Essential Biochemistry 5th Edition

Charlotte W. Pratt
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Amino Acid Structures and Abbreviations
Hydrophobic amino acids
COO– COO– CH3 COO– COO–
H C CH3 H C CH H C CH2 H C CH2
NH+
3 NH+
3 CH3 NH+
3 NH+
3
N
H
Alanine (Ala, A) Valine (Val, V) Phenylalanine (Phe, F) Tryptophan (Trp, W)

COO– CH3 COO– CH3 COO– COO–

CH2
H C CH2 CH H C CH CH2 CH3 H C CH2 CH2 S CH3 H C
CH2
NH+
3 CH3 NH+
3 NH+
3 H2N+
CH2
Leucine (Leu, L) Isoleucine (Ile, I) Methionine (Met, M) Proline (Pro, P)

Polar amino acids

COO– COO– CH3 COO– COO–
H C CH2 OH H C CH OH H C CH2 OH H C CH2 SH
NH+
3 NH+
3 NH+
3 NH+
3

Serine (Ser, S) Threonine (Thr, T) Tyrosine (Tyr, Y) Cysteine (Cys, C)

COO– O COO– O COO– COO–

N
H C CH2 C NH2 H C CH2 CH2 C NH2 H C CH2 H C H
NH+ NH+ N
3 3 NH+
3 H NH+
3

Asparagine (Asn, N) Glutamine (Gln, Q) Histidine (His, H) Glycine (Gly, G)

Charged amino acids

COO– O COO– O COO– COO– NH2
H C CH2 C O–
H C CH2 CH2 C O –
H C CH2 CH2 CH2 CH2 NH+
3 H C CH2 CH2 CH2 NH C NH+
2

NH+
3 NH+
3 NH+
3 NH+
3

Aspartate (Asp, D) Glutamate (Glu, E) Lysine (Lys, K) Arginine (Arg, R)

Essential Biochemistry
Fifth Edition

CH A RLOT TE W. PR AT T
Seattle Pacific University

K ATHLEEN CORNELY
Providence College
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ISBN 9781119712855

Library of Congress Cataloging-in-Publication Data

Names: Pratt, Charlotte W., author. | Cornely, Kathleen, author.

Title: Essential biochemistry / Charlotte W. Pratt, Seattle Pacific
University, Kathleen Cornely, Providence College.
Description: Fifth edition. | Hoboken : Wiley, 2021. | Includes index.
Identifiers: LCCN 2020055734 (print) | LCCN 2020055735 (ebook) | ISBN
9781119713203 (paperback) | ISBN 9781119718987 (adobe pdf) | ISBN
9781119712855 (epub)
Subjects: LCSH: Biochemistry.
Classification: LCC QD415 .P67 2021 (print) | LCC QD415 (ebook) | DDC
572--dc23
LC record available at https://lccn.loc.gov/2020055734
LC ebook record available at https://lccn.loc.gov/2020055735

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1
 About the Authors

C H A R LO T T E P R AT T received a B.S. in biology from the University of Notre Dame and

a Ph.D. in biochemistry from Duke University. She is a protein chemist who has conducted
research in blood coagulation and inflammation at the University of North Carolina at
Chapel Hill. She is currently Associate Professor in the Biology Department at Seattle ­Pacific
­University. Her interests include molecular evolution, enzyme action, and the relationship
between metabolic processes and disease. She has written numerous research and review
­articles, has worked as a textbook editor, and is a co-author, with Donald Voet and Judith G.
Voet, of Fundamentals of Biochemistry, published by John Wiley & Sons, Inc.

K AT H LE E N CO R N E LY holds a B.S. in chemistry from Bowling Green (Ohio) State Univer-

sity, an M.S. in biochemistry from Indiana University, and a Ph.D. in nutritional b
­ iochemistry
from Cornell University. She is currently the Robert H. Walsh ’39 Endowed Professor in Chem-
istry and Biochemistry at Providence College, where she has focused on expanding the use
of case studies and guided inquiry across a broad spectrum of classes. Her interest in active
pedagogy has led to her involvement in national programs including Project ­Kaleidoscope, the
POGIL Project, and the Howard Hughes Medical Institute SEA PHAGES program, which has
also fueled her current experimental research in phage genomics. She has been a member of
the editorial board of Biochemistry and Molecular Biology Education and has served for several
years as coordinator of the undergraduate poster competition at the annual meeting of the
American Society for Biochemistry and Molecular Biology.

v
Brief Contents

PREFACE xiv
Part 3 Metabolism
Part 1 Foundations 12 Metabolism and Bioenergetics 337

1 The Chemical Basis of Life 1 13 Glucose Metabolism 366

2 Aqueous Chemistry 27 14 The Citric Acid Cycle 403

15 Oxidative Phosphorylation 428

Part 2 Molecular Structure and 16 Photosynthesis 458
Function 17 Lipid Metabolism 483
3 Nucleic Acid Structure and Function 57
18 Nitrogen Metabolism 518
4 Protein Structure 86
19 Regulation of Mammalian Fuel
5 Protein Function 125 Metabolism 555

6 How Enzymes Work 167

Part 4 Genetic Information
7 Enzyme Kinetics and Inhibition 198
20 DNA Replication and Repair 582
8 Lipids and Membranes 234
21 Transcription and RNA 627
9 Membrane Transport 258
22 Protein Synthesis 663
10 Signaling 287

11 Carbohydrates 315

vi
 Contents

PREFACE xiv
Part 2 Molecular Structure and
Part 1 Foundations Function

1 The Chemical Basis of Life 1

3 Nucleic Acid Structure and
Function 57
1.1 What Is Biochemistry? 1
1.2 Biological Molecules 3 3.1 Nucleotides 57
Cells contain four major types of biomolecules 3 Nucleic acids are polymers of nucleotides 58
There are three major kinds of biological Some nucleotides have other functions 60
polymers 6 3.2 Nucleic Acid Structure 61
Box 1.A Units Used in Biochemistry 7 DNA is a double helix 62
1.3 Energy and Metabolism 10 RNA is single-stranded 64
Enthalpy and entropy are components of free Nucleic acids can be denatured and
energy 11 renatured 64
∆G is less than zero for a spontaneous process 12 3.3 The Central Dogma 67
Life is thermodynamically possible 12 Box 3.A Replication, Mitosis, Meiosis, and Mendel’s
1.4 The Origin of Cells 14 Laws 67
Prebiotic evolution led to cells 15 DNA must be decoded 70
Box 1.B How Does Evolution Work? 17 A mutated gene can cause disease 71
Eukaryotes are more complex than prokaryotes 17 Genes can be altered 72
The human body includes microorganisms 19 Box 3.B Genetically Modified Organisms 73
3.4 Genomics 74
The exact number of human genes is not
2 Aqueous Chemistry 27 known 75
Genome size varies 75
2.1 Water Molecules and Hydrogen Bonds 27 Genomics has practical applications 77
Hydrogen bonds are one type of electrostatic Box 3.C Viruses 78
force 29
Water dissolves many compounds 31 4 Protein Structure 86
Box 2.A Why Do Some Drugs Contain Fluorine? 31
2.2 The Hydrophobic Effect 33 4.1 Amino Acids, the Building Blocks
Amphiphilic molecules experience both hydrophilic of Proteins 86
interactions and the hydrophobic effect 35 The 20 amino acids have different chemical
The hydrophobic core of a lipid bilayer is a barrier to properties 88
diffusion 35 Box 4.A Does Chirality Matter? 89
Box 2.B Sweat, Exercise, and Sports Drinks 36 Box 4.B Monosodium Glutamate 91
2.3 Acid–Base Chemistry 37 Peptide bonds link amino acids in proteins 91
[H+] and [OH–] are inversely related 38 The amino acid sequence is the first level
The pH of a solution can be altered 39 of protein structure 94
Box 2.C Atmospheric CO2 and Ocean Acidification 39 4.2 Secondary Structure: The Conformation of the
A pK value describes an acid’s tendency to Peptide Group 95
ionize 40 The α helix exhibits a twisted backbone
The pH of a solution of acid is related to the pK 41 conformation 96
2.4 Tools and Techniques: Buffers 44 The β sheet contains multiple polypeptide
2.5 Clinical Connection: Acid–Base Balance in strands 96
Humans 46 Proteins also contain irregular secondary
structure 98
vii
viii CON TENTS
4.3 Tertiary Structure and Protein Stability 99
Proteins can be described in different ways 99
Globular proteins have a hydrophobic core 100
Protein structures are stabilized mainly by the
hydrophobic effect 101
Box 4.C Thioester Bonds as Spring-Loaded Traps 103
Protein folding is a dynamic process 103
Box 4.D Baking and Gluten Denaturation 104
Disorder is a feature of many proteins 105
Protein functions may depend on disordered
regions 106
4.4 Quaternary Structure 107
4.5 Clinical Connection: Protein Misfolding and
Disease 109
4.6 Tools and Techniques: Analyzing Protein
Structure 111
Chromatography takes advantage of a polypeptide’s
unique properties 111
Mass spectrometry reveals amino acid
sequences 114
Box 4.E Mass Spectrometry Applications 116
Protein structures are determined by NMR
spectroscopy, X-ray crystallography, and
cryo-electron microscopy 116
5 Protein Function 125
5.1 Myoglobin and Hemoglobin: Oxygen-Binding
Proteins 126
Oxygen binding to myoglobin depends
on the oxygen concentration 127
Myoglobin and hemoglobin are related by
evolution 128
Oxygen binds cooperatively to hemoglobin 129
A conformational shift explains hemoglobin’s
cooperative behavior 130
Box 5.A Carbon Monoxide Poisoning 130
H+ ions and bisphosphoglycerate regulate oxygen
binding to hemoglobin in vivo 132
5.2 Clinical Connection: Hemoglobin Variants 134
5.3 Structural Proteins 136
Actin filaments are most abundant 137
Actin filaments continuously extend and
retract 138
Tubulin forms hollow microtubules 139
Keratin is an intermediate filament 142
Collagen is a triple helix 144
Box 5.B Vitamin C Deficiency Causes Scurvy 144
Collagen molecules are covalently cross-linked 145
Box 5.C Bone and Collagen Defects 147
5.4 Motor Proteins 148
Myosin has two heads and a long tail 148
Myosin operates through a lever mechanism 150
Kinesin is a microtubule-associated motor
protein 151
Box 5.D Myosin Mutations and Deafness 151
Kinesin is a processive motor 152
5.5 Antibodies 154
Immunoglobulin G includes two antigen-binding
sites 154
B lymphocytes produce diverse antibodies 156
Researchers take advantage of antibodies’
affinity and specificity 157
6 How Enzymes Work 167
6.1 What Is an Enzyme? 167
Enzymes are usually named after the reaction they
catalyze 170
6.2 Chemical Catalytic Mechanisms 171
A catalyst provides a reaction pathway with a lower
activation energy barrier 173
Enzymes use chemical catalytic
mechanisms 173
Box 6.A Depicting Reaction Mechanisms 175
The catalytic triad of chymotrypsin promotes
peptide bond hydrolysis 177
6.3 Unique Properties of Enzyme Catalysts 180
Enzymes stabilize the transition state 180
Efficient catalysis depends on proximity
and orientation effects 181
The active-site microenvironment
promotes catalysis 182
6.4 Chymotrypsin in Context 183
Not all serine proteases are related by
evolution 183
Enzymes with similar mechanisms exhibit different
substrate specificity 184
Chymotrypsin is activated by proteolysis 185
Protease inhibitors limit protease activity 186
6.5 Clinical Connection: Blood Coagulation 187
7 Enzyme Kinetics and Inhibition 198
7.1 Introduction to Enzyme Kinetics 198
7.2 Derivation and Meaning of the Michaelis–Menten
Equation 201
Rate equations describe chemical processes 201
The Michaelis–Menten equation is a rate equation
for an enzyme-catalyzed reaction 202
KM is the substrate concentration at which velocity is
half-maximal 204
The catalytic constant describes how quickly
an enzyme can act 204
kcat/KM indicates catalytic efficiency 205

KM and Vmax are experimentally determined 205
Not all enzymes fit the simple Michaelis–Menten
model 207
7.3 Enzyme Inhibition 209
Some inhibitors act irreversibly 209
Competitive inhibition is the most common
form of reversible enzyme inhibition 210
Transition state analogs inhibit enzymes 212
Other types of inhibitors affect Vmax 213
Box 7.A Inhibitors of HIV Protease 214
Allosteric enzyme regulation includes inhibition
and activation 216
Several factors may influence enzyme
activity 219
7.4 Clinical Connection: Drug
Development 219
8 Lipids and Membranes 234
8.1 Lipids 234
Fatty acids contain long hydrocarbon chains 235
Box 8.A Omega-3 Fatty Acids 236
Some lipids contain polar head groups 237
Lipids perform a variety of physiological
functions 239
Box 8.B The Lipid Vitamins A, D, E, and K 240
8.2 The Lipid Bilayer 241
The bilayer is a fluid structure 242
Natural bilayers are asymmetric 243
8.3 Membrane Proteins 244
Integral membrane proteins span the bilayer 245
An α helix can cross the bilayer 245
A transmembrane β sheet forms a barrel 246
Lipid-linked proteins are anchored in the
membrane 246
8.4 The Fluid Mosaic Model 248
Membrane proteins have a fixed orientation 249
Lipid asymmetry is maintained by enzymes 250
9 Membrane Transport 258
9.1 The Thermodynamics of Membrane Transport 258
Ion movements alter membrane potential 259
Membrane proteins mediate transmembrane
ion movement 260
9.2 Passive Transport 263
Porins are β barrel proteins 263
Ion channels are highly selective 264
Gated channels undergo conformational
changes 265
Box 9.A Pores Can Kill 265
Aquaporins are water-specific pores 266
CO NTENTS ix
Some transport proteins alternate between
conformations 268
9.3 Active Transport 269
The Na,K-ATPase changes conformation as it pumps
ions across the membrane 269
ABC transporters mediate drug resistance 271
Secondary active transport exploits existing
gradients 271
9.4 Membrane Fusion 272
SNAREs link vesicle and plasma membranes 273
Box 9.B Antidepressants Block Serotonin Transport 275
Endocytosis is the reverse of exocytosis 276
Autophagosomes enclose cell materials for
degradation 277
Box 9.C Exosomes 278
10 Signaling 287
10.1 General Features of Signaling Pathways 287
A ligand binds to a receptor with a characteristic
affinity 288
Most signaling occurs through two types of
receptors 289
The effects of signaling are limited 290
10.2 G Protein Signaling Pathways 291
G protein–coupled receptors include seven
transmembrane helices 292
The receptor activates a G protein 293
The second messenger cyclic AMP activates protein
kinase A 294
Arrestin competes with G proteins 296
Signaling pathways must be switched off 296
The phosphoinositide signaling pathway generates
two second messengers 297
Many sensory receptors are GPCRs 298
Box 10.A Opioids 299
10.3 Receptor Tyrosine Kinases 300
The insulin receptor dimer changes
conformation 300
The receptor undergoes autophosphorylation 302
Box 10.B Cell Signaling and Cancer 303
10.4 Lipid Hormone Signaling 303
Eicosanoids are short-range signals 305
Box 10.C Inhibitors of Cyclooxygenase 306
11 Carbohydrates 315
11.1 Monosaccharides 315
Most carbohydrates are chiral compounds 316
Cyclization generates α and β anomers 317
Monosaccharides can be derivatized
in many different ways 318
x CON TEN TS
Box 11.A The Maillard Reaction 319
11.2 Polysaccharides 320
Lactose and sucrose are the most common
disaccharides 321
Starch and glycogen are fuel-storage
molecules 321
Cellulose and chitin provide structural support 322
Box 11.B Cellulosic Biofuel 323
Bacterial polysaccharides form a biofilm 324
11.3 Glycoproteins 325
Oligosaccharides are N-linked or O-linked 325
Oligosaccharide groups are biological markers 326
Box 11.C The ABO Blood Group System 327
Proteoglycans contain long glycosaminoglycan
chains 327
Bacterial cell walls are made of peptidoglycan 328
Part 3 Metabolism
12 Metabolism and Bioenergetics 337
12.1 Food and Fuel 337
Cells take up the products of digestion 338
Monomers are stored as polymers 339
Fuels are mobilized as needed 340
12.2 Metabolic Pathways 343
Some major metabolic pathways share a few
common intermediates 343
Many metabolic pathways include
oxidation–reduction reactions 344
Metabolic pathways are complex 346
Human metabolism depends on vitamins 347
Box 12.A The Transcriptome, the Proteome, and the
Metabolome 348
Box 12.B Iron Metabolism 351
12.3 Free Energy Changes in Metabolic Reactions 352
The free energy change depends on reactant
concentrations 352
Unfavorable reactions are coupled to favorable
reactions 354
Energy can take different forms 356
Regulation occurs at the steps with the largest free
energy changes 357
13 Glucose Metabolism 366
13.1 Glycolysis 366
Energy is invested at the start of glycolysis 367
ATP is generated near the end of glycolysis 373
Box 13.A Catabolism of Other Sugars 378
Some cells convert pyruvate to lactate or
ethanol 379
Box 13.B Alcohol Metabolism 380
Pyruvate is the precursor of other molecules 381
13.2 Gluconeogenesis 383
Four gluconeogenic enzymes plus some glycolytic
enzymes convert pyruvate to glucose 383
Gluconeogenesis is regulated at the fructose
bisphosphatase step 385
13.3 Glycogen Synthesis and Degradation 386
Glycogen synthesis consumes the energy
of UTP 386
Glycogen phosphorylase catalyzes
glycogenolysis 388
13.4 The Pentose Phosphate Pathway 389
The oxidative reactions of the pentose phosphate
pathway produce NADPH 389
Isomerization and interconversion reactions
generate a variety of monosaccharides 390
A summary of glucose metabolism 392
13.5 Clinical Connection: Disorders of Carbohydrate
Metabolism 393
Glycogen storage diseases affect liver and muscle 394
14 The Citric Acid Cycle 403
14.1 The Pyruvate Dehydrogenase Reaction 403
The pyruvate dehydrogenase complex contains
multiple copies of three different
enzymes 404
Pyruvate dehydrogenase converts pyruvate
to acetyl-CoA 404
14.2 The Eight Reactions of the Citric Acid Cycle 406
1. Citrate synthase adds an acetyl group
to oxaloacetate 407
2. Aconitase isomerizes citrate to isocitrate 409
3. Isocitrate dehydrogenase releases the first
CO2 410
4. α-Ketoglutarate dehydrogenase releases
the second CO2 410
5. Succinyl-CoA synthetase catalyzes substrate-level
phosphorylation 411
6. Succinate dehydrogenase generates
ubiquinol 412
7. Fumarase catalyzes a hydration reaction 412
8. Malate dehydrogenase regenerates
oxaloacetate 412
14.3 Thermodynamics of the Citric Acid Cycle 413
The citric acid cycle is an energy-generating
catalytic cycle 413
The citric acid cycle is regulated at three
steps 414
Box 14.A Mutations in Citric Acid Cycle Enzymes 415
The citric acid cycle probably evolved as a synthetic
pathway 415
 CO NTENTS xi

14.4 Anabolic and Catabolic Functions of the Citric 16.2 The Light Reactions 463
Acid Cycle 416 Photosystem II is a light-activated
Citric acid cycle intermediates are precursors oxidation–reduction enzyme 463
of other molecules 416 The oxygen-evolving complex of Photosystem II
Anaplerotic reactions replenish citric acid oxidizes water 464
cycle intermediates 418 Cytochrome b6f links Photosystems I and II 466
Box 14.B The Glyoxylate Pathway 419 A second photooxidation occurs at Photosystem I 467
Chemiosmosis provides the free energy for ATP
15 Oxidative Phosphorylation 428 synthesis 469
16.3 Carbon Fixation 471
15.1 The Thermodynamics of Rubisco catalyzes CO2 fixation 471
Oxidation–Reduction Reactions 428 The Calvin cycle rearranges sugar molecules 472
Reduction potential indicates a substance’s Box 16.A The C4 Pathway 473
tendency to accept electrons 429 The availability of light regulates carbon fixation 475
The free energy change can be calculated Calvin cycle products are used to synthesize
from the change in reduction potential 431 sucrose and starch 476
15.2 Mitochondrial Electron Transport 432
Mitochondrial membranes define two
compartments 433
17 Lipid Metabolism 483
Complex I transfers electrons from NADH to
17.1 Lipid Transport 483
ubiquinone 434
17.2 Fatty Acid Oxidation 486
Other oxidation reactions contribute to the
Fatty acids are activated before they are
ubiquinol pool 436
degraded 487
Complex III transfers electrons from ubiquinol to
Each round of β oxidation has four reactions 488
cytochrome c 437
Degradation of unsaturated fatty acids requires
Complex IV oxidizes cytochrome c and reduces
isomerization and reduction 491
O2 439
Oxidation of odd-chain fatty acids yields
Respiratory complexes associate with each
propionyl-CoA 492
other 441
Some fatty acid oxidation occurs in
Box 15.A Reactive Oxygen Species 442
peroxisomes 494
15.3 Chemiosmosis 443
17.3 Fatty Acid Synthesis 495
Chemiosmosis links electron transport and oxidative
Acetyl-CoA carboxylase catalyzes the first step of
phosphorylation 443
fatty acid synthesis 496
The proton gradient is an electrochemical
Fatty acid synthase catalyzes seven reactions 497
gradient 443
Other enzymes elongate and desaturate newly
15.4 ATP Synthase 445
synthesized fatty acids 500
Proton translocation rotates the c ring of ATP
Box 17.A Fats, Diet, and Heart Disease 500
synthase 445
Fatty acid synthesis can be activated and
The binding change mechanism explains how ATP
inhibited 501
is made 447
Box 17.B Inhibitors of Fatty Acid Synthesis 502
The P:O ratio describes the stoichiometry of
Acetyl-CoA can be converted to ketone
oxidative phosphorylation 447
bodies 503
Box 15.B Uncoupling Agents Prevent ATP Synthesis 448
17.4 Synthesis of Other Lipids 505
The rate of oxidative phosphorylation
Triacylglycerols and phospholipids are built
reflects the need for ATP 448
from acyl-CoA groups 505
Box 15.C Powering Human Muscles 449
Cholesterol synthesis begins with acetyl-CoA 508

16 Photosynthesis 458
A summary of lipid metabolism 510

16.1 Chloroplasts and Solar Energy 458 18 Nitrogen Metabolism 518

Pigments absorb light of different wavelengths 459
Light-harvesting complexes transfer energy to the 18.1 Nitrogen Fixation and Assimilation 518
reaction center 461 Nitrogenase converts N2 to NH3 519
xii CON TENTS
Ammonia is assimilated by glutamine synthetase
and glutamate synthase 519
Transamination moves amino groups
between compounds 521
Box 18.A Transaminases in the Clinic 523
18.2 Amino Acid Biosynthesis 523
Several amino acids are easily synthesized
from common metabolites 524
Amino acids with sulfur, branched chains,
or aromatic groups are more difficult to
synthesize 526
Box 18.B Homocysteine, Methionine, and One-Carbon
Chemistry 527
Box 18.C Glyphosate, the Most Popular Herbicide 528
Amino acids are the precursors of some
signaling molecules 530
Box 18.D Nitric Oxide 531
18.3 Amino Acid Catabolism 532
Amino acids are glucogenic, ketogenic, or both 532
Box 18.E Diseases of Amino Acid Metabolism 535
18.4 Nitrogen Disposal: The Urea Cycle 536
Glutamate supplies nitrogen to the urea cycle 537
The urea cycle consists of four reactions 538
18.5 Nucleotide Metabolism 540
Purine nucleotide synthesis yields IMP and then
AMP and GMP 541
Pyrimidine nucleotide synthesis yields UTP and
CTP 542
Ribonucleotide reductase converts ribonucleotides
to deoxyribonucleotides 543
Thymidine nucleotides are produced by
methylation 544
Nucleotide degradation produces urate
or amino acids 545
19 Regulation of Mammalian Fuel
Metabolism 555
19.1 Integration of Fuel Metabolism 555
Organs are specialized for different functions 556
Metabolites travel between organs 557
Box 19.A The Intestinal Microbiota Contribute to
Metabolism 558
19.2 Hormonal Control of Fuel Metabolism 560
Insulin is released in response to glucose 560
Insulin promotes fuel use and storage 561
mTOR responds to insulin signaling 563
Glucagon and epinephrine trigger fuel
mobilization 564
Additional hormones influence
fuel metabolism 565
AMP-dependent protein kinase acts as a fuel
sensor 566
Fuel metabolism is also controlled by redox
balance and oxygen 566
19.3 Disorders of Fuel Metabolism 568
The body generates glucose and ketone
bodies during starvation 568
Box 19.B Marasmus and Kwashiorkor 568
Obesity has multiple causes 569
Diabetes is characterized by hyperglycemia 570
Obesity, diabetes, and cardiovascular disease are
linked 572
19.4 Clinical Connection: Cancer Metabolism 573
Aerobic glycolysis supports biosynthesis 573
Cancer cells consume large amounts of
glutamine 574
Part 4 Genetic Information
20 DNA Replication
and Repair 582
20.1 The DNA Replication Machinery 582
Replication occurs in factories 583
Helicases convert double-stranded DNA
to single-stranded DNA 584
DNA polymerase faces two problems 585
DNA polymerases share a common structure
and mechanism 587
DNA polymerase proofreads newly
synthesized DNA 589
An RNase and a ligase are required to complete
the lagging strand 590
20.2 Telomeres 593
Telomerase extends chromosomes 594
Box 20.A HIV Reverse Transcriptase 595
Is telomerase activity linked to cell
immortality? 596
20.3 DNA Damage and Repair 596
DNA damage is unavoidable 597
Repair enzymes restore some types of damaged
DNA 598
Base excision repair corrects the most frequent DNA
lesions 598
Nucleotide excision repair targets the second most
common form of DNA damage 599
Double-strand breaks can be repaired by joining the
ends 601
Recombination also restores broken
DNA molecules 601
Box 20.B Gene Editing with CRISPR 602
20.4 Clinical Connection: Cancer as
a Genetic Disease 604
Tumor growth depends on multiple events 605

DNA repair pathways are closely linked to
cancer 605
20.5 DNA Packaging 607
DNA is negatively supercoiled 607
Topoisomerases alter DNA supercoiling 608
Eukaryotic DNA is packaged in nucleosomes 610
20.6 Tools and Techniques: Manipulating DNA 611
Cutting and pasting generates recombinant
DNA 612
The polymerase chain reaction amplifies DNA 614
DNA sequencing uses DNA polymerase to make a
complementary strand 615
21 Transcription and RNA 627
21.1 Initiating Transcription 627
What is a gene? 628
DNA packaging affects transcription 628
DNA also undergoes covalent modification 631
Transcription begins at promoters 631
Transcription factors recognize eukaryotic
promoters 633
Mediator integrates multiple regulatory signals 634
Box 21.A DNA-Binding Proteins 635
Prokaryotic operons allow coordinated
gene expression 636
21.2 RNA Polymerase 638
RNA polymerases have a common structure
and mechanism 639
Box 21.B RNA-Dependent RNA Polymerase 640
RNA polymerase is a processive enzyme 641
Transcription elongation requires changes
in RNA polymerase 642
Transcription is terminated in several ways 644
21.3 RNA Processing 645
Eukaryotic mRNAs receive a 5′ cap and a 3′ poly(A)
tail 645
Splicing removes introns from eukaryotic RNA 646
mRNA turnover and RNA interference limit gene
expression 649
Box 21.C The Nuclear Pore Complex 649
CO NTENTS xiii
rRNA and tRNA processing includes the addition,
deletion, and modification of nucleotides 652
RNAs have extensive secondary structure 653
22 Protein Synthesis 663
22.1 tRNA and the Genetic Code 663
The genetic code is redundant 664
tRNAs have a common structure 665
tRNA aminoacylation consumes ATP 666
Editing increases the accuracy of
aminoacylation 667
tRNA anticodons pair with mRNA codons 668
Box 22.A The Genetic Code Expanded 669
22.2 Ribosome Structure 669
The ribosome is mostly RNA 670
Three tRNAs and one mRNA bind to the
ribosome 671
22.3 Translation 673
Initiation requires an initiator tRNA 673
The appropriate tRNAs are delivered
to the ribosome during elongation 675
The peptidyl transferase active site catalyzes peptide
bond formation 677
Box 22.B Antibiotic Inhibitors of Protein Synthesis 679
Release factors mediate translation
termination 680
Translation is efficient and dynamic 681
22.4 Post-Translational Events 683
Chaperones promote protein folding 684
The signal recognition particle targets some proteins
for membrane translocation 685
Many proteins undergo covalent modification 687
GLOSSARY G-1
ODD-NUMBERED SOLUTIONS S-1
INDEX I-1
Preface
Our goal in writing Essential Biochemistry has been to provide
students with a succinct guide to modern biochemistry that
includes plenty of chemistry, biological context, and problem-
solving opportunities. We want our book to be readable and
practical, presenting the basic concepts of molecular structure
and function, metabolism, and molecular biology along with
some insights into the biochemistry of health and disease.
This fifth edition of Essential Biochemistry is our most
ambitious revision—almost every page has at least minor
changes. We looked for better ways to focus on the chemis-
try behind the biology, and we added some new topics to help
students make connections between biochemistry and other
subjects. We worked hard to integrate the updates so that stu-
dents would find this book—like the previous editions—clear,
concise, and manageable.
We kept the organization mostly the same, and the chap-
ters include all the helpful pedagogical features you’re used
to. And because we believe that students learn by doing, at
the end of each chapter you’ll find even more problems for
students to test their understanding. Of the 1960 problems—
averaging about 90 per chapter—20% are new to this edition.
Among the major differences in the new edition is a
streamlined Chapter 3, now called Nucleic Acid Structure
and Function, to provide a solid foundation for understanding
protein structure and function. New material also helps stu-
dents relate biochemistry to previously encountered biological
concepts such as chromosome division and the laws of inheri-
tance. Material related to manipulating DNA has been moved
to Chapter 20 (DNA Replication and Repair), which provides
the appropriate context for appreciating techniques for copy-
ing, pasting, and sequencing DNA.
In this edition, Chapter 4 includes an updated section
on protein folding and stability, with information about met-
amorphic proteins and intrinsically disordered proteins. We
added a new section on antibody structure and function to
Chapter 5 to present key features of immunoglobulins and
some current applications. We used a new approach to define
uncompetitive and noncompetitive enzyme inhibition, which
should help students better visualize these situations (Chapter
7). Additional diagrams now present all the intermediates of
the pentose phosphate pathway (Chapter 13) and the Calvin
cycle (Chapter 16).
Other notable changes are 10 new boxes covering topics
such as virus structures and viral replication, thioesters, opi-
oids, the Maillard reaction, iron metabolism, and the nuclear
pore complex. Significant updates in the text itself address prac-
tical application of genomics (Chapter 3), autophagy (Chapter
9), the structures and mechanisms of sensory and other signal-
ing proteins (Chapter 10), supermolecular complexes in respi-
ration and photosynthesis (Chapters 15 and 16), the regulation
of metabolism by sterols and oxygen (Chapters 17 and 19), and
next-generation DNA sequencing (Chapter 20).
xiv
In addition to many small adjustments to improve clarity
and readability, we have refreshed some diagrams and have
moved information from figure captions to the text so that stu-
dents won’t overlook key details. Finally, the list of selected
readings for each chapter has been revised with the goal of pro-
viding current and accessible reviews that students can follow.
We hope you’ll find the fifth edition a valuable resource
for your students. As always, we welcome your feedback and
suggestions,
Charlotte Pratt
Kathleen Cornely
Pedagogical Elements
We hope that students will not simply memorize what they
read but will use the textbook as a guide and learn to think
and explore on their own. To that end, we have built into the
chapters a variety of features to facilitate learning outside the
lecture hall.
• Do You Remember review questions at the start of
each chapter help students tie new topics to previously
encountered material.
• Learning Objectives for each section are based on
verbs, giving students an indication of what they need to
be able to do, not just know.
• Before Going On study hints at the end of each section
suggest activities that support learning.
• Questions following selected tables and figures prompt
students to inspect information more closely and make
comparisons.
• Key sentences summarizing main points are printed in
italics to help students focus and review.
• Metabolism overview figures introduced in Chapter 12
and revisited in subsequent chapters help students place
individual metabolic pathways into a broader context.
• Chapter Summaries, organized by section headings,
highlight the most important concepts in each section.
• Key terms are in boldface and are listed at the end of the
chapter, with complete definitions in the Glossary.
• Tools and Techniques sections appear at the end of
Chapters 2, 4, and 20 to showcase practical aspects of
biochemistry and provide an overview of experimental
techniques that students will encounter in their reading
or laboratory experience.
• Clinical Connection sections in Chapters 2, 4, 5, 6, 7,
13, 19, and 20 provide more in-depth exploration of the
biochemical basis of diseases.

• Selected Readings are listed at the end of each chapter,
with short descriptions, for students to consult as sources
of additional information and context.
• Problems for each chapter—20% more than in the last
edition—are grouped by section and are offered in pairs,
with the answers to odd-numbered problems provided in
an appendix.
Organization
We have chosen to focus on aspects of biochemistry that
tend to receive little coverage in other courses or present
a ­challenge to many students. Thus, in this textbook, we
devote proportionately more space to topics such as acid–base
chemistry, enzyme mechanisms, enzyme kinetics, oxidation–­
reduction reactions, oxidative phosphorylation, photosynthe-
sis, and the enzymology of DNA replication, transcription,
and translation. At the same time, we appreciate that students
can become overwhelmed with information. To counteract
this tendency, we have intentionally left out some details, par-
ticularly in the chapters on metabolic pathways, in order to
emphasize some general themes, such as the stepwise nature
of pathways, their evolution, and their regulation.
The 22 chapters of Essential Biochemistry are relatively
short, so that students can spend less time reading and more
time extending their learning through active problem-solving.
Most of the problems require some analysis rather than simple
recall of facts. Many problems based on research data provide
students a glimpse of the “real world” of science and medicine.
Although each chapter of Essential Biochemistry, Fifth
Edition is designed to be self-contained so that it can be cov-
ered at any point in the syllabus, the 22 chapters are organized
into four parts that span the major themes of biochemistry,
including some chemistry background, structure–function
relationships, the transformation of matter and energy, and
how genetic information is stored and made accessible.
Part 1 of the textbook includes an introductory chapter and
a chapter on water. Students with extensive exposure to chem-
istry can use this material for review. For students with little
previous experience, these two chapters provide the chemistry
background they will need to appreciate the molecular struc-
tures and metabolic reactions they will encounter later.
Part 2 begins with a chapter on the genetic basis of mac-
romolecular structure and function (Chapter 3, Nucleic Acid
Structure and Function). This is followed by chapters on pro-
tein structure (Chapter 4) and protein function (Chapter 5),
with coverage of myoglobin and hemoglobin, cytoskeletal
and motor proteins, and antibodies. An explanation of how
enzymes work (Chapter 6) precedes a discussion of enzyme
kinetics (Chapter 7), an arrangement that allows students to
grasp the importance of enzymes and to focus on the chemistry
P reface xv
of enzyme-catalyzed reactions before delving into the more
quantitative aspects of enzyme kinetics. A chapter on lipid
chemistry (Chapter 8, Lipids and Membranes) is followed by
two chapters that discuss critical biological functions of mem-
branes (Chapter 9, Membrane Transport, and Chapter 10,
Signaling). The section ends with a chapter on carbohydrate
chemistry (Chapter 11), completing the survey of molecular
structure and function.
Part 3 begins with an introduction to metabolism that
provides an overview of fuel acquisition, storage, and mobi-
lization as well as the thermodynamics of metabolic reactions
(Chapter 12). This is followed, in traditional fashion, by chap-
ters on glucose and glycogen metabolism (Chapter 13); the
citric acid cycle (Chapter 14); electron transport and oxida­tive
phosphorylation (Chapter 15); the light and dark reactions of
photosynthesis (Chapter 16); lipid catabolism and biosynthe-
sis (Chapter 17); and pathways involving nitrogen-containing
compounds, including the synthesis and degradation of
amino acids, the synthesis and degradation of nucleotides,
and the nitrogen cycle (Chapter 18). The final chapter of Part
2 ­explores the integration of mammalian metabolism, with
extensive discussions of hormonal control of metabolic path-
ways, disorders of fuel metabolism, and cancer (Chapter 19).
Part 4, the management of genetic information, ­includes
three chapters, covering DNA replication and repair (Chap-
ter 20), transcription (Chapter 21), and protein ­ synthesis
(Chapter 22). Because these topics are typically also covered
in other courses, Chapters 20–22 emphasize the relevant bio-
chemical details, such as topoisomerase ­action, nucleosome
structure, mechanisms of polymerases and other enzymes,
structures of accessory proteins, proofreading strategies, and
­chaperone-assisted protein folding.
The WileyPLUS Advantage
WileyPLUS is a research-based online environment for effec-
tive teaching and learning. The customization features, qual-
ity question banks, interactive eTextbook, and analytical tools
allow you to quickly create a customized course that tracks
student learning trends. Your students can stay engaged and
on track with the use of intuitive tools like the syncing cal­
endar and the student mobile app. All Wiley educational prod-
ucts and services are born accessible, designed for users of
all abilities.
Guided Tours cover the major topics of the course. These
multi-part tutorials explain biochemistry in time and space.
Interactive questions at the end of each tour reinforce learning.
Assignable End-of-Chapter Questions, over 20 per
chapter, can be assigned to students through WileyPLUS.
Twenty-four Sample Calculation Videos walk students
through each step of the sample calculations.
xvi Preface
Brief Bioinformatics Exercises crafted by Rakesh
Mogul at California State Polytechnic University, Pomona,
provide detailed instructions for novices to access and use
bioinformatics databases and software tools. Each of the 57
exercises includes multiple-choice questions to help students
gauge their success in learning from these resources.
Do You Remember Practice Quizzes help students
prepare for new material by reinforcing relevant topics from
previous chapters.
Concept Check Questions for each section allow stu-
dents to test their knowledge.
Discussion Questions are thought-provoking questions
that serve as a point of departure for student discussion and
engagement with content.
Twenty-three Animated Process Diagrams bring
multi-step figures to life.
Bioinformatics Projects, written by Paul Craig at Roch-
ester Institute of Technology, provide guidance for 12 extended
explorations of online databases, with questions, many open-
ended, for students to learn on their own.
Acknowledgments
Unless otherwise noted, molecular graphics images were created using
data from the Protein Data Bank (www.rcsb.org) with the PyMol Molec-
ular Graphics System Version 2.1, Schrödinger LLC, originally developed
by Warren DeLano, or with the Swiss-Pdb Viewer [Guex, N., Peitsch,
M.C., SWISS-MODEL and the Swiss-Pdb Viewer: an environment for
comparative protein modeling, Electrophoresis 18, ­2714–2723 (1997).
We would like to thank everyone who helped develop Essential Bio-
chemistry, Fifth Edition, including Associate Publisher Sladjana Bruno,
Senior Editor Jennifer Yee, Senior Course Production Operations Spe-
cialist Patricia Gutierrez, Course Content Developers Corrina Santos
and Andrew Moore, Senior Designer Thomas Nery, Editorial Assis-
tant Samantha Hart, and the Lumina Datamatics team.
We also thank all the reviewers who provided essential feedback on
manuscript and media, corrected errors, and made valuable sugges-
tions for improvements that have been so important in the writing
and development of Essential Biochemistry, Fifth Edition
Fifth Edition Reviewers:
Arkansas
Cindy L. White, Harding University
California
M. Nidanie Henderson-Stull, Soka University of America
Rakesh Mogul, California State Polytechnic University, Pomona
Florida
Vijaya Narayanan, Florida International University
Massachusetts
Emily Westover, Brandeis University
Michigan
Allison C. Lamanna, University of Michigan
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in WileyPLUS
• PowerPoint Art Slides.
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versity and Anne Grippo, Arkansas State University.
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P reface xvii
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 CHAPTER 1

The Chemical
Basis of Life
This first chapter offers a preview of the study of biochemis­

DSP/deepseaphotography
try, broken down into three sections that reflect how topics
in this book are organized. First come brief descriptions of
the four major types of small biological molecules and their
polymeric forms. Next is a summary of the thermodynamics
that apply to metabolic reactions. Finally, there is a discus­
sion of the origin of self-replicating life-forms and their evo­
lution into modern cells. These short discussions introduce
some of the key players and major themes of biochemistry The chemical reactions of living systems take place across a wide
and provide a foundation for the topics that will be encoun­ range of conditions. Although many microbial species can tolerate
extreme heat, multicellular organisms require much more temper­
tered in subsequent chapters.
ate habitats. One exception is Alvinella pompejana, the Pompeii
worm, which lives near deep-sea hydrothermal vents and thrives
at 42°C (107°F). Hair-like colonies of symbiotic bacteria may help
insulate its body.

1.1 What Is Biochemistry?

LEARNING OBJECTIVE

Recognize the main themes of biochemistry.

Biochemistry is the scientific discipline that seeks to explain life at the molecular level. It
uses the tools and terminology of chemistry to describe the various attributes of living organ­
isms. Biochemistry offers answers to such fundamental questions as “What are we made
of?” and “How do we work?” Biochemistry is also a practical science: It generates powerful
techniques that underlie advances in other fields, such as genetics, cell biology, and immu­
nology; it offers insights into the treatment of diseases such as cancer and diabetes; and it
improves the efficiency of industries such as wastewater treatment, food production, and
drug manufacturing.
Some aspects of biochemistry can be approached by studying individual molecules iso­
lated from cells. A thorough understanding of each molecule’s physical structure and chem­
ical reactivity helps lead to an understanding of how molecules cooperate and combine to
form larger functional units and, ultimately, the intact organism (Fig. 1.1). However, just
as a clock completely disassembled no longer resembles a clock, information about a multi­
tude of biological molecules does not necessarily reveal how an organism lives. Biochemists
therefore investigate how organisms behave under different conditions or when a particular
molecule is modified or absent. In addition, they collect vast amounts of information about
molecular structures and functions—information that is stored and analyzed by computer, a
field of study known as bioinformatics. A biochemist’s laboratory is as likely to hold racks
of test tubes as flasks of bacteria or computers.
Chapters 3 through 22 of this book are divided into three groups that roughly correspond
to three major themes of biochemistry:
1
2 C hA pTER 1 The Chemical Basis of Life

Organism
Organ
Cell

Liver Organelle

Hepatocyte

Mitochondrion
Molecules
Human
FIGURE 1.1 Levels of
organization in a living Citrate synthase
organism. Biochemistry
focuses on the structures and
functions of molecules. Interac­

Photodisc/Getty Images
tions between molecules give rise
to higher­order structures (for DNA
Citrate
example, organelles), which may
themselves be components of
larger entities, leading ultimately
Ubiquinone
to the entire organism.

1. Living organisms are made of macromolecules. Some molecules are responsible for the
physical shapes of cells. Others carry out various activities in the cell. (For convenience,
we often use cell interchangeably with organism since the simplest living entity is a
single cell.) In all cases, the structure of a molecule is intimately linked to its function.
Understanding a molecule’s structural characteristics is therefore an important key to
understanding its functional significance.
2. Organisms acquire, transform, store, and use energy. The ability of a cell to carry out
metabolic reactions—to synthesize its constituents and to move, grow, and reproduce—
requires the input of energy. A cell must extract this energy from the environment and
spend it or store it in a manageable form.
3. Biological information is transmitted from generation to generation. Modern human
beings look much like they did 100,000 years ago. Certain bacteria have persisted for
millions, if not billions, of years. In all organisms, the genetic information that specifies
a cell’s structural composition and functional capacity must be safely maintained and
transmitted each time the cell divides.

Several other themes run throughout biochemistry and we will highlight these where
appropriate.

4. Cells maintain a state of homeostasis. Even within its own lifetime, a cell may dramati­
cally alter its shape or metabolic activities, but it does so within certain limits. In order
to remain in a steady, nonequilibrium state—homeostasis—the cell must recognize
changing internal and external conditions and regulate its activities.
5. Organisms evolve. Over long periods of time, the genetic composition of a population
of organisms changes. Examining the molecular makeup of living organisms allows
biochemists to identify the genetic features that distinguish groups of organisms and to
trace their evolutionary history.
6. Diseases can be explained at the biochemical level. Identifying the molecular defects
that underlie human diseases, or investigating the pathways that allow one organism
to infect another, is the first step in diagnosing, treating, preventing, or curing a host
of ailments.
 1.2 Biological Molecules 3

1.2 Biological Molecules

LEARNING OBJECTIVES

Identify the major classes of biological molecules.

• List the elements found in biological molecules.
• Draw and name the common functional groups in biological molecules.
• Draw and name the common linkages in biological molecules.
• D
 istinguish the main structural features of amino acids, carbohydrates, nucleotides,
and lipids.
• I dentify the monomers and linkages in polypeptides, polysaccharides, and
nucleic acids.
• Summarize the biological functions of the major classes of biological molecules.

Even the simplest organisms contain a staggering number of different molecules, yet this
number represents only an infinitesimal portion of all the molecules that are chemically
possible. For one thing, only a small subset of the known elements are found in living systems
(Fig. 1.2). The most abundant of these are C, N, O, and H, followed by Ca, P, K, S, Cl, Na, and
Mg. Certain trace elements are also present in very small quantities.
Virtually all the molecules in a living organism contain carbon, so biochemistry can be
considered to be a branch of organic chemistry. In addition, nearly all biological molecules
are constructed from H, N, O, P, and S. Most of these molecules belong to one of a few struc­
tural classes, which are described below.
Similarly, the chemical reactivity of biomolecules is limited relative to the reactivity of all
chemical compounds. A few of the functional groups and intramolecular linkages that are
common in biochemistry are listed in Table 1.1. Familiarity with these functional groups is
essential for understanding the behavior of the different types of biological molecules we will
encounter throughout this book.

Cells contain four major types of biomolecules

Most of the cell’s small molecules can be divided into four classes. Although each class
contains many members, they are united under a single structural or functional definition.
­Identifying a particular molecule’s class may help predict its chemical properties and possibly
its role in the cell.

1
H
5 6 7 8 9
B C N O F
11 12 13 14 15 16 17
Na Mg Al Si P S Cl
19 20 23 24 25 26 27 28 29 30 33 34 35
K Ca V Cr Mn Fe Co Ni Cu Zn As Se Br
42 48 53
Mo Cd I
74
W

FIGURE 1.2 Elements found in biological systems. The most abundant elements are most
darkly shaded; trace elements are most lightly shaded. Not every organism contains every trace
element. Biological molecules primarily contain H, C, N, O, P, and S.
4 C h apter 1 The Chemical Basis of Life

TA BLE 1 .1 Common Functional Groups and Linkages in Biochemistry

Compound name Structure a Functional group

RNH2 or RNH3

Amine b R2NH or R2NH2 N or N (amino group)
R3N or R3NH
Alcohol ROH OH (hydroxyl group)
Thiol RSH SH (sulfhydryl group)
Ether ROR O (ether linkage)
O O O

Aldehyde R C H C (carbonyl group), R C (acyl group)

O O O
Ketone R C R C (carbonyl group), R C (acyl group)

O O
Carboxylic acid b R C OH or C OH (carboxyl group) or
(Carboxylate) O O
R C O C O (carboxylate group)
O O
Ester R C OR C O (ester linkage)

S S
Thioester R C OR C O (thioester linkage)

O
R C NH2
O O
Amide
R C NHR C N (amido group)
O
R C NR2
Imine b R NH or R NH
2  H
R NR or R NHR C N or C N (imino group)

O O
R O P OH or O P O (phosphoester linkage)

Phosphoric acid OH OH
ester b, c O O O

R O P O P OH or P O (phosphoryl group)
O OH O
O O O O
R O P O P OH or O P O P O (phosphoanhydride linkage)

Diphosphoric acid OH OH OH OH
ester b, d O O O O O O

R O P O P O P O P OH or P O P O
O O OH OH O O
(diphosphoryl group, pyrophosphoryl group)

a
R represents any carbon-containing group. In a molecule with more than one R group, the groups may be the
same or different.
b
Under physiological conditions, these groups are ionized and hence bear a positive or negative charge.
c
When R = H, the molecule is inorganic phosphate (abbreviated Pi ), usually ​​H2PO​  − 2−
4​  ​​ or ​​HPO​  4​  ​​.
d
When R = H, the molecule is pyrophosphate (abbreviated PPi ).
Question Cover the structure column and draw the structure for each compound listed on the left. Do
the same for each functional group.
 1.2 Biological Molecules 5

COO–
H C CH3
NH+
3
a.
A structural formula includes
all the atoms and the major
bonds. Some bonds, such as c.
the C—O and N—H bonds, The space-filling model best represents
are implied. The central carbon b. the actual shape of the molecule but
has tetrahedral geometry. A ball-and-stick representation more accurately may obscure some of its atoms and linkages.
The horizontal bonds extend reveals the arrangement of atoms in space, Each atom is shown as a sphere whose
slightly above the plane of the although it does not show their relative sizes or radius (the van der Waals radius)
page and the vertical bonds electrical charges. The atoms are color-coded by corresponds to the distance of closest
extend slightly behind it. convention: C gray, N blue, O red, and H white. approach by another atom.

FIGURE 1.3 Representations of alanine. a. Structural formula, b. ball-and-stick model, and

c. space-filling model.

1. Amino Acids Among the simplest compounds are the amino acids, so named

physiological conditions, these groups are actually ionized to ​NH​  +

3​  ​​ and COO . The com­
because they contain an amino group (NH2) and a carboxylic acid group (COOH). Under
−

mon amino acid alanine—like other small molecules—can be depicted in different ways, for
example, by a structural formula, a ball-and-stick model, or a space-filling model (Fig. 1.3).
Other amino acids resemble alanine in basic structure, but instead of a methyl group (CH3),
they have another group—called a side chain or R group—that may also contain N, O, or S;
for example,

COO– O COO–
H C CH2 C H C CH2 SH
NH+ NH2 NH+
3 3
Asparagine Cysteine

2. Carbohydrates Simple carbohydrates (also called monosaccharides or just sug­

ars) have the formula (CH2O)n, where n is ≥ 3. Glucose, a monosaccharide with six carbon
atoms, has the formula C6H12O6. It is sometimes convenient to draw it as a ladder-like chain
(left); however, glucose forms a cyclic structure in solution (right):

O H
C
H C OH CH2OH
HO C H O
H H H
H C OH
OH H
H C OH HO OH

CH2OH H OH
Glucose

In the representation of the cyclic structure, the darker bonds project in front of the page and

are replaced by other groups, but the ring structure and multiple OH groups of these mole­
the lighter bonds project behind it. In many monosaccharides, one or more hydroxyl groups

cules allow them to be easily recognized as carbohydrates.

6 C h apter 1 The Chemical Basis of Life

3. Nucleotides A five-carbon sugar, a nitrogen-containing ring, and one or more

phosphate groups are the components of nucleotides. For example, adenosine triphosphate
(ATP) contains the nitrogenous group adenine linked to the monosaccharide ribose, to which
a triphosphate group is also attached:

NH2
N Adenine
N
Triphosphate
O O O N N
−
O P O P O P O CH2 O
O− O− O− H H Ribose
H H

OH OH
Adenosine triphosphate (ATP)

The most common nucleotides are mono-, di-, and triphosphates containing the nitrogenous
ring compounds (or “bases”) adenine, cytosine, guanine, thymine, or uracil (abbreviated A,
C, G, T, and U).

4. Lipids The fourth major group of biomolecules consists of the lipids. These com­
pounds cannot be described by a single structural formula since they are a diverse collection
of mole­cules. However, they all tend to be poorly soluble in water because the bulk of their
structure is hydrocarbon-like. For example, palmitic acid consists of a highly insoluble chain
of 15 carbons attached to a carboxylic acid group, which is ionized under physiological condi­
tions. The anionic lipid is therefore called palmitate.

O
CH2 CH2 CH2 CH2 CH2 CH2 CH2 C O−
H3C CH2 CH2 CH2 CH2 CH2 CH2 CH2
Palmitate

Cholesterol, although it differs significantly in structure from palmitate, is also poorly soluble
in water because of its hydrocarbon-like composition.

CH3 CH3
CH CH2 CH2 CH2 CH
CH3
CH3
CH3

HO
Cholesterol

Cells also contain a few other small molecules that cannot be easily classified into the groups
above or that are constructed from molecules belonging to more than one group.

There are three major kinds of biological polymers

In addition to small molecules consisting of relatively few atoms, organisms contain macro­
molecules that may consist of thousands of atoms. Such huge molecules are not synthesized
in one piece but are built from smaller units. This is a universal feature of nature: A few kinds
 1.2 Biological Molecules 7

Box 1.A Units Used in Biochemistry

Biochemists follow certain conventions when quantifying objects mega (M) 106 nano (n) 10−9
on a molecular scale. For example, the mass of a molecule can be kilo (k) 103
pico (p) 10−12
expressed in atomic mass units; however, the masses of biolog­ical
milli (m) 10−3 femto (f) 10−15
molecules—especially very large ones—are typically given with­ −6
out units. Here it is understood that the mass is expressed relative micro ( µ) 10
to one-twelfth the mass of an atom of the common carbon isotope For example, the concentration of the sugar glucose in human
12
C (12.011 atomic mass units). Occasionally, units of daltons (D) blood is about 5 mM, but many intracellular molecules are pres­
are used (1 dalton = 1 atomic mass unit), often with the prefix ent at concentrations of µM or less.
kilo, k (kD). This is useful for macromolecules such as proteins, Distances are customarily expressed in angstroms, Å (1 Å =
many of which have masses in the range from 20,000 (20 kD) to 10−10 m) or in nanometers, nm (1 nm = 10−9 m). For example, the
over 1,000,000 (1000 kD). distance between the centers of carbon atoms in a CC bond is
The standard metric prefixes are also necessary for express­ about 1.5 Å and the diameter of a DNA molecule is about 20 Å.
ing the minute concentrations of biomolecules in living cells. Con­
centrations are usually given as moles per liter (mol · L−1 or M), Question The diameter of a typical spherical bacterial cell
with the appropriate prefix, such as m, µ, or n: is about 1 µm. What is the cell’s volume?

of building blocks can be combined in different ways to produce a wide variety of larger struc-
tures. This is advantageous for a cell, which can get by with a limited array of raw materi­
als. In addition, the very act of chemically linking individual units (monomers) into longer
strings (polymers) is a way of encoding information (the sequence of the monomeric units)
in a stable form. Biochemists use certain units of measure to describe both large and small
molecules (Box 1.A).
Amino acids, monosaccharides, and nucleotides each form polymeric structures with
widely varying properties. In most cases, the individual monomers become covalently linked
in head-to-tail fashion:

Residue

Monomers Polymer

The linkage between monomeric units is characteristic of each type of polymer. The mono­
mers are called residues after they have been incorporated into the polymer. Strictly speak­
ing, lipids do not form polymers, although they do tend to aggregate to form larger structures
such as cell membranes. Most of the mass of a cell consists of polymers, with proteins
accounting for the greatest share (Fig. 1.4).

Inorganic ions
Small molecules

Nucleic acids

Carbohydrates

Proteins

Lipids

FIGURE 1.4 Mass of a mammalian cell. Proteins and lipids account for about 75% of the dry
mass of a typical mammalian cell.
8 C h apter 1 The Chemical Basis of Life

1. Proteins Polymers of amino acids are called polypeptides or proteins. Twenty dif­
ferent amino acids serve as building blocks for proteins, which may contain many hundreds
of amino acid residues. The amino acid residues are linked to each other by amide bonds
called peptide bonds. A peptide bond (arrow) links the two residues in a dipeptide (the side
chains of the amino acids are represented by R1 and R2).

R1 O R2 O
+
H3N C C N C C
H H H O–

a.
Because the side chains of the 20 amino acids have different sizes, shapes, and chemical prop­
erties, the exact conformation (three-dimensional shape) of the polypeptide chain depends
on its amino acid composition and sequence. For example, the small polypeptide endothelin,
with 21 residues, assumes a compact shape in which the polymer bends and folds to accom­
modate the functional groups of its amino acid residues (Fig. 1.5).
The 20 different amino acids can be combined in almost any order and in almost any pro­
portion to produce myriad polypeptides, all of which have unique three-dimensional shapes.
This property makes proteins as a class the most structurally variable and therefore the most
functionally versatile of all the biopolymers. Accordingly, proteins perform a wide variety of
tasks in the cell, such as mediating chemical reactions and providing structural support.

2. Nucleic Acids Polymers of nucleotides are termed polynucleotides or nucleic

acids, better known as DNA and RNA. Unlike polypeptides, with 20 different amino acids
available for polymerization, each nucleic acid is made from just four different nucleotides.
For exam­ple, the residues in RNA contain the bases adenine, cytosine, guanine, and uracil,
whereas the residues in DNA contain adenine, cytosine, guanine, and thymine. Polymeriza­
b.
tion involves the phosphate and sugar groups of the nucleotides, which become linked by
FIGURE 1.5 Structure of phosphodiester bonds.
human endothelin. The 21
amino acid residues of this poly­
peptide, shaded from blue to red, O–
form a compact structure. In –
a, each amino acid residue is O P O
represented by a sphere. The ball-
O
and-stick model b shows all the
atoms except hydrogen. CH2 O Base
H H
H H

O H
Phosphodiester bond –
O P O
O
CH2 O Base
H H
H H

OH H

In part because nucleotides are much less variable in structure and chemistry than amino
acids, nucleic acids tend to have more regular structures than proteins. This is in keeping with
their primary role as carriers of genetic information, which is contained in their sequence of
 1.2 Biological Molecules 9

nucleotide residues rather than in their three-dimensional shape (Fig. 1.6). Nevertheless, many CGUACG
nucleic acids do bend and fold into compact globular shapes, as proteins do. a.

3. Polysaccharides Polysaccharides usually contain only one or a few different

types of monosaccharide residues, so even though a cell may synthesize dozens of differ­
ent kinds of monosaccharides, most of its polysaccharides are homogeneous polymers. This
tends to limit their potential for carrying genetic information in the sequence of their resi­
dues (as nu­cleic acids do) or for adopting a large variety of shapes and mediating chemical
reactions (as proteins do). On the other hand, polysaccharides perform essential cell functions
by serving as fuel-storage molecules and by providing structural support. For example, plants
link the monosaccharide glucose, which is a fuel for virtually all cells, into the polysaccharide
starch for long-term storage. The glucose residues are linked by glycosidic bonds (the bond
is shown in red in this disaccharide):

CH2OH CH2OH
O O
H H H H H H

HO OH H O OH H OH
b.

H OH H OH FIGURE 1.6 Structure of a

nucleic acid. a. Sequence of
nucleotide residues, using one-letter
Glucose monomers are also the building blocks for cellulose, the extended polymer that helps abbreviations. b. Ball-and-stick
make plant cell walls rigid (Fig. 1.7). The starch and cellulose polymers differ in the arrange­ model of the polynucleotide, show­
ment of the glycosidic bonds between glucose residues. ing all atoms except hydrogen (this
structure is a six-residue segment
The brief descriptions of biological polymers given above are generalizations, meant to of RNA).
convey some appreciation for the possible structures and functions of these macromolecules.
Exceptions to the generalizations abound. For example, some small polysaccharides encode
information that allows cells bearing the molecules on their surfaces to recognize each other.
Likewise, some nucleic acids perform structural roles, for example, by serving as scaffolding
in ribosomes, the small machines where protein synthesis takes place. Under certain condi­
tions, proteins are called on as fuel-storage molecules. A summary of the major and minor
functions of proteins, polysaccharides, and nucleic acids is presented in Table 1.2.

Glucose Starch

Cellulose

FIGURE 1.7 Glucose and its polymers. Both starch and cellulose are polysaccharides containing
glucose residues. They differ in the type of chemical linkage between the monosaccharide units. Starch
molecules have a loose helical conformation, whereas cellulose molecules are extended and relatively stiff.
10 C ha pter 1 The Chemical Basis of Life

TAB L E 1. 2 Functions of Biopolymers

Carry out Support

Encode metabolic cellular
Biopolymer information reactions Store energy structures
Proteins — ✔ ✓ ✔
Nucleic acids ✔ ✓ — ✓
Polysaccharides ✓ — ✔ ✔

✔ major function
✓ minor function

Before Going On
• List the six most abundant elements in biological molecules.
• Name the common functional groups and linkages shown in Table 1.1.
• Give the structural or functional definitions for amino acids, monosaccharides, nucleotides,
and lipids.
• Describe the advantage of building a polymer from monomers.
• Give the structural definitions and major functions of proteins, polysaccharides, and
nucleic acids.
• Name the linkage in each type of polymer.
• List the major functions of proteins, polysaccharides, and nucleic acids.

1.3 Energy and Metabolism

LEARNING OBJECTIVES

Explain how enthalpy, entropy, and free energy apply to biological systems.
• Define enthalpy, entropy, and free energy.
• Write the equation that links changes in enthalpy, entropy, and free energy.
• Relate changes in enthalpy and entropy to the spontaneity of a process.
• Describe the energy flow that makes living systems thermodynamically possible.

Assembling small molecules into polymeric macromolecules requires energy. And unless
the monomeric units are readily available, a cell must synthesize the monomers, which
also requires energy. In fact, cells require energy for all the functions of living, growing,
and reproducing.
It is useful to describe the energy in biological systems using the terminology of thermody­
namics (the study of heat and power). An organism, like any chemical system, is subject to the
laws of thermodynamics. According to the first law of thermodynamics, energy cannot be cre­
ated or destroyed. However, it can be transformed. For example, the energy of a river flowing
over a dam can be harnessed as electricity, which can then be used to produce heat or perform
mechanical work. Cells can be considered to be very small machines that use chemical energy
to drive metabolic reactions, which may also produce heat or carry out mechanical work.
 1.3 Energy and Metabolism 11

Enthalpy and entropy are components of free energy

The energy relevant to biochemical systems is called the Gibbs free energy (after the scien­
tist who defined it) or just free energy. It is abbreviated G and has units of joules per mol
(J · mol−1). Free energy has two components: enthalpy and entropy. Enthalpy (abbreviated
H, with units of J · mol−1) is taken to be equivalent to the heat content of the system. Entropy
(abbreviated S, with units of J · K−1 · mol−1) is a measure of how the energy is dispersed within
that system. Entropy can therefore be considered to be a measure of the system’s disorder or
randomness, because the more ways a system’s components can be arranged, the more dis­
persed its energy. For example, consider a pool table at the start of a game when all 15 balls
are arranged in one neat triangle (a state of high order or low entropy). After play has begun,
the balls are scattered across the table, which is now in a state of disorder and high entropy
(Fig. 1.8).
Free energy, enthalpy, and entropy are related by the equation

G = H − TS (1.1)

where T represents temperature in Kelvin (equivalent to degrees Celsius plus 273). Tempera­
ture is a coefficient of the entropy term because entropy varies with temperature; the entropy
of a substance increases when it is warmed because more thermal energy has been dispersed
within it. The enthalpy of a chemical system can be measured, although with some difficulty,
but it is next to impossible to measure a system’s entropy because this would require counting
all the possible arrangements of its components or all the ways its energy could be spread out
among them. Therefore, it is more practical to deal with changes in these quantities (change is
indicated by the Greek letter delta, ∆) so that

∆G = ∆H − T∆S (1.2)

Biochemists can measure how the free energy, enthalpy, and entropy of a system differ
before and after a chemical reaction. For example, exothermic reactions are accompanied
by the release of heat to the surroundings (Hfinal − Hinitial = ∆H < 0), whereas endother-
mic ­reactions absorb heat from the surroundings (∆H > 0). Similarly, the entropy change,
Sfinal − S­initial = ∆S, can be positive or negative. When ∆H and ∆S for a process are known,
Equation 1.2 can be used to calculate the value of ∆G at a given temperature (see Sample
Calculation 1.1).

a. b.
FIGURE 1.8 Illustration of entropy. Entropy is a measure of the dispersal of energy in a system,
so it reflects the system’s randomness or disorder. a. Entropy is low when all the balls are arranged in
a single area of the pool table. b. Entropy is high after the balls have been scattered, because there are
now a large number of different possible arrangements of the balls on the table.
Question Compare the entropy of a ball of yarn before and after a cat has played with it.
12 C ha pter 1 The Chemical Basis of Life

SA MP L E CALCU LAT I O N 1 . 1
Problem Use the information below to calculate the change in Solution
enthalpy and the change in entropy for the reaction A → B. ∆H = HB − HA ∆S = SB − SA
−1 −1
= 75 kJ · mol − 60 kJ · mol = 97 J · K−1 · mol−1
Enthalpy (kJ · mol−1) Entropy (J · K−1 · mol−1)
= 15 kJ · mol − 22 J · K−1 · mol−1
−1
A 60 22
= 15,000 J · mol−1 = 75 J · K−1 · mol−1
B 75 97

∆G is less than zero for a spontaneous process

SEE SAMPLE
CALCULATION A china cup dropped from a great height will break, but the pieces will never reassemble
VIDEOS themselves to restore the cup. The thermodynamic explanation is that the broken pieces have
less free energy than the intact cup. In order for a process to occur, the overall change in free
energy (∆G) must be negative. For a chemical reaction, this means that the free energy of the
products must be less than the free energy of the reactants:

∆G = Gproducts − Greactants < 0 (1.3)

When ∆G is less than zero, the reaction is said to be spontaneous or exergonic. A non-
spontaneous or endergonic reaction has a free energy change greater than zero; in this
case, the reverse reaction is spontaneous:

A→B B→A
∆G > 0 ∆G < 0
Nonspontaneous Spontaneous

Note that thermodynamic spontaneity does not indicate how fast a reaction occurs, only whether
it will occur as written. (The rate of a reaction depends on other factors, such as the concentra­
tions of the reacting molecules, the temperature, and the presence of a catalyst.) When a reac­
tion, such as A → B, is at equilibrium, the rate of the forward reaction is equal to the rate of the
reverse reaction, so there is no net change in the system. In this situation, ∆G = 0.
A quick examination of Equation 1.2 reveals that a reaction that occurs with a decrease
in enthalpy and an increase in entropy is spontaneous at all temperatures because ∆G is always
less than zero. These results are consistent with everyday experience. For example, heat moves
spontaneously from a hot object to a cool object, and items that are neatly arranged tend to
become disordered, never the other way around. (This is a manifestation of the second law
of thermodynamics, which states that energy tends to spread out.) Accordingly, reactions in
which the enthalpy increases and entropy decreases do not occur. If enthalpy and entropy
both increase or both decrease during a reaction, the value of ∆G then depends on the tem­
perature, which governs whether the T∆S term of Equation 1.2 is greater than or less than
the ∆H term. This means that a large increase in entropy can offset an unfavorable (positive)
change in enthalpy. Conversely, the release of a large amount of heat (∆H < 0) during a reac­
tion can offset an unfavorable decrease in entropy (see Sample Calculation 1.2).

Life is thermodynamically possible

In order to exist, life must be thermodynamically spontaneous. Does this hold at the molec­
ular level? When analyzed in a test tube (in vitro, literally “in glass”), many of a cell’s met­
abolic reactions have free energy changes that are less than zero, but some reactions do not.
Nevertheless, the nonspontaneous reactions are able to proceed in vivo (in a living organism)
because they occur in concert with other reactions that are thermodynamically favorable.
Consider two reactions in vitro, one nonspontaneous (∆G > 0) and one spontaneous (∆G < 0):

A → B   ∆G = +15 kJ · mol−1 (nonspontaneous)

B → C  ∆G = −20 kJ · mol−1 (spontaneous)
 1.3 Energy and Metabolism 13

SA MP L E CA LCULAT I ON 1. 2
Problem Use the information given in Sample Calculation 1.1 = 15,000 − 22,400 J · mol−1
to determine whether the reaction A → B is spontaneous at 25°C. = −7400 J · mol−1
Solution Substitute the values for ∆H and ∆S, calculated in = −7.4 kJ · mol−1
Sample Calculation 1.1, into Equation 1.2. To express the tem­
perature in Kelvin, add 273 to the temperature in degrees Celsius: Because ∆G is less than zero, the reaction is spontaneous. Even
273 + 25 = 298 K. though the change in enthalpy is unfavorable, the large increase
in entropy makes ∆G favorable.
∆G = ∆H − T∆S
= 15,000 J · mol−1 − 298 K (75 J · K−1 · mol−1)

When the reactions are combined, their ∆G values are added, so the overall process has a
negative change in free energy: SEE SAMPLE
CALCULATION
A + B → B + C   ∆G = (15 kJ · mol−1) + (−20 kJ · mol−1)
VIDEOS
A → C  ∆G = −5 kJ · mol−1
     

This phenomenon is shown graphically in Figure 1.9. In effect, the unfavorable “uphill”
reaction A → B is pulled along by the more favorable “downhill” reaction B → C.
Cells couple unfavorable metabolic processes with favorable ones so that the net change in
free energy is negative. Note that it is permissible to add ∆G values because the free energy, G,
depends only on the initial and final states of the system, without regard to the specific chem­
ical or mechanical work that occurred in going from one state to the other.
Most macroscopic life on earth today is sustained by the energy of the sun (this was
not always the case, nor is it true of all organisms). In photosynthetic organisms, such
as green plants, light energy excites certain molecules so that their subsequent chemi­
cal reactions occur with a net negative change in free energy. These thermodynamically
favorable (spontaneous) reactions are coupled to the unfavorable synthesis of monosac­
charides from atmospheric CO2 (Fig. 1.10). In this process, the carbon is reduced. Reduc­
tion, the gain of electrons, is accomplished by the addition of hydrogen or the removal of
oxygen (the oxidation states of carbon are reviewed in Table 1.3). The plant—or an ani­
mal that eats the plant—can then break down the monosaccharide to use it as a fuel to
power other metabolic activities. In the process, the carbon is oxidized—it loses elec­
trons through the addition of oxygen or the removal of hydrogen—and ultimately
becomes CO2. The oxidation of carbon is thermodynamically favorable, so it can be cou­
pled to energy-requiring processes such as the synthesis of building blocks and their
polymerization to form macromolecules.

B B

Free energy
(G)
A

Reaction coordinate
FIGURE 1.9 Free energy changes in coupled reactions. A nonspontaneous reaction, such as
A → B, which has a positive value of ∆G, can be coupled to another reaction, B → C, which has a
negative value of ∆G and is therefore spontaneous. The reactions are coupled because the product of
the first reaction, B, is a reactant for the second reaction.
Question Which reaction occurs spontaneously in reverse: C → B, B → A, or C → A?
 14 C ha pter 1 The Chemical Basis of Life

Free
Light energy
energy

O C O H C OH O C O
Reduction Oxidation
(unfavorable) Carbon of (favorable)
a monosaccharide
FIGURE 1.10 Reduction and reoxidation of carbon compounds. The sun pro­
vides the free energy to convert CO2 to reduced compounds such as monosaccharides.
The reoxidation of these compounds to CO2 is thermodynamically spontaneous, so free
TA BLE 1 .3 Oxidation States of Carbon energy can be made available for other metabolic processes. Note that free energy is not
actually a substance that is physically released from a molecule.
Compounda Formula
Carbon dioxideCarbon dioxide O C OO C O
most oxidizedmost oxidized
Virtually all metabolic processes occur with the aid of catalysts called
(least reduced(least
) reduced )
H OH Oenzymes, most of which are proteins (a catalyst greatly increases the rate of
a reaction without itself undergoing any net change). For example, specific
Acetic acid Acetic acid H C CH C C
enzymes catalyze the formation of peptide, phosphodiester, and glycosidic link­
OH OH
H H ages during polymer synthesis. Other enzymes catalyze cleavage of these bonds
Carbon monoxide
Carbon monoxide C O C O to break the polymers into their monomeric units.
A living organism—with its high level of organization of atoms, molecules,
O O
and larger structures—represents a state of low entropy relative to its surround­
Formic acid Formic acid H C H C
ings. Yet the organism can maintain this thermodynamically unfavorable state
OH OH as long as it continually obtains free energy from its food. Thus, living organ­
O O isms do indeed obey the laws of thermodynamics. When the organism ceases to
H H H H
obtain a source of free energy from its surroundings or exhausts its stored food,
Acetone Acetone H C C H C C HC C H
the chemical reactions in its cells reach equilibrium (∆G = 0), which results
H H H H
in death.
H H
O O
AcetaldehydeAcetaldehyde H C CH C C
H H
Before Going On
H H
• Make up values for ∆H and ∆S to generate ∆G values corresponding to a
H H
spontaneous and a nonspontaneous reaction.
Formaldehyde
Formaldehyde C O C O
• Show how increasing temperature affects ∆G when ∆H and ∆S are constant.
H H
• Explain how thermodynamically unfavorable reactions proceed in vivo.
Acetylene Acetylene H C CH HC C H
• Explain why an organism must have a steady supply of food.
H H H H
• Describe the cycle of carbon reduction and oxidation in photosynthesis and
Ethanol Ethanol H C CH OH
C C OH in the breakdown of a compound such as a monosaccharide.

H H H H
H HH H
Ethene Ethene C C C C
H HH H 1.4 The Origin of Cells
H H H H
Ethane Ethane H C CH HC C LE A RNING OBJECTIVES
H
H H H H Summarize the evolutionary history of cells.
H H
• List the events that must have occurred during prebiotic evolution.
Methane Methane H C HH C H
• Name the three domains of life.
least oxidizedleast oxidized
(most reduced(most
) reduced ) H H • Distinguish prokaryotic and eukaryotic cells.
a
Compounds are listed in order of decreasing • Summarize the importance of the human microbiota.
­oxidation state of the red carbon atom.
 1.4 The Origin of Cells 15

Every living cell originates from the division of a parental cell.

Thus, the ability to replicate (make a replica or copy of itself)
is one of the universal characteristics of living organisms. In
order to leave descendants that closely resemble itself, a cell must
contain a set of instructions—and the means for carrying them
out—that can be transmitted from generation to generation.
Over time, the instructions change gradually, so that species
also change, or evolve. By carefully examining an organism’s
genetic information and the cellular machinery that supports

SPL/Science Source
it, biochemists can draw some conclusions about the organ­
ism’s relationship to more ancient life-forms. The history of
evolution is therefore contained not just within the fossil record
but also in the molecular makeup of all living cells. For exam­
ple, nucleic acids participate in the storage and transmission of
genetic information in all organisms, and the oxidation of glu­ FIGURE 1.11 A hydrothermal vent. Life may have originated
cose is an almost universal means for generating metabolic free at these “black smokers,” where high temperatures, H2S, and metal
energy. Consequently, DNA, RNA, and glucose must have been sulfides might have stimulated the formation of biological molecules.
present in the ancestor of all cells.

Prebiotic evolution led to cells

Experimental evidence strongly supports the hypothesis that early in the earth’s history, small
biological molecules such as amino acids and monosaccharides—and even the more elabo­
rate nucleotides—arose spontaneously from inorganic (prebiotic) materials like H2O, CH4,
and HCN. Such reactions, which need an energy source, might have occurred near hydrother­
mal vents, where water as hot as 350°C emerges from the sea floor (Fig. 1.11), or in terrestrial
ponds exposed to lighting and ultraviolet radiation. A less-popular hypothesis is that organic
molecules were delivered to the earth by meteorites, although the origin of those molecules
also needs an explanation. Researchers have recovered amino acids and other biological mol­
ecules from hydrothermal vents and from laboratory experiments designed to mimic condi­
tions on the early earth. Even with some uncertainty about the exact temperatures, reactant
concentrations, and the involvement of catalysts like iron or nickel, organic molecules could
have formed through hypothetical processes such as these:

H H
N
O H
O O H C
C C H N
N C
3H C H H C O 5H C N C H
H C C
H H N N
Glyceraldehyde H
(carbohydrate) Adenine
(nucleotide base)

O O
H H H H
H C H + H C N + O H C N
O C H
H
Glycine
(amino acid)

Regardless of how they formed, the first biological building blocks must have accu­
mulated, acquired reactive phosphate or thioester groups, and reached concentrations that
allowed the formation of polymers. Polymerization might have been stimulated when the
organic molecules—often bearing anionic (negatively charged) groups—aligned themselves
on a cationic (positively charged) mineral surface:
16 C ha pter 1 The Chemical Basis of Life

− Monomers
− Polymer
−
− − − − −
− − − −
+ + + + + + + + + + + +
Clay

In fact, in the laboratory, common clay promotes the polymerization of nucleotides into RNA.
Primitive polymers would have had to gain the capacity for self-replication. Otherwise, no mat­
ter how stable or chemically versatile, such molecules would never have given rise to any­
thing larger or more complicated: The probability of assembling a fully functional cell from a
solution of thousands of separate small molecules is practically nil. Because RNA in modern
cells represents a form of genetic information and participates in all aspects of expressing that
information, it may be similar to the first self-replicating biopolymer. It might have made a
copy of itself by first making a complement, a sort of mirror image, that could then make a
complement of itself, which would be identical to the original molecule (Fig. 1.12).
A replicating molecule’s chances of increasing in number depend on natural selection,
the phenomenon whereby the entities best suited to the prevailing conditions are the likeliest
to survive and multiply (Box 1.B). This would have favored a replicator that was chemically
stable and had a ready supply of building blocks and free energy for making copies of itself.
Accordingly, it would have been advanta­geous to become enclosed in some sort of membrane
that could prevent valuable small molecules from diffusing away. Natural selection would
also have favored replicating systems that developed the means for synthesizing their own
building blocks and for more efficiently harnessing sources of free energy. Fossil evidence
for microscopic life dates to about 3.5 billion years ago, about a billion years after the earth
formed from interstellar dust.
The first cells were probably able to “fix” CO2—that is, convert it to reduced organic
­c ompounds—using the free energy released in the oxidation of readily available inor­
ganic compounds such as H2S or Fe2+. Vestiges of these processes can be seen in modern
metabolic reactions that involve sulfur and iron.
Later, photosynthetic organisms similar to present-day cyanobacteria (also called blue-
green algae) used the sun’s energy to fix CO2:

CO2 + H2O → (CH2O) + O2

The concomitant oxidation of H 2 O to O 2 dramatically increased the concentra­

tion of atmospheric O 2, about 2.5 billion years ago, and made it possible for aerobic

1. The polyA molecule serves

as a template for the
synthesis of a polymer 3. The polyU molecule 4. The chains again separate
containing uracil nucleotides, 2. The two serves as a template and the polyU polymer is
U, which are complementary polymer for the synthesis of a discarded, leaving the original
to adenine nucleotides (in chains new complementary polyA molecule and its exact
modern RNA, A pairs with U). separate. polyA chain. copy.

U U
U U U
U A A
U
A U A A A A A A A A A
U U U U
A A U A U A U A U A A
A A U A + U A + U A A + A
A A U A U A U A A A
A A U A U A U A A A

Original Original Complement Original Copy

FIGURE 1.12 Possible mechanism for the self-replication of a primitive RNA molecule.
For simplicity, the RNA molecule is shown as a polymer of adenine nucleotides, A.
Question Draw a diagram showing how polyU would be replicated.
 1.4 The Origin of Cells 17

Box 1.B How Does Evolution Work?

Documenting evolutionary change is relatively straightforward, but
the mechanisms whereby evolution occurs are prone to misunder­
standing. Populations change over time, and new species arise as a
result of natural selection. Selection operates on individuals, but
its effects can be seen in a population only over a period of time.
Most populations are collections of individuals that share an overall
genetic makeup but also exhibit small variations due to random alter­
ations (mutations) in their genetic material as it is passed from parent
to offspring. In general, the survival of an individual depends on how
well suited it is to the particular conditions under which it lives.
Individuals whose genetic makeup grants them the greatest
rate of survival have more opportunities to leave offspring with
the same genetic makeup. Consequently, their characteristics
become widespread in a population and, over time, the popula­
tion appears to adapt to its environment. A species that is well
suited to its environment tends to persist; a poorly adapted species
fails to reproduce and therefore dies out.
Because evolution is the result of random variations and
changing probabilities for successful reproduction, it is inherently
random and unpredictable. Furthermore, natural selection acts
on the raw materials at hand. It cannot create something out of
nothing but must operate in increments. For example, the insect
wing did not suddenly appear in the offspring of a wingless par­
ent but most likely developed bit by bit, over many generations,
by modification of a heat-exchange appendage. Each step of the
wing’s development would have been subject to natural selection,
eventually making an individual that bore the appendage more
likely to survive, perhaps by being able to first glide and then actu­
ally fly in pursuit of food or to evade predators.
Although we tend to think of evolution as an impercepti­
bly slow process, occurring on a geological time scale, it can be
observed. For example, under optimal conditions, the bacterium
Escherichia coli requires only about 20 minutes to produce a new
generation. In the laboratory, a culture of E. coli cells can prog­
ress through about 2500 generations in a year (in contrast, 2500
human generations would require about 60,000 years). Hence, it
is possible to subject a population of cultured bacterial cells to
some “artificial” selection—for example, by making an essential
nutrient scarce—and observe how the genetic composition of the
population changes over time.
Experiments such as these have revealed that even after an
initial period of rapid adaptation to the new conditions, the popu­
lation continues to change, suggesting that evolution is an ongo­
ing process with no fixed end point. In addition, so-called neutral
mutations, which do not significantly affect an organism’s fitness,
randomly accumulate. For this reason, it is impossible to explain
all genetic changes in terms of adaptations to specific conditions.
Question Why can’t acquired (rather than genetic) charac-
teristics serve as the raw material for evolution?

(oxygen-using) organisms to take advantage of this powerful oxidizing agent. The anaer-
obic origins of life are still visible in the most basic metabolic reactions of modern organ­
isms; these reactions proceed in the absence of oxygen. Now that the earth’s atmosphere
contains about 20% oxygen, anaerobic organisms have not disappeared, but they have been
restricted to microenvironments where O2 is scarce, such as the digestive systems of ani­
mals or underwater sediments.

Eukaryotes are more complex than prokaryotes

The earth’s present-day life-forms are of two types, which are distinguished by their cellular
architecture:

1. Prokaryotes are small unicellular organisms that lack a discrete nucleus and usually
contain no internal membrane systems. This group comprises two subgroups that
are remarkably different metabolically, although they are similar in appearance: the
eubacteria (usually just called bacteria), exemplified by E. coli, and the archaea (or
archaebacteria), best known as organisms that inhabit extreme environments, although
they are actually found almost everywhere (Fig. 1.13).
2. Eukaryotic cells are usually larger than prokaryotic cells and contain a nucleus and
other membrane-bounded cellular compartments (such as mitochondria, chloroplasts,
and endoplasmic reticulum). Eukaryotes may be unicellular or multicellular. This
group (also called the eukarya) includes microscopic organisms as well as familiar
macroscopic plants and animals (Fig. 1.14).

By analyzing the sequences of nucleotides in certain genes that are present in all species,
it is possible to construct a diagram that indicates how the bacteria, archaea, and eukarya
are related. The number of sequence differences between two groups of organisms indicates how
long ago they diverged from a common ancestor. Species with similar sequences have a longer
shared evolutionary history than species with dissimilar sequences. This sort of analysis has
produced the evolutionary tree shown in Figure 1.15.
18 C ha pter 1 The Chemical Basis of Life

Dr. David J. Patterson/Science Source

E. Gray/Science Source
FIGURE 1.14 A eukaryotic cell. The paramecium, a one-
FIGURE 1.13 Prokaryotic cells. celled organism, contains a nucleus and other membrane-bounded
These single-celled Escherichia coli compartments.
bacteria lack a nucleus and internal Question Describe the visible differences between
membrane systems. prokaryotic and eukaryotic cells (Figures 1.13 and 1.14).

FIGURE 1.15 Evolutionary tree based on nucleotide Prokaryotes Eukaryotes

sequences. This diagram reveals that the ancestors of
archaea and bacteria separated before the eukarya emerged Animals
Eukarya
from an archaea-like ancestor. Note that the closely spaced Archaea Fungi
fungi, plants, and animals are actually more similar to each Bacteria Plants
other than are many groups of prokaryotes.

Eukaryotic cells are likely to have evolved from a mixed population of prokaryotic cells
about 1.8 billion years ago. Over many generations of living in close proximity and sharing
each other’s metabolic products, some of the bacterial cells became stably incorporated inside
archaeal cells, which accounts for the mosaic character of modern eukaryotic cells (Fig. 1.16).
The descendants of the once free-living bacteria became mitochondria, which carry out
most of the eukaryote’s oxidative metabolism, or chloroplasts, which carry out photosynthesis
in plants and closely resemble the photosynthetic cyanobacteria. In fact, both mitochondria
and chloroplasts contain their own genetic material and protein-synthesizing machinery and
can grow and divide independently of the rest of the cell. Remnants of the archaeal ancestor
of eukaryotes are found in the eukaryotic cytoskeleton and DNA-replication enzymes.

Nucleus

DNA Organelles
FIGURE 1.16 Possible origin of eukaryotic cells. The close
association of different kinds of free-living cells gradually led to the
modern eukaryotic cell, which appears to be a mosaic of bacterial and
archaeal features and contains organelles that resemble whole
bacterial cells.
 1.4 The Origin of Cells 19

The evolution of eukaryotes included the development of extensive

intracellular membranes, many of which enclose discrete compartments, or
organelles, with specialized functions, such as lysosomes (for the degradation Plasma
membrane
of macromolecules), p ­ eroxisomes (for some oxidative reactions), and vacuoles
(for storage). Like mitochondria and chloroplasts, the nucleus is surrounded Endoplasmic
by a double membrane; the outer nuclear membrane bends and folds exten­ reticulum
sively to form the endoplasmic reticulum. Some key features of eukaryotic Mitochondrion
cell structure are shown in Figure 1.17. A few types of prokaryotic cells also
contain membrane-enclosed compartments devoted to storage or to chemical

Science Source/Science Source

Nucleus
processes that could potentially damage the rest of the cell, but these cells lack
a nucleus and the variety of organelles that characterize eukaryotic cells.
Many types of prokaryotic and eukaryotic cells live in colonies, which
may increase metabolic efficiency through the cooperation of individual
cells. However, a true multicellular lifestyle, which entails the division
of labor and specialization among different types of cells, occurs only in
eukaryotes. Multicellular organisms first appeared in the fossil record
about 600 million years ago. FIGURE 1.17 Eukaryotic cell structure. Key
The earth currently sustains about 10 million different species components of an animal cell are labeled in this
(although estimates vary widely). Perhaps some 500 million species have electron micrograph. A typical plant cell also contains
appeared and vanished over the course of evolutionary history. It chloroplasts and is surrounded by a cell wall.
is unlikely that the earth harbors more than a few mammals that have yet
to be discovered, but new microbial species are routinely described. Although the number of
known prokaryotes (about 10,000) is much less than the number of known eukaryotes (for
example, there are about 900,000 known species of insect), p ­ rokaryotic metabolic lifestyles
are amazingly varied.

The human body includes microorganisms

The human body consists of an estimated 10 trillion (1013) cells, and there may be as many as
40 to 100 trillion microorganisms living in and on the body, including bacteria, archaea, and
fungi (viruses are also present but are molecular parasites rather than true cells). The “for­
eign” cells, mostly living in the intestine, form an integrated community called the micro-
biota. Very few of these cells are pathogens that cause disease; in fact, a diverse and stable
microbiota actually helps to prevent the growth of harmful species.
Analysis of microbial DNA has allowed characterization of the microbiome, the genetic
information contributed by the organisms that make up the microbiota. The microbiome
reveals that the human species hosts several thousand different species of microorganisms.
Many have not yet been identified, and relatively few have been cultured. However, an indi­
vidual person typically harbors only a few hundred species of microorganisms. Establishing
this community of cells begins at birth and is mostly complete after about a year. The mix of
species remains fairly constant throughout the person’s lifetime, although the proportions
may fluctuate somewhat. The microbiota can vary markedly among individuals, even in the
same household. However, the overall metabolic capabilities of the microbial community
seem to matter more than which species are actually present. Contrary to expectations, there
is no core microbiota that is common to all individuals.
The gut microbiota in particular plays a large role in digestion, providing nutrients to the
host and regulating metabolic functions. However, byproducts of microbial metabolism can
act as hormones and neurotransmitters with possible links to anxiety and depression. In turn,
antibiotics, other types of drugs, and even some personal care products can alter the commu­
nity of microorganisms and the chemicals they produce. All the while, the human immune
system must ignore—or “tolerate”—the microbiota. If this balance is disrupted, the immune
system may react to the microorganisms, generating inflammatory responses that can lead to
diabetes or inflammatory bowel disease. Untangling these complicated relationships is the
goal of the Integrated Human Microbiome Project (https://hmpdacc.org/ihmp/), which orga­
nizes data describing the species that inhabit the human body and contribute to human health
and disease.
20 C ha pter 1 The Chemical Basis of Life

Before Going On
• Describe how simple prebiotic compounds could give rise to biological monomers and polymers.
• Explain why anaerobic organisms arose before aerobic organisms.
• Describe the differences between prokaryotes and eukaryotes.
• Explain why eukaryotic cells appear to be mosaics.
• List some functions of the human microbiota.

Summary
1.2 Biological Molecules • Life is thermodynamically possible because unfavorable ender­
gonic processes are coupled to favorable exergonic processes.
• The most abundant elements in biological molecules are H, C,
N, O, P, and S, but a variety of other elements are also present in
living systems.
1.4 The Origin of Cells
• The major classes of small molecules in cells are amino acids, • The earliest cells may have evolved in concentrated solutions of
monosaccharides, nucleotides, and lipids. The major types of bio­ molecules or near hydrothermal vents.
logical polymers are proteins, nucleic acids, and polysaccharides. • Eukaryotic cells contain membrane-bounded organelles. Prokar­
yotic cells, which are smaller and simpler, include the bacteria
1.3 Energy and Metabolism and the archaea.

• Free energy has two components: enthalpy (heat content) and

entropy (disorder). Free energy decreases in a spontaneous process.

Key Terms
bioinformatics phosphodiester bond enzyme
homeostasis polysaccharide replication
trace element glycosidic bond evolution
amino acid free energy (G) complement
carbohydrate enthalpy (H) natural selection
monosaccharide entropy (S) aerobic
nucleotide exothermic reaction anaerobic
lipid endothermic reaction prokaryote
monomer ∆G bacteria
polymer spontaneous process archaea
residue exergonic reaction eukaryote
polypeptide nonspontaneous process eukarya
protein endergonic reaction organelle
peptide bond in vitro microbiota
conformation in vivo microbiome
polynucleotide reduction
nucleic acid oxidation

Bioinformatics
Brief Bioinformatics Exercises 1.2 Organic Functional Groups and the Three-Dimensional Struc­
1.1 The Periodic Table of the Elements and Domains of Life ture of Vitamin C
 Problems 21

Problems
CH3 CH3
1.2 Biological Molecules H3C CH3
CH2OH
1. Use Table 1.1 to assign the appropriate compound name to each
molecule. Retinol
O
a. H3C (CH2)14 C OH CH3 CH3 O
H3C CH3
C
b. H3C CH2 NH2 H
Retinal
O
c. H3C C O CH2 CH3 CH3 CH3 O
H3C CH3
C
d. H3C CH2 OH OH
Retinoic acid
2. Use Table 1.1 to assign the appropriate compound name to each
molecule. 5. Investigators synthesized a series of compounds that showed
promise as drugs for the treatment of Alzheimer’s disease. The struc­
a. H3C O CH3
ture of one of the compounds is shown below. Use Table 1.1 to iden­
OH tify the functional groups in this compound.

b. H3C O P O CH3 OH

O
N
c. H3C CH2 SH
CH3
O O
d. H3C C CH3 6. The structures of several molecules are shown below. Use Table
1.1 to identify the functional groups in each structure.
3. Use Table 1.1 to assign the appropriate compound name to
each molecule.
O
a. OH
O O
H2 H O C
C C C C CH2OH OH
H3C C C H H
H2 H HO OH N
Vitamin C Nicotinic acid (niacin)
b.
N
O
O2N H3C CH3 H3CO CH3
CH3
c. O
H2 H3CO (CH2 CH C CH2)10H
C CH3
H3C C S O
H2 Coenzyme Q

d. 7. Coenzyme A is an important carrier of acetyl groups in metabo­

O O
CH3 lism. Its structure is shown in Figure 3.2. Use Table 1.1 to identify the
CH2 P P functional groups in this molecule.
H3C C O O O−
H O− O− 8. If an acetyl group is attached to the sulfhydryl group of coenzyme
A (see Solution 1.7), what new functional group is formed?
4. The structures of three forms of vitamin A are shown. Use 9. Name the four types of small biological molecules. Which three
Table 1.1 to assign the appropriate compound name to each are capable of forming polymeric structures? What are the names of
molecule. the polymeric structures that are formed?
22 C ha pter 1 The Chemical Basis of Life

10. To which of the four classes of biomolecules do the following d. OCH3

compounds belong?
N N
a. CH2OH
O
O HO CH2 N N NH2
H OH
H
H H
OH H H H
HO H
O H
H NH C CH3
O P O−
O
O−
b. NH2
12. The compound shown below was isolated from the starfish
N Anthenea aspera. What two types of biomolecules are found in this
compound?
O O N
−O O
P O CH2
O− H H
H H O
OH OH NH
O
HO OH O
c. HS CH2 CH2 CH COO−
OH HO
NH+
3 OH
OCH3
d.
d.

13. The nutritive quality of food can be analyzed by measuring the

amounts of the chemical elements it contains. Most foods are mix­
tures of the three major types of molecules: a. fats (lipids), b. car­
O bohydrates, and c. proteins. What elements are present in each of
these types of molecules?
R C O
14. A compound present in many foods has the formula C44H86O8NP.
11. To which of the four classes of biomolecules do the following To which class of molecules does this compound belong? Explain
compounds belong? your answer.
15. A healthy diet must include some protein. Assuming you had
a. O a way to measure the amount of each element in a sample of food,
which element would you measure in order to tell whether the food
O− contained protein?
16. The structures of three compounds are shown below. Based on
b. your answer to Problem 15, which of the three compounds would
O
you add to a food sample so that it would appear to contain more
+
H3N CH C O− protein? Which of the three compounds would already be present in
a food sample that actually did contain protein? Explain.
CH2
Se
O
H
+H O−
H 3N CH C
O NH2
c. CH2OH C CH2
O N N
HO H H C OH CH2
H
2− N
OH H CH2OPO3 H2N NH2 C O
H OH
O−
H OH A B C
 Problems 23

17. The structure of the compound urea is shown. Urea is a waste b. O−

product of metabolism excreted by the kidneys into the urine. Why H3C CH3
do doctors tell patients with kidney damage that they should con­ O O O
sume a low-protein diet? + H
H3N N O−
N N
O H H
O CH3 O
H2N C NH2
Urea

18. The structures of the amino acids asparagine (Asn) and cysteine c. O
(Cys) are shown in Section 1.2. What functional group does Asn have H3C
that Cys does not? What functional group does Cys have that Asn −O NH
does not? 5′ O
O P O CH2 N O
19. Consult Table 4.1 for the structures of the amino acids serine and
lysine. What functional group does serine have that lysine does not? −O
4′ H H
20. Many amino acid side chains are modified after translation. H H NH2
Use the structures of serine and lysine from Problem 19 to draw the 3′ 2′
structures of the following modified amino acids: a. phosphoserine, O H N
b. hydroxylysine, and c. acetyllysine. 5′ O
O P O CH2 O
21. The “straight-chain” structure of glucose is shown in Section 1.2. N
−O
What functional groups are present in the glucose molecule? 4′
H H
22. Consider the monosaccharide fructose. a. How does its molec­ H H
3′ 2′
ular formula differ from that of glucose? b. How does its structure
differ from the structure of glucose? OH H

26. The structure of the artificial sweetener aspartame is shown

CH2OH
below. What type of linkage is found in this compound?
C O
O O
HO C H H
+H N CH C N CH C OCH3
3
H C OH
CH2 CH2
H C OH
C O
CH2OH
O−
Fructose
Aspartame
23. The structures of the nitrogenous bases uracil and cytosine are
shown below. How do their functional groups differ? 27. Compare the solubilities in water of alanine, glucose, palmitate,
and cholesterol, and explain your reasoning.
O NH2
28. Cell membranes are largely hydrophobic structures. Which
compound will pass through a membrane more easily, glucose or
HN N
2,4-dinitro­phenol? Explain.
O N O N OH
H H NO2
Uracil Cytosine

24. What are the structural components of the biological molecules

called nucleotides? NO2
25. What types of linkages are found in the following compounds? 2,4-Dinitrophenol
a. 6 6
CH2OH CH2OH 29. What polymeric molecule forms a more regular structure, DNA
5 5 or protein? Explain this observation in terms of the cellular roles of
O O
HO H OH the two different molecules.
H H
4 1(β)O 4 1(β) 30. What are the two major biological roles of polysaccharides?
OH H OH H
H H H 31. Pancreatic amylase digests the glycosidic bonds that link glucose
3 2 3 2 residues together in starch. Would you expect this enzyme to digest
H OH H OH the glycosidic bonds in cellulose as well? Explain why or why not.
Galactose Glucose 32. The complete digestion of starch in mammals yields 4 kilocalo­
Lactose ries per gram (see Problem 31). What is the energy yield for cellulose?
24 C ha pter 1 The Chemical Basis of Life

1.3 Energy and Metabolism
33. What is the sign of the entropy change for each of the following
processes? a. Water freezes. b. Water evaporates. c. Dry ice sub­
limes. d. Sodium chloride dissolves in water. e. Several different
types of lipid molecules assemble to form a membrane.
34. Does entropy increase or decrease in the following reactions in
aqueous solution?
a. COO−
a. COO−
C O + CO2(g) C O
CH3 CH2
COO−
b. COO− H Assume a temperature of 25°C.
C O + H+ C O + CO2(g)
CH3 CH3
35. Which has the greater entropy, a polymeric molecule or a mix­
ture of its constituent monomers?
36. How does the entropy change when glucose undergoes
combustion?
C6H12O6 + 6 O2 → 6 CO2 + 6 H2O
37. A soccer coach keeps a couple of instant cold packs in her bag
in case one of her players suffers a muscle injury. Instant cold packs
are composed of a plastic bag containing a smaller water bag and
solid ammonium nitrate. In order to activate the cold pack, the bag
is kneaded until the smaller water bag breaks, which allows the
released water to dissolve the ammonium nitrate. The equation for
the dissolution of ammonium nitrate in water is shown below. How
does the cold pack work?
H2O
NH4NO3 (s) ​​NH​  +
4​  ​​  (aq) + ​​NO​  3​  ​​  (aq)
ΔH = 26.4 kJ · mol−1
38. Campers carry hot packs with them, especially when camping
during the winter months or at high altitudes. The design is simi­
lar to that described in Problem 37, except that calcium chloride is
used in place of the ammonium nitrate. The equation for the disso­
lution of calcium chloride in water is shown below. How does the
hot pack work?
H2O
CaCl2 (s) Ca2+(aq) + 2 Cl−(aq)  ΔH = −81 kJ · mol−1
39. Urea (NH2CONH2) dissolves readily in water; i.e., this is a spon­
taneous process. A beaker containing the dissolved compound is cold
to the touch. What conclusions can you make about the sign of the
a. enthalpy change and b. entropy change for this process?
40. Would you expect the reaction shown in Problem 36 to be ender­
gonic or exergonic? Explain.
41. Calculate ∆H and ∆S, as described in Sample Calculation 1.1, for
the reaction in which reactant A is converted to product B.
42. Is the reaction described in Problem 41 favorable at a. 4°C and
b. 37°C?
43. For a given reaction, the value of ΔH is 15 kJ · mol−1 and the
value of ΔS is 51 J · K−1 · mol−1. Above what temperature will this
reaction be spontaneous?
44. Which of the following processes are spontaneous? a. A reac­
tion that occurs with any size decrease in enthalpy and any size
increase in entropy. b. A reaction that occurs with a small increase
in enthalpy and a large increase in entropy. c. A reaction that
occurs with a large decrease in enthalpy and a small decrease in
entropy. d. A reaction that occurs with any size increase in enthalpy
and any size decrease in entropy.
45. Given that the process described in Problem 37 is spontaneous,
what are the signs of ΔS and ΔG? Confirm your answer by using the
enthalpy change provided to calculate the sign and magnitude of ΔS.
46. Given that the process described in Problem 38 is spontaneous,
what are the signs of ΔS and ΔG? Confirm your answer by using the
enthalpy change provided to calculate the sign and magnitude of ΔS.
Assume a temperature of 25°C.
47. The hydrolysis of pyrophosphate at 25°C is spontaneous. The
enthalpy change for this reaction is −14.3 kJ · mol−1. What is the sign
and the magnitude of ΔS for this reaction?
48. Phosphoenolpyruvate donates a phosphate group to ADP to
produce pyruvate and ATP. The ∆G value for this reaction at 25°C is
−63 kJ · mol−1 and the value of ΔS is 190 J · K−1 · mol−1. What is the
value of ∆H? Is heat absorbed from or released to the surroundings?
49. A monoclonal antibody binds to the protein cytochrome c. The
ΔH value for binding at 25°C is −87.9 kJ · mol−1 and the ΔS is −118
J · K−1 · mol−1. a. Does entropy increase or decrease when the anti­
body binds to the protein? b. Calculate ΔG for the formation of the
antibody–protein complex. Does the complex form spontaneously?
c. The ΔG value for the binding of a second monoclonal antibody to
cytochrome c is −58.2 kJ · mol−1. Which antibody binds more readily
to the protein?
50. Phosphofructokinase catalyzes the transfer of a phosphate
−
group (from ATP) to fructose-6-phosphate to produce fructose-
1,6-bisphosphate. The ΔH value for this reaction is −9.5 kJ · mol−1
and the ΔG is −17.2 kJ · mol−1 at 37°C. a. Is heat absorbed from
or released to the surroundings? b. What is the value of ΔS for the
reaction? Does this reaction proceed with an increase or decrease in
entropy? c. Which component makes a greater contribution to the
free energy change: the ΔH or ΔS value? Comment on the significance
of this observation.
51. Glucose can be converted to glucose-6-phosphate:
glucose + phosphate → glucose-6-phosphate + H2O
ΔG is 13.8 kJ · mol−1
a. Is this reaction favorable? Explain.
b. Suppose the synthesis of glucose-6-phosphate is coupled with the
hydrolysis of ATP. Write the overall equation for the coupled process
and calculate the ΔG for the coupled reaction. Is the conversion of
glucose to glucose-6-phosphate favorable under these conditions?
Explain.
ATP + H2O → ADP + phosphate   ∆G = −30.5 kJ · mol−1

H (kJ · mol−1) S (J · K−1 · mol−1) 52. Glyceraldehyde-3-phosphate (GAP) is converted to 1,3-bis­

A 54 22 phosphoglycerate (1,3BPG) as shown.
B 60 43 GAP + Pi + NAD+ → 1,3BPG + NADH ΔG = 6.7 kJ · mol−1
 Problems 25

a. Is this reaction spontaneous? 59. In some cells, lipids such as palmitate (shown in Section 1.2),
b. The reaction shown above is coupled to the following reaction in rather than monosaccharides, serve as the primary metabolic fuel.
which 1,3BPG is converted to 3-phosphoglycerate (3PG): a. Consider the oxidation state of palmitate’s carbon atoms and
explain how it fits into a scheme such as the one shown in Figure
1,3BPG + ADP → 3PG + ATP ΔG = −18.8 kJ · mol−1 1.10. b. On a per-carbon basis, which would make more energy
Write the equation for the overall conversion of GAP to 3PG. Is the available for metabolic reactions: palmitate or glucose?
coupled reaction favorable? 60. Which yields more free energy when completely oxidized, stea­
53. Place these molecules in order from the most oxidized to the rate or α-linolenate?
most reduced.
O H H3C (CH2)16 COO−
Stearate
H C OH H C H O C O
H H3C CH2 (CH CHCH2)3 (CH2)6 COO−
A B C α-Linolenate

54. Identify the process described in the following statements as an

61. A protein folds from a random coil into a highly ordered struc­
oxidation or reduction process.
ture. How does this process, which proceeds with a loss of entropy,
a. Monosaccharides are synthesized from carbon dioxide by plants obey the laws of thermodynamics?
during photosynthesis.
62. An enzyme binds to a substrate, forming an enzyme–substrate
b. An animal eats the plant and breaks down the monosaccharide in complex. Explain how this process obeys the laws of thermodynamics.
order to obtain energy for cellular processes.
55. Given the following reactions, tell whether the reactant is being
oxidized or reduced. Reactions may not be balanced. 1.4 The Origin of Cells
a. O O 63. Why is molecular information so important for classifying and
tracing the evolutionary relatedness of bacterial species but less
CH3 (CH2)14 C O− 8 CH3 C S CoA important for vertebrate species?
64. The first theories to explain the similarities between bacteria and
b. COO− COO−
mitochondria or chloroplasts suggested that an early eukaryotic cell
CH2 CH2 engulfed but failed to fully digest a free-living prokaryotic cell. Why
is such an event unlikely to account for the origin of mitochondria
CH OH C O or chloroplasts?
COO− COO− 65. Draw a simple evolutionary tree that shows the relationships
between species A, B, and C based on the DNA sequences given here.
c. COO− COO−
Species A T C G T C G A G T C
CH CH2 Species B T G G A C T A G C C

CH CH OH Species C T G G A C C A G C C

COO− COO− 66. A portion of the evolutionary tree for a flu virus is shown
here. Different strains are identified by an H followed by a num­
d. O ber. a. Identify two pairs of closely related flu strains. b. Which
strain(s) is(are) most closely related to strain H3?
+H O−
3N CH C
H15
CH2
O
S H7
+ H2 +H O−
2 3N CH C
S H10
CH2
CH2 H3
SH
−O C CH NH+
3 H4
O
H14
56. For each of the reactions in Problem 55, tell whether an oxidizing
agent or a reducing agent is needed to accomplish the reaction. 67. Propose an explanation why taking antibiotics sometimes leads
57. Rank the forms of vitamin A (see Problem 4) in order from most to illness caused by the intestinal bacterium Clostridium difficile.
oxidized to most reduced. 68. Clinicians know that a drug may be ineffective as an antibiotic
58. The reaction shown in Problem 52 requires the coenzyme NAD+, when tested with pure cultures of bacteria in the laboratory. Yet when
which is reduced to NADH during the reaction. Which is more oxi­ the drug is orally administered to a patient, it has the desired antibac­
dized, GAP or 1,3BPG? terial effect against the same bacteria. Explain.
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 Wallace looked in the glass. For a moment, as he eyed his
reflection, sheer horror gripped him. Then suddenly, as he gazed, he
became aware that his first feelings were changing. The initial shock
over, he was becoming calmer. He waggled his right leg with a
certain sang-froid.
There is a certain passage in the works of the poet Pope with
which you may be familiar. It runs as follows:

“Vice is a monster of so frightful mien

As to be hated needs but to be seen:
Yet seen too oft, familiar with her face,
We first endure, then pity, then embrace.”

Even so was it with Wallace Chesney and these Plus Fours. At

first he had recoiled from them as any decent-minded man would
have done. Then, after a while, almost abruptly he found himself in
the grip of a new emotion. After an unsuccessful attempt to analyse
this, he suddenly got it. Amazing as it may seem, it was pleasure
that he felt. He caught his eye in the mirror, and it was smirking. Now
that the things were actually on, by Hutchinson, they didn’t look half
bad. By Braid, they didn’t. There was a sort of something about
them. Take away that expanse of bare leg with its unsightly sock-
suspender and substitute a woolly stocking, and you would have the
lower section of a golfer. For the first time in his life, he thought, he
looked like a man who could play golf.
There came to him an odd sensation of masterfulness. He was still
holding the putter, and now he swung it up above his shoulder. A fine
swing, all lissomness and supple grace, quite different from any
swing he had ever done before.
Wallace Chesney gasped. He knew that at last he had discovered
that prime grand secret of golf for which he had searched so long. It
was the costume that did it. All you had to do was wear Plus Fours.
He had always hitherto played in grey flannel trousers. Naturally he
had not been able to do himself justice. Golf required an easy dash,
and how could you be easily dashing in concertina-shaped trousers
with a patch on the knee? He saw now—what he had never seen
before—that it was not because they were crack players that crack
players wore Plus Fours: it was because they wore Plus Fours that
they were crack players. And these Plus Fours had been the
property of an Open Champion. Wallace Chesney’s bosom swelled,
and he was filled, as by some strange gas, with joy—with excitement
—with confidence. Yes, for the first time in his golfing life, he felt
really confident.
True, the things might have been a shade less gaudy: they might
perhaps have hit the eye with a slightly less violent punch: but what
of that? True, again, he could scarcely hope to avoid the censure of
his club-mates when he appeared like this on the links: but what of
that? His club-mates must set their teeth and learn to bear these
Plus Fours like men. That was what Wallace Chesney thought about
it. If they did not like his Plus Fours, let them go and play golf
somewhere else.
“How much?” he muttered, thickly. And the Brothers Cohen
clustered grimly round with note-books and pencils.
In predicting a stormy reception for his new apparel, Wallace
Chesney had not been unduly pessimistic. The moment he entered
the club-house Disaffection reared its ugly head. Friends of years’
standing called loudly for the committee, and there was a small and
vehement party of the left wing, headed by Raymond Gandle, who
was an artist by profession, and consequently had a sensitive eye,
which advocated the tearing off and public burial of the obnoxious
garment. But, prepared as he had been for some such
demonstration on the part of the coarser-minded, Wallace had hoped
for better things when he should meet Charlotte Dix, the girl who
loved him. Charlotte, he had supposed, would understand and
sympathise.
Instead of which, she uttered a piercing cry and staggered to a
bench, whence a moment later she delivered her ultimatum.
“Quick!” she said. “Before I have to look again.”
 “What do you mean?”
“Pop straight back into the changing-room while I’ve got my eyes
shut, and remove the fancy-dress.”
“What’s wrong with them?”
“Darling,” said Charlotte, “I think it’s sweet and patriotic of you to
be proud of your cycling club colours or whatever they are, but you
mustn’t wear them on the links. It will unsettle the caddies.”
“They are a trifle on the bright side,” admitted Wallace. “But it
helps my game, wearing them. I was trying a few practice-shots just
now, and I couldn’t go wrong. Slammed the ball on the meat every
time. They inspire me, if you know what I mean. Come on, let’s be
starting.”
Charlotte opened her eyes incredulously.
“You can’t seriously mean that you’re really going to play in—
those? It’s against the rules. There must be a rule somewhere in the
book against coming out looking like a sunset. Won’t you go and
burn them for my sake?”
“But I tell you they give me confidence. I sort of squint down at
them when I’m addressing the ball, and I feel like a pro.”
“Then the only thing to do is for me to play you for them. Come on,
Wally, be a sportsman. I’ll give you a half and play you for the whole
outfit—the breeches, the red jacket, the little cap, and the belt with
the snake’s-head buckle. I’m sure all those things must have gone
with the breeches. Is it a bargain?”

Strolling on the club-house terrace some two hours later,

Raymond Gandle encountered Charlotte and Wallace coming up
from the eighteenth green.
“Just the girl I wanted to see,” said Raymond. “Miss Dix, I
represent a select committee of my fellow-members, and I have
come to ask you on their behalf to use the influence of a good
woman to induce Wally to destroy those Plus Fours of his, which we
all consider nothing short of Bolshevik propaganda and a menace to
the public weal. May I rely on you?”
“You may not,” retorted Charlotte. “They are the poor boy’s
mascot. You’ve no idea how they have improved his game. He has
just beaten me hollow. I am going to try to learn to bear them, so you
must. Really, you’ve no notion how he has come on. My cripple won’t
be able to give him more than a couple of bisques if he keeps up this
form.”
“It’s something about the things,” said Wallace. “They give me
confidence.”
“They give me a pain in the neck,” said Raymond Gandle.

To the thinking man nothing is more remarkable in this life than the
way in which Humanity adjusts itself to conditions which at their
outset might well have appeared intolerable. Some great cataclysm
occurs, some storm or earthquake, shaking the community to its
foundations; and after the first pardonable consternation one finds
the sufferers resuming their ordinary pursuits as if nothing had
happened. There have been few more striking examples of this
adaptability than the behaviour of the members of our golf-club
under the impact of Wallace Chesney’s Plus Fours. For the first few
days it is not too much to say that they were stunned. Nervous
players sent their caddies on in front of them at blind holes, so that
they might be warned in time of Wallace’s presence ahead and not
have him happening to them all of a sudden. And even the pro. was
not unaffected. Brought up in Scotland in an atmosphere of tartan
kilts, he nevertheless winced, and a startled “Hoots!” was forced
from his lips when Wallace Chesney suddenly appeared in the valley
as he was about to drive from the fifth tee.
But in about a week conditions were back to normalcy. Within ten
days the Plus Fours became a familiar feature of the landscape, and
were accepted as such without comment. They were pointed out to
strangers together with the waterfall, the Lover’s Leap, and the view
from the eighth green as things you ought not to miss when visiting
the course; but apart from that one might almost say they were
ignored. And meanwhile Wallace Chesney continued day by day to
make the most extraordinary progress in his play.
As I said before, and I think you will agree with me when I have
told you what happened subsequently, it was probably a case of
auto-hypnosis. There is no other sphere in which a belief in oneself
has such immediate effects as it has in golf. And Wallace, having
acquired self-confidence, went on from strength to strength. In under
a week he had ploughed his way through the Unfortunate Incidents
—of which class Peter Willard was the best example—and was
challenging the fellows who kept three shots in five somewhere on
the fairway. A month later he was holding his own with ten-handicap
men. And by the middle of the summer he was so far advanced that
his name occasionally cropped up in speculative talks on the subject
of the July medal. One might have been excused for supposing that,
as far as Wallace Chesney was concerned, all was for the best in the
best of all possible worlds.
And yet—
The first inkling I received that anything was wrong came through
a chance meeting with Raymond Gandle, who happened to pass my
gate on his way back from the links just as I drove up in my taxi; for I
had been away from home for many weeks on a protracted business
tour. I welcomed Gandle’s advent and invited him in to smoke a pipe
and put me abreast of local gossip. He came readily enough—and
seemed, indeed, to have something on his mind and to be glad of
the opportunity of revealing it to a sympathetic auditor.
“And how,” I asked him, when we were comfortably settled, “did
your game this afternoon come out?”
“Oh, he beat me,” said Gandle, and it seemed to me that there
was a note of bitterness in his voice.
 “Then He, whoever he was, must have been an extremely
competent performer?” I replied, courteously, for Gandle was one of
the finest players in the club. “Unless, of course, you were giving him
some impossible handicap.”
“No; we played level.”
“Indeed! Who was your opponent?”
“Chesney.”
“Wallace Chesney! And he beat you, playing level! This is the most
amazing thing I have ever heard.”
“He’s improved out of all knowledge.”
“He must have done. Do you think he would ever beat you again?”
“No. Because he won’t have the chance.”
“You surely do not mean that you will not play him because you
are afraid of being beaten?”
“It isn’t being beaten I mind—”
And if I omit to report the remainder of his speech it is not merely
because it contained expressions with which I am reluctant to sully
my lips, but because, omitting these expletives, what he said was
almost word for word what you were saying to me just now about
Nathaniel Frisby. It was, it seemed, Wallace Chesney’s manner, his
arrogance, his attitude of belonging to some superior order of being
that had so wounded Raymond Gandle. Wallace Chesney had, it
appeared, criticised Gandle’s mashie-play in no friendly spirit; had
hung up the game on the fourteenth tee in order to show him how to
place his feet; and on the way back to the club-house had said that
the beauty of golf was that the best player could enjoy a round even
with a dud, because, though there might be no interest in the match,
he could always amuse himself by playing for his medal score.
I was profoundly shaken.
“Wallace Chesney!” I exclaimed. “Was it really Wallace Chesney
who behaved in the manner you describe?”
 “Unless he’s got a twin brother of the same name, it was.”
“Wallace Chesney a victim to swelled head! I can hardly credit it.”
“Well, you needn’t take my word for it unless you want to. Ask
anybody. It isn’t often he can get any one to play with him now.”
“You horrify me!”
Raymond Gandle smoked awhile in brooding silence.
“You’ve heard about his engagement?” he said at length.
“I have heard nothing, nothing. What about his engagement?”
“Charlotte Dix has broken it off.”
“No!”
“Yes. Couldn’t stand him any longer.”
I got rid of Gandle as soon as I could. I made my way as quickly
as possible to the house where Charlotte lived with her aunt. I was
determined to sift this matter to the bottom and to do all that lay in
my power to heal the breach between two young people for whom I
had a great affection.
“I have just heard the news,” I said, when the aunt had retired to
some secret lair, as aunts do, and Charlotte and I were alone.
“What news?” said Charlotte, dully. I thought she looked pale and
ill, and she had certainly grown thinner.
“This dreadful news about your engagement to Wallace Chesney.
Tell me, why did you do this thing? Is there no hope of a
reconciliation?”
“Not unless Wally becomes his old self again.”
“But I had always regarded you two as ideally suited to one
another.”
“Wally has completely changed in the last few weeks. Haven’t you
heard?”
“Only sketchily, from Raymond Gandle.”
 “I refuse,” said Charlotte, proudly, all the woman in her leaping to
her eyes, “to marry a man who treats me as if I were a kronen at the
present rate of exchange, merely because I slice an occasional tee-
shot. The afternoon I broke off the engagement”—her voice shook,
and I could see that her indifference was but a mask—“the afternoon
I broke off the en-gug-gug-gage-ment, he t-told me I ought to use an
iron off the tee instead of a dud-dud-driver.”
And the stricken girl burst into an uncontrollable fit of sobbing. And
realising that, if matters had gone as far as that, there was little I
could do, I pressed her hand silently and left her.

But though it seemed hopeless I decided to persevere. I turned my

steps towards Wallace Chesney’s bungalow, resolved to make one
appeal to the man’s better feelings. He was in his sitting-room when I
arrived, polishing a putter; and it seemed significant to me, even in
that tense moment, that the putter was quite an ordinary one, such
as any capable player might use. In the brave old happy days of his
dudhood, the only putters you ever found in the society of Wallace
Chesney were patent self-adjusting things that looked like croquet
mallets that had taken the wrong turning in childhood.
“Well, Wallace, my boy,” I said.
“Hallo!” said Wallace Chesney. “So you’re back?”
We fell into conversation, and I had not been in the room two
minutes before I realised that what I had been told about the change
in him was nothing more than the truth. The man’s bearing and his
every remark were insufferably bumptious. He spoke of his
prospects in the July medal competition as if the issue were already
settled. He scoffed at his rivals.
I had some little difficulty in bringing the talk round to the matter
which I had come to discuss.
“My boy,” I said at length, “I have just heard the sad news.”
 “What sad news?”
“I have been talking to Charlotte—”
“Oh, that!” said Wallace Chesney.
“She was telling me—”
“Perhaps it’s all for the best.”
“All for the best? What do you mean?”
“Well,” said Wallace, “one doesn’t wish, of course, to say anything
ungallant, but, after all, poor Charlotte’s handicap is fourteen and
wouldn’t appear to have much chance of getting any lower. I mean,
there’s such a thing as a fellow throwing himself away.”
Was I revolted at these callous words? For a moment, yes. Then it
struck me that, though he had uttered them with a light laugh, that
laugh had had in it more than a touch of bravado. I looked at him
keenly. There was a bored, discontented expression in his eyes, a
line of pain about his mouth.
“My boy,” I said, gravely, “you are not happy.”
For an instant I think he would have denied the imputation. But my
visit had coincided with one of those twilight moods in which a man
requires, above all else, sympathy. He uttered a weary sigh.
“I’m fed up,” he admitted. “It’s a funny thing. When I was a dud, I
used to think how perfect it must be to be scratch. I used to watch
the cracks buzzing round the course and envy them. It’s all a fraud.
The only time when you enjoy golf is when an occasional decent
shot is enough to make you happy for the day. I’m plus two, and I’m
bored to death. I’m too good. And what’s the result? Everybody’s
jealous of me. Everybody’s got it in for me. Nobody loves me.”
His voice rose in a note of anguish, and at the sound his terrier,
which had been sleeping on the rug, crept forward and licked his
hand.
“The dog loves you,” I said, gently, for I was touched.
“Yes, but I don’t love the dog,” said Wallace Chesney.
 “Now come, Wallace,” I said. “Be reasonable, my boy. It is only
your unfortunate manner on the links which has made you perhaps a
little unpopular at the moment. Why not pull yourself up? Why ruin
your whole life with this arrogance? All that you need is a little tact, a
little forbearance. Charlotte, I am sure, is just as fond of you as ever,
but you have wounded her pride. Why must you be unkind about her
tee-shots?”
Wallace Chesney shook his head despondently.
“I can’t help it,” he said. “It exasperates me to see any one
foozling, and I have to say so.”
“Then there is nothing to be done,” I said, sadly.

All the medal competitions at our club are, as you know, important
events; but, as you are also aware, none of them is looked forward
to so keenly or contested so hotly as the one in July. At the
beginning of the year of which I am speaking, Raymond Gandle had
been considered the probable winner of the fixture; but as the
season progressed and Wallace Chesney’s skill developed to such a
remarkable extent most of us were reluctantly inclined to put our
money on the latter. Reluctantly, because Wallace’s unpopularity
was now so general that the thought of his winning was distasteful to
all. It grieved me to see how cold his fellow-members were towards
him. He drove off from the first tee without a solitary hand-clap; and,
though the drive was of admirable quality and nearly carried the
green, there was not a single cheer. I noticed Charlotte Dix among
the spectators. The poor girl was looking sad and wan.
In the draw for partners Wallace had had Peter Willard allotted to
him; and he muttered to me in a quite audible voice that it was as
bad as handicapping him half-a-dozen strokes to make him play with
such a hopeless performer. I do not think Peter heard, but it would
not have made much difference to him if he had, for I doubt if
anything could have had much effect for the worse on his game.
Peter Willard always entered for the medal competition, because he
said that competition-play was good for the nerves.
On this occasion he topped his ball badly, and Wallace lit his pipe
with the exaggeratedly patient air of an irritated man. When Peter
topped his second also, Wallace was moved to speech.
“For goodness’ sake,” he snapped, “what’s the good of playing at
all if you insist on lifting your head? Keep it down, man, keep it down.
You don’t need to watch to see where the ball is going. It isn’t likely
to go as far as all that. Make up your mind to count three before you
look up.”
“Thanks,” said Peter, meekly. There was no pride in Peter to be
wounded. He knew the sort of player he was.
The couples were now moving off with smooth rapidity, and the
course was dotted with the figures of players and their
accompanying spectators. A fair proportion of these latter had
decided to follow the fortunes of Raymond Gandle, but by far the
larger number were sticking to Wallace, who right from the start
showed that Gandle or any one else would have to return a very fine
card to beat him. He was out in thirty-seven, two above bogey, and
with the assistance of a superb second, which landed the ball within
a foot of the pin, got a three on the tenth, where a four is considered
good. I mention this to show that by the time he arrived at the short
lake-hole Wallace Chesney was at the top of his form. Not even the
fact that he had been obliged to let the next couple through owing to
Peter Willard losing his ball had been enough to upset him.

The course has been rearranged since, but at that time the lake-
hole, which is now the second, was the eleventh, and was generally
looked on as the crucial hole in a medal round. Wallace no doubt
realised this, but the knowledge did not seem to affect him. He lit his
pipe with the utmost coolness: and, having replaced the match-box
in his hip-pocket, stood smoking nonchalantly as he waited for the
couple in front to get off the green.
 They holed out eventually, and Wallace walked to the tee. As he
did so, he was startled to receive a resounding smack.
“Sorry,” said Peter Willard, apologetically. “Hope I didn’t hurt you. A
wasp.”
And he pointed to the corpse, which was lying in a used-up
attitude on the ground.
“Afraid it would sting you,” said Peter.
“Oh, thanks,” said Wallace.
He spoke a little stiffly, for Peter Willard had a large, hard, flat
hand, the impact of which had shaken him up considerably. Also,
there had been laughter in the crowd. He was fuming as he bent to
address his ball, and his annoyance became acute when, just as he
reached the top of his swing, Peter Willard suddenly spoke.
“Just a second, old man,” said Peter. Wallace spun round,
outraged.
“What is it? I do wish you would wait till I’ve made my shot.”
“Just as you like,” said Peter, humbly.
“There is no greater crime that a man can commit on the links than
to speak to a fellow when he’s making his stroke.”
“Of course, of course,” acquiesced Peter, crushed.
Wallace turned to his ball once more. He was vaguely conscious
of a discomfort to which he could not at the moment give a name. At
first he thought that he was having a spasm of lumbago, and this
surprised him, for he had never in his life been subject to even a
suspicion of that malady. A moment later he realised that this
diagnosis had been wrong.
“Good heavens!” he cried, leaping nimbly some two feet into the
air. “I’m on fire!”
“Yes,” said Peter, delighted at his ready grasp of the situation.
“That’s what I wanted to mention just now.”
Wallace slapped vigorously at the seat of his Plus Fours.
 “It must have been when I killed that wasp,” said Peter, beginning
to see clearly into the matter. “You had a match-box in your pocket.”
Wallace was in no mood to stop and discuss first causes. He was
springing up and down on his pyre, beating at the flames.
“Do you know what I should do if I were you?” said Peter Willard. “I
should jump into the lake.”
One of the cardinal rules of golf is that a player shall accept no
advice from any one but his own caddie; but the warmth about his
lower limbs had now become so generous that Wallace was
prepared to stretch a point. He took three rapid strides and entered
the water with a splash.
The lake, though muddy, is not deep, and presently Wallace was
to be observed standing up to his waist some few feet from the
shore.
“That ought to have put it out,” said Peter Willard. “It was a bit of
luck that it happened at this hole.” He stretched out a hand to the
bather. “Catch hold, old man, and I’ll pull you out.”
“No!” said Wallace Chesney.
“Why not?”
“Never mind!” said Wallace, austerely. He bent as near to Peter as
he was able.
“Send a caddie up to the club-house to fetch my grey flannel
trousers from my locker,” he whispered, tensely.
“Oh, ah!” said Peter.
It was some little time before Wallace, encircled by a group of
male spectators, was enabled to change his costume; and during the
interval he continued to stand waist-deep in the water, to the chagrin
of various couples who came to the tee in the course of their round
and complained with not a little bitterness that his presence there
added a mental hazard to an already difficult hole. Eventually,
however, he found himself back ashore, his ball before him, his
mashie in his hand.
 “Carry on,” said Peter Willard, as the couple in front left the green.
“All clear now.”
Wallace Chesney addressed his ball. And, even as he did so, he
was suddenly aware that an odd psychological change had taken
place in himself. He was aware of a strange weakness. The charred
remains of the Plus Fours were lying under an adjacent bush; and,
clad in the old grey flannels of his early golfing days, Wallace felt
diffident, feeble, uncertain of himself. It was as though virtue had
gone out of him, as if some indispensable adjunct to good play had
been removed. His corrugated trouser-leg caught his eye as he
waggled, and all at once he became acutely alive to the fact that
many eyes were watching him. The audience seemed to press on
him like a blanket. He felt as he had been wont to feel in the old days
when he had had to drive off the first tee in front of a terrace-full of
scoffing critics.
The next moment his ball had bounded weakly over the
intervening patch of turf and was in the water.
“Hard luck!” said Peter Willard, ever a generous foe. And the
words seemed to touch some almost atrophied chord in Wallace’s
breast. A sudden love for his species flooded over him. Dashed
decent of Peter, he thought, to sympathise. Peter was a good chap.
So were the spectators good chaps. So was everybody, even his
caddie.
Peter Willard, as if resolved to make his sympathy practical, also
rolled his ball into the lake.
“Hard luck!” said Wallace Chesney, and started as he said it; for
many weeks had passed since he had commiserated with an
opponent. He felt a changed man. A better, sweeter, kindlier man. It
was as if a curse had fallen from him.
He teed up another ball, and swung.
“Hard luck!” said Peter.
“Hard luck!” said Wallace, a moment later.
“Hard luck!” said Peter, a moment after that.
 Wallace Chesney stood on the tee watching the spot in the water
where his third ball had fallen. The crowd was now openly amused,
and, as he listened to their happy laughter, it was borne in upon
Wallace that he, too, was amused and happy. A weird, almost
effervescent exhilaration filled him. He turned and beamed upon the
spectators. He waved his mashie cheerily at them. This, he felt, was
something like golf. This was golf as it should be—not the dull,
mechanical thing which had bored him during all these past weeks of
his perfection, but a gay, rollicking adventure. That was the soul of
golf, the thing that made it the wonderful pursuit it was—that
speculativeness, that not knowing where the dickens your ball was
going when you hit it, that eternal hoping for the best, that never-
failing chanciness. It is better to travel hopefully than to arrive, and at
last this great truth had come home to Wallace Chesney. He realised
now why pros were all grave, silent men who seemed to struggle
manfully against some secret sorrow. It was because they were too
darned good. Golf had no surprises for them, no gallant spirit of
adventure.
“I’m going to get a ball over if I stay here all night,” cried Wallace
Chesney, gaily, and the crowd echoed his mirth. On the face of
Charlotte Dix was the look of a mother whose prodigal son has rolled
into the old home once more. She caught Wallace’s eye and
gesticulated to him blithely.
“The cripple says he’ll give you a stroke a hole, Wally!” she
shouted.
“I’m ready for him!” bellowed Wallace.
“Hard luck!” said Peter Willard.
Under their bush the Plus Fours, charred and dripping, lurked
unnoticed. But Wallace Chesney saw them. They caught his eye as
he sliced his eleventh into the marshes on the right. It seemed to him
that they looked sullen. Disappointed. Baffled.
Wallace Chesney was himself again.
 CHAPTER VI
THE AWAKENING OF ROLLO PODMARSH

Down on the new bowling-green behind the club-house some sort

of competition was in progress. The seats about the smooth strip of
turf were crowded, and the weak-minded yapping of the patients
made itself plainly audible to the Oldest Member as he sat in his
favourite chair in the smoking-room. He shifted restlessly, and a
frown marred the placidity of his venerable brow. To the Oldest
Member a golf-club was a golf-club, and he resented the introduction
of any alien element. He had opposed the institution of tennis-courts;
and the suggestion of a bowling-green had stirred him to his depths.
A young man in spectacles came into the smoking-room. His high
forehead was aglow, and he lapped up a ginger-ale with the air of
one who considers that he has earned it.
“Capital exercise!” he said, beaming upon the Oldest Member.
The Oldest Member laid down his Vardon On Casual Water, and
peered suspiciously at his companion.
“What did you go round in?” he asked.
“Oh, I wasn’t playing golf,” said the young man. “Bowls.”
“A nauseous pursuit!” said the Oldest Member, coldly, and
resumed his reading.
The young man seemed nettled.
“I don’t know why you should say that,” he retorted. “It’s a splendid
game.”
“I rank it,” said the Oldest Member, “with the juvenile pastime of
marbles.”
The young man pondered for some moments.
 “Well, anyway,” he said at length, “it was good enough for Drake.”
“As I have not the pleasure of the acquaintance of your friend
Drake, I am unable to estimate the value of his endorsement.”
“The Drake. The Spanish Armada Drake. He was playing bowls on
Plymouth Hoe when they told him that the Armada was in sight.
‘There is time to finish the game,’ he replied. That’s what Drake
thought of bowls.”
“If he had been a golfer he would have ignored the Armada
altogether.”
“It’s easy enough to say that,” said the young man, with spirit, “but
can the history of golf show a parallel case?”
“A million, I should imagine.”
“But you’ve forgotten them, eh?” said the young man, satirically.
“On the contrary,” said the Oldest Member. “As a typical instance,
neither more nor less remarkable than a hundred others, I will select
the story of Rollo Podmarsh.” He settled himself comfortably in his
chair, and placed the tips of his fingers together. “This Rollo
Podmarsh—”
“No, I say!” protested the young man, looking at his watch.
“This Rollo Podmarsh—”
“Yes, but—”
This Rollo Podmarsh (said the Oldest Member) was the only son
of his mother, and she was a widow; and like other young men in
that position he had rather allowed a mother’s tender care to take
the edge off what you might call his rugged manliness. Not to put too
fine a point on it, he had permitted his parent to coddle him ever
since he had been in the nursery; and now, in his twenty-eighth year,
he invariably wore flannel next his skin, changed his shoes the
moment they got wet, and—from September to May, inclusive—
never went to bed without partaking of a bowl of hot arrowroot. Not,
you would say, the stuff of which heroes are made. But you would be
wrong. Rollo Podmarsh was a golfer, and consequently pure gold at
heart; and in his hour of crisis all the good in him came to the
surface.
In giving you this character-sketch of Rollo, I have been at pains to
make it crisp, for I observe that you are wriggling in a restless
manner and you persist in pulling out that watch of yours and gazing
at it. Let me tell you that, if a mere skeleton outline of the man has
this effect upon you, I am glad for your sake that you never met his
mother. Mrs. Podmarsh could talk with enjoyment for hours on end
about her son’s character and habits. And, on the September
evening on which I introduce her to you, though she had, as a fact,
been speaking only for some ten minutes, it had seemed like hours
to the girl, Mary Kent, who was the party of the second part to the
conversation.
Mary Kent was the daughter of an old school-friend of Mrs.
Podmarsh, and she had come to spend the autumn and winter with
her while her parents were abroad. The scheme had never looked
particularly good to Mary, and after ten minutes of her hostess on the
subject of Rollo she was beginning to weave dreams of knotted
sheets and a swift getaway through the bedroom window in the dark
of the night.
“He is a strict teetotaller,” said Mrs. Podmarsh.
“Really?”
“And has never smoked in his life.”
“Fancy that!”
“But here is the dear boy now,” said Mrs. Podmarsh, fondly.

Down the road towards them was coming a tall, well-knit figure in
a Norfolk coat and grey flannel trousers. Over his broad shoulders
was suspended a bag of golf-clubs.
“Is that Mr. Podmarsh?” exclaimed Mary.
 She was surprised. After all she had been listening to about the
arrowroot and the flannel next the skin and the rest of it, she had
pictured the son of the house as a far weedier specimen. She had
been expecting to meet a small, slender young man with an eyebrow
moustache, and pince-nez; and this person approaching might have
stepped straight out of Jack Dempsey’s training-camp.
“Does he play golf?” asked Mary, herself an enthusiast.
“Oh, yes,” said Mrs. Podmarsh. “He makes a point of going out on
the links once a day. He says the fresh air gives him such an
appetite.”
Mary, who had taken a violent dislike to Rollo on the evidence of
his mother’s description of his habits, had softened towards him on
discovering that he was a golfer. She now reverted to her previous
opinion. A man who could play the noble game from such ignoble
motives was beyond the pale.
“Rollo is exceedingly good at golf,” proceeded Mrs. Podmarsh. “He
scores more than a hundred and twenty every time, while Mr. Burns,
who is supposed to be one of the best players in the club, seldom
manages to reach eighty. But Rollo is very modest—modesty is one
of his best qualities—and you would never guess he was so skilful
unless you were told.”
“Well, Rollo darling, did you have a nice game? You didn’t get your
feet wet, I hope? This is Mary Kent, dear.”
Rollo Podmarsh shook hands with Mary. And at her touch the
strange dizzy feeling which had come over him at the sight of her
suddenly became increased a thousand-fold. As I see that you are
consulting your watch once more, I will not describe his emotions as
exhaustively as I might. I will merely say that he had never felt
anything resembling this sensation of dazed ecstasy since the
occasion when a twenty-foot putt of his, which had been going well
off the line, as his putts generally did, had hit a worm-cast sou’-sou’-
east of the hole and popped in, giving him a snappy six. Rollo
Podmarsh, as you will have divined, was in love at first sight. Which
makes it all the sadder to think Mary at the moment was regarding
him as an outcast and a blister.
Mrs. Podmarsh, having enfolded her son in a vehement embrace,
drew back with a startled exclamation, sniffing.
“Rollo!” she cried. “You smell of tobacco smoke.”
Rollo looked embarrassed.
“Well, the fact is, mother—”
A hard protuberance in his coat-pocket attracted Mrs. Podmarsh’s
notice. She swooped and drew out a big-bowled pipe.
“Rollo!” she exclaimed, aghast.
“Well, the fact is, mother—”
“Don’t you know,” cried Mrs. Podmarsh, “that smoking is
poisonous, and injurious to the health?”
“Yes. But the fact is, mother—”
“It causes nervous dyspepsia, sleeplessness, gnawing of the
stomach, headache, weak eyes, red spots on the skin, throat
irritation, asthma, bronchitis, heart failure, lung trouble, catarrh,
melancholy, neurasthenia, loss of memory, impaired will-power,
rheumatism, lumbago, sciatica, neuritis, heartburn, torpid liver, loss
of appetite, enervation, lassitude, lack of ambition, and falling out of
hair.”
“Yes, I know, mother. But the fact is, Ted Ray smokes all the time
he’s playing, and I thought it might improve my game.”
And it was at these splendid words that Mary Kent felt for the first
time that something might be made of Rollo Podmarsh. That she
experienced one-millionth of the fervour which was gnawing at his
vitals I will not say. A woman does not fall in love in a flash like a
man. But at least she no longer regarded him with loathing. On the
contrary, she found herself liking him. There was, she considered,
the right stuff in Rollo. And if, as seemed probable from his mother’s
conversation, it would take a bit of digging to bring it up, well—she
liked rescue-work and had plenty of time.