapter 27 New molecular graphic of mTORC1, the master integrator of information

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

Instructor and Student Resources

Reviewers for the 7th edition

Reginald H. Garrett Charles M. Grisham

Phenomena “…everything that living things do can be

 A sperm fertilizing an egg.

Essential Question Key Questions

Science Photo Library/Alamy

degree of organization in their intricate three-dimensional architecture, even though

Figure 1.2 ​ATP and NADPH, two biochemically important O

Living systems have a remarkable capacity for self-replication. Generation after

Figure 1.3 ​Organisms resemble their parents. Orangutan with infant.

were significantly greater, the evolution of organisms would be hampered. This is so

1.2 What Kinds of Molecules Are Biomolecules?

[2OPO322] derivatives) and sulfur, also play important roles in biomolecules.

1.2a Biomolecules Are Carbon Compounds

Figure 1.5 ​Covalent bond formation by e2 ​pair

FOUND AFTER MANY DAYS.

"HE LEVELLED HIS RIFLE IN READINESS

But at the sound of her voice they started as if greatly

MRS. GRUNDY'S GOBBLERS.

It was an intensely dark night and blowing half a gale. all of

One of the Fur Commissioners of the Hudson Bay Company at

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itration Curves Illustrate the Progressive

eripheral Membrane Proteins Associate Loosely

ext-Generation Sequencing by Synthesis 348

lagellar Filaments Are Composed of Protofilaments of

tilization of Glucose-6-P Depends on the Cell’s Need

ukaryotic Cells Also Contain a Number of Different DNA

he Regulation of Gene Expression Is More Complex in

eptide Chain Elongation Requires Two G-Protein Family

31 teroid Hormones Act in the Nucleus or at the

Figure 1.2 ATP and NADPH, two biochemically important O

Figure 1.3 Organisms resemble their parents. Orangutan with infant.

Figure 1.5 Covalent bond formation by e2 pair