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 Biochemistry
Raymond S. Ochs
St. John’s University

57366_FMxx_i_xx.indd 1 9/7/12 1:48 PM

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Library of Congress Cataloging-in-Publication Data

Ochs, Raymond S.
Biochemistry / Ray Ochs. — 1st ed.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-7637-5736-6 (alk. paper)
I. Title.
[DNLM: 1. Biochemistry. 2. Biochemical Phenomena. QU 4]
572—dc23 2012008575

6048

Printed in the United States of America

16 15 14 13 12 10 9 8 7 6 5 4 3 2 1

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 To my wife, Jessica, for her immeasurable support.

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 Brief Contents

Preface xvi
Chapter 1 Foundations 1
Chapter 2 Water 12
Chapter 3 Lipids 29
Chapter 4 Carbohydrates 43
Chapter 5 Amino Acids and Proteins 61
Chapter 6 Enzymes 83
Chapter 7 Metabolism and Energy 104
Chapter 8 Glycolysis 124
Chapter 9 The Krebs Cycle 148
Chapter 10 Oxidative Phosphorylation 165
Chapter 11 Photosynthesis 191
Chapter 12 Carbohydrate Pathways Related to Glycolysis 214
Chapter 13 Lipid Metabolism 245
Chapter 14 Nitrogen Metabolism 280
Chapter 15 Nucleic Acids 319
Chapter 16 Protein Synthesis and Degradation 341
Appendix 359
Glossary 386
Index 403

Image © Dr. Mark J. Winter/Photo Researchers, Inc.

iv

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 Contents

Preface xvi

Chapter 1 Foundations 1
1.1 Origins of Biochemistry 2
1.2 Some Chemical Ideas 3
Reactions and Their Kinetic Description 3
Equilibrium 4
The Steady State 5
1.3 Energy 7
1.4 Cell Theory 8
1.5 The Species Hierarchy and Evolution 9
1.6 Biological Systems 10
Key Terms 11
References 11
Box 1.1 WORD ORIGINS: Organic 1
Chapter 2 Water 12
2.1 Structure of Water 13
Gas Phase Water 13
Partial Charges and Electronegativity 14
Condensed Phase Water: Hydrogen Bonding 15
2.2 Properties of Water Follow from the Hydrogen
Bonded Structure 17
2.3 The Hydrophobic Effect 18
2.4 Molecules Soluble in Water 18
2.5 High Heat Retention: The Unusual Specific Heat of
Liquid Water 21
2.6 Ionization of Water 21
2.7 Some Definitions for the Study of
Acids and Bases 22
2.8 The pH Scale 23
2.9 The Henderson–Hasselbalch Equation 24
2.10 Titration and Buffering 25
Summary 26
Key Terms 27
Review Questions 27
References 28
Image © Dr. Mark J. Winter/Photo Researchers, Inc. v

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 Box 2.1 Covalent and Ionic: Discreet or Continuous
Distinction? 16
Box 2.2 WORD ORIGINS: Hydrophobic 18
Box 2.3 A Thermodynamic Look at the
Hydrophobic Effect 19

Chapter 3 Lipids 29
3.1 Significance 30
3.2 Fatty Acids 30
3.3 Triacylglycerols 33
3.4 Phospholipids 35
3.5 Cholesterol 37
3.6 Lipid–Water Interactions of Amphipathic
Molecules 37
3.7 Water Permeability of Membranes and Osmosis 38
3.8 Effect of Lipids on Membrane Composition 40
Summary 40
Key Terms 41
Review Questions 41
References 41
Box 3.1 On Steak and Fish: Polyunsaturated Fats,
Trans Fats, and Health Risks 31
Box 3.2 Lipid Composition of Pizza 34
Box 3.3 Lecithin and Emulsification 36
Box 3.4 WORD ORIGINS: Osmosis 40
Chapter 4 Carbohydrates 43
4.1 Monosaccharides 44
4.2 Ring Formation in Sugars 45
4.3 Disaccharides 48
4.4 Polysaccharides 51
Linear Polysaccharides 52
Branched Polysaccharides 53
4.5 Carbohydrate Derivatives 54
Simple Modifications 54
Substituted Carbohydrates 55
Summary 57
Key Terms 60
Review Questions 60
References 60
Box 4.1 Stereochemical Conventions: Little d/l 46
Box 4.2 WORD ORIGINS: Reducing 51
Box 4.3 Irony of Intramolecular Hydrogen Bonds 53
Box 4.4 Medical Connections: Sugars and Digestion 59

Chapter 5 Amino Acids and Proteins 61

5.1 Identity and Roles of Amino Acids 62

vi Contents

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 5.2 Amino Acid Individuality: The R Groups 62
Polarities 62
Functional Groups 62
5.3 Acid–Base Properties and Charge 64
Titration and Net Charge 64
Zwitterions 67
Multiple Dissociable Groups 67
5.4 The Peptide Bond 68
5.5 Peptides and Proteins 68
5.6 Levels of Protein Structure 69
Primary Structure 70
Secondary Structure 70
Domains 71
Tertiary Structure 73
Quaternary Structure 73
5.7 Protein Folding 74
5.8 Oxygen Binding in Myoglobin and Hemoglobin 74
5.9 Protein Purification and Analysis 78
Purification 78
Analysis 79
Summary 80
Key Terms 81
Review Questions 81
References 82
Box 5.1 Fractional Charges 66
Box 5.2 Protein Digestion: Proteins, Peptides, and
Amino Acids 69
Box 5.3 Domain Names 72
Box 5.4 WORD ORIGINS: Chromatography 79
Chapter 6 Enzymes 83
6.1 A Brief Look at Enzyme Energetics and Enzyme
Chemistry 84
6.2 The Enzyme Assay and Initial Velocity 86
6.3 A Simple Kinetic Mechanism 87
Assumptions 88
The Michaelis–Menten Equation 88
6.4 How the Michaelis–Menten Equation Describes
Enzyme Behavior 89
6.5 The Meaning of Km 90
6.6 Reversible Inhibition 91
Competitive Inhibition 92
Anticompetitive Inhibition (Uncompetitive) 93
Mixed Inhibition (Noncompetitive) 94
6.7 Double-Reciprocal or Lineweaver–Burk Plot 96
6.8 Allosteric Enzymes 97
6.9 Irreversible Inhibition 98

Contents vii

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 6.10 Enzyme Mechanisms 98
Nucleophilic Substitution 99
Acid–Base Catalysis 99
6.11 Enzyme Categories 99
6.12 Enzyme-Like Qualities of Membrane Transport
Proteins 100
Summary 101
Key Terms 102
Review Questions 102
References 103
Box 6.1 Activation Energy and Murphy’s Law 85
Box 6.2 The Spectrophotometer and Beer’s Law 86
Box 6.3 Inhibition and Active Sites 91
Box 6.4WORD ORIGINS: Noncompetitive and
Uncompetitive 94
Box 6.5 Can Km Explain Enzyme Inhibition? 96
Chapter 7 Metabolism and Energy 104
7.1 Origins of Thermodynamics 105
7.2 First Law of Thermodynamics 105
Heat and Work 105
Enthalpy 107
7.3 Entropy and the Second Law of Thermodynamics 108
Entropy as a Ratio of Heat to Temperature 108
Entropy as a Statistical Distribution of States 109
7.4 Free Energy 109
7.5 Standard Free Energy 110
7.6 Nonstandard Free Energy Changes 111
7.7 Near-Equilibrium and Metabolically Irreversible
Reactions 112
7.8 ATP 113
7.9 Energy Coupling with ATP 115
Creatine Phosphokinase 117
NDP Kinase 117
Adenylate Kinase 118
7.10 NADH 119
7.11 Mobile Cofactors and the Pathway View 120
Summary 121
Key Terms 122
Review Questions 122
References 123
Box 7.1 Joules, Calories, and Food Calories 106
Box 7.2 WORD ORIGINS: Spontaneous 112
Box 7.3 Standard Thermodynamic Values 113
Chapter 8 Glycolysis 124
8.1 Glucose Transport 125

viii Contents

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 8.2 From Glucose to Pyruvate 127
Hexokinase 127
Glucose Phosphate Isomerase 129
Phosphofructokinase 130
Aldolase 131
Triose Phosphate Isomerase 132
Glyceraldehyde Phosphate Dehydrogenase 133
Phosphoglycerate Kinase 135
Phosphoglycerate Mutase 135
Enolase 135
Pyruvate Kinase 136
8.3 Completing the Pathway 138
Lactate Formation 138
Ethanol Formation 138
8.4 Energetics of Glycolysis 140
Pathway Thermodynamics 141
Red Blood Cell Shunt Pathway 142
Arsenate Poisoning 143
Fructose Metabolism 143
8.5 Metabolic Connections to Glycolysis 145
Alternative Entry Points 145
Glycolytic Intermediates as Intersection Points 145
Alternative Endpoints of Glycolysis 145
Summary 146
Key Terms 146
Review Questions 146
References 147
Box 8.1 WORD ORIGINS: Zymo 125
Box 8.2 A Separate Class of Glucose Transporters 126
Box 8.3 In Vitro Modulators of PFK 130
Box 8.4 Vitamins 139
Box 8.5 High-Fructose Corn Syrup 144

Chapter 9 The Krebs Cycle 148

9.1 A Cyclic Pathway 149
9.2 Acetyl-CoA: Substrate of the Krebs Cycle 150
9.3 Overview of Carbon Flow 152
9.4 Steps of the Pathway 153
Citrate Synthase 154
Aconitase 155
Fluoroacetate Poisoning Involves the First Two Enzymes of the
Krebs Cycle 156
Isocitrate DH 156
2-Ketoglutarate DH Complex 157
Succinyl-CoA Synthetase 157
Succinate DH 159
Fumarase 159
Malate DH 159
9.5 Energy Balance 160

Contents ix

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 9.6 Regulation 161
9.7 Krebs Cycle as a Second Crossroad of Metabolic
Pathways 162
Summary 163
Key Terms 164
Review Questions 164
References 164
Box 9.1 WORD ORIGINS: Krebs Cycle Intermediates 149
Box 9.2 Estimating ATP Energy Equivalents 160
Chapter 10 Oxidative Phosphorylation 165
10.1 The Phenomenon 166
10.2 Mitochondrial Inner Membrane 167
10.3 Carriers of Electrons, Protons, or Both 167
Carriers of Electrons 167
Carriers of Protons 168
Carriers of Both Electrons and Protons 168
10.4 Membrane-Bound Complexes 168
10.5 Electron Pathways 169
Electrochemical Cells 169
Sequence of Electron Flow 170
Energetics of Electron Flow 171
10.6 Mechanisms for Electron and Proton Flows Through
the Mitochondrial Membrane 172
Complex I: Proton Pump 172
Complex II: Succinate Dehydrogenase 175
Complex III: Loop Mechanism 175
Complex IV: Pump and Annihilation 177
Complex V: ATP Synthesis 178
10.7 Mitochondrial Membrane Transport 180
Adenine Nucleotide Translocase 181
Phosphate Exchange 181
Other Transport Proteins 182
10.8 Coupling of Oxidation and Phosphorylation 182
10.9 Uncoupling 183
10.10 Superoxide Formation by Mitochondria 183
10.11 Control of Mitochondria 185
10.12 How Mitochondria Can Utilize Cytosolic NADH 185
Glycerol Phosphate Shuttle 186
Malate/Aspartate Shuttle 187
Summary 188
Key Terms 189
Review Questions 189
References 190
Box 10.1 WORD ORIGINS: Flavins 168
Box 10.2 A New Class of Complex II Inhibitors 173
Box 10.3 The Once and Future Uncoupling Diet 184

x Contents

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 Chapter 11 Photosynthesis 191
11.1 Light and Dark Reactions 192
11.2 Chloroplasts 193
Orientations: N and P Sides of the Membrane 193
Light Reactions of Photosynthesis as a “Reversed Oxidative
Phosphorylation” 194
Dark Reactions of Photosynthesis: “CO2 Fixation” 195
11.3 Harnessing Light Energy 196
Light Absorption and the Antennae 196
Electron Transfer at Reaction Centers 197
11.4 Proton and Electron Flow for the Light
Reactions 198
11.5 Cyclic Electron Transfer and Other Variations 201
11.6 The Calvin Cycle 202
Ribulose Bisphosphate Carboxylase 202
Reaction Steps Following Carbon Fixation to Glyceraldehyde-P:
Energy Consuming Portion 203
From GAP to the RuBisCo Step: Overview 204
From GAP to the RuBisCo Step: Reactions 205
11.7 Variations in CO2 Handling: C3, C4, and
CAM Plants 208
11.8 Pathway Endpoints: Sucrose and Starch 210
Summary 211
Key Terms 212
Review Questions 212
References 213
Box 11.1 WORD ORIGINS: Behind the Z-Scheme 199
Box 11.2 Plants and the Visual Cycle 211
Chapter 12 Carbohydrate Pathways Related to Glycolysis 214
12.1 Glycogen Metabolism 216
Glycogen Synthesis 216
Glycogenolysis 219
Physiological Context of Glycogen Metabolism 222
Regulation of Glycogen Metabolism by Glucagon 222
Regulation of Glycogen Metabolism by Epinephrine 225
Regulation of Glycogen Metabolism by Insulin 226
Regulation of Glycogen Metabolism by AMP Kinase 228
12.2 Gluconeogenesis 229
Lactate Dehydrogenase as a Gluconeogenic Enzyme 229
Pyruvate to PEP 229
Indirect Transport of Oxaloacetate from Mitochondria to
Cytosol 233
Fructose-1,6-P2 to Fructose-6-P 234
Glucose-6-P to Glucose 235
Pathway Integration: Glycolysis, Glycogen Metabolism, and
Gluconeogenesis 236
12.3 The Pentose Phosphate Shunt 238
Oxidative Stage 238
Nonoxidative Stage 239
Distribution Between NADPH Production and Ribose-5-P 241
Contents xi

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 12.4 Galactose Utilization 241
Summary 243
Key Terms 244
Review Questions 244
References 244
Box 12.1 Glycogen Storage Diseases 221
Box 12.2 WORD ORIGINS: What’s Really New About
Gluconeogenesis? 229
Box 12.3 CO2 Fixation in Animals? 233
Box 12.4 Alligators and the Resting–Exercise
Transition 237

Chapter 13 Lipid Metabolism 245

13.1 Absorption of Dietary Lipids 246
13.2 Fatty Acid Oxidation 248
Activation 249
Transport 250
β-Oxidation 251
Ancillary Enzymes 253
13.3 Ketone Body Metabolism 254
13.4 Fatty Acid Biosynthesis 256
Export of Acetyl-CoA to the Cytosol 257
Carboxylation of Acetyl-CoA to Malonyl-CoA 258
Sequential Addition of Two-Carbon Fragments to Form
Palmitate 260
13.5 Triacylglycerol Formation 262
13.6 Phospholipid Metabolism 265
13.7 Cholesterol Metabolism 267
13.8 Other Lipids 270
Eicosanoids 270
Sphingolipids 272
Unusual Bacterial Fatty Acids 272
13.9 Overview of Lipid Metabolism in the Fed and
Fasted States 272
13.10 Integration of Lipid and Carbohydrate
Metabolism 276
Lipid and Carbohydrate Intersections in the Feeding–Fasting
Transition 276
Lipid and Carbohydrate Intersections in the Resting–Exercise
Transition 276
Lipid and Carbohydrate Intersections in Diabetes
Mellitus 277
Summary 277
Key Terms 279
Review Questions 279
References 279
Box 13.1 Fatty Acid Binding Proteins 247
Box 13.2 WORD ORIGINS: Oleate 253

xii Contents

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 Box 13.3 Acetone Breath 256
Box 13.4 Regulatory Circuit of Lipid Metabolism 260
Box 13.5 Origins of the Triacylglycerol Backbone 265
Chapter 14 Nitrogen Metabolism 280
14.1 The Nitrogen Cycle 281
14.2 Reaction Types in NH3 Assimilation 283
Redox Neutral 283
Redox Active 283
Redox Balanced 283
14.3 Metabolically Irreversible Nitrogen Exchange
Reactions 283
14.4 Near-Equilibrium Nitrogen Exchange Reactions 284
Glutamate DH 284
Transaminases 285
14.5 The Urea Cycle 286
[NH3] Exceeds [Aspartate] 287
[Aspartate] Exceeds [NH3] 287
Steps from NH3 to Citrulline 288
Cytosolic Steps of the Urea Cycle 289
Overall Urea Cycle 290
14.6 Amino Acid Metabolism: Catabolism 291
Branched-Chain Amino Acid Breakdown 291
Threonine 293
Lysine 293
Tryptophan 293
Phenylalanine and Tyrosine Degradation 293
Amino Acids Directly Connected to Major Metabolic
Pathways 295
Arginine, Proline, and Histidine Are All Converted to
Glutamate 295
One-Carbon (1C) Metabolism and Serine, Glycine, and
Methionine Breakdown 297
14.7 Amino Acids: Anabolism 300
Nonessential Amino Acids 301
Essential Amino Acids 302
Aromatic Amino Acid Biosynthesis 302
14.8 Nucleotide Metabolism 304
Pyrimidine Synthesis 306
Pyrimidine Degradation 307
Purine Synthesis 307
Purine Degradation 309
Salvage Reactions 311
Purine Nucleotide Regulation 311
Purine Nucleotide Cycle 311
Deoxynucleotide Formation 312
A Unique Methylation to Form dTMP 314
14.9 Other Nitrogen Pathways 316
Summary 317
Key Terms 318

Contents xiii

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 Review Questions 318
References 318
Box 14.1 Clinical Cases of Defects in Amino Acid
Metabolism 292
Box 14.2 WORD ORIGINS: Folate 297
Box 14.3 Vitamin B12 and Folate Deficiencies 301
Box 14.4 The Chorismate Pathway and Weed Control 304
Chapter 15 Nucleic Acids 319
15.1 Strand Structures of the Nucleic Acids 320
15.2 Structure of the Double Helix 321
15.3 Supercoiling 325
15.4 Histones 326
15.5 Replication 327
Initiation 327
Replication Fork and the Replisome 328
Primer Formation 329
Creating the Double Helix 330
Distinctive Features of Eukaryotic Replication 330
15.6 DNA Repair 331
15.7 Transcription 332
RNA Polymerase Binding to DNA 333
Transcription Events in E. coli 333
Eukaryotic Transcription 335
Summary 338
Key Terms 340
Review Questions 340
References 340
Box 15.1 WORD ORIGINS: Palindrome 335
Box 15.2 Exome Sequencing 338
Chapter 16 Protein Synthesis and Degradation 341
16.1 Three Forms of RNA Are Employed in Protein
Synthesis 342
tRNA 342
rRNA and the Ribosomes 344
16.2 The Genetic Code 345
16.3 Steps in Protein Synthesis 346
Initiation 346
Elongation 346
Termination 350
Distinctive Features of Eukaryotic Translation 350
Regulation of Eukaryotic Translation 350
16.4 Posttranslational Modifications of Proteins 351
Immediate Modifications 351
Longer Term Modifications 352
16.5 Protein Degradation 353
Extracellular Proteases 353
Intracellular Proteases 353

xiv Contents

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 16.6 The mTOR Pathway in the Control of Protein
Synthesis 356
Summary 357
Key Terms 357
Review Questions 358
References 358
Box 16.1 UNIT ORIGINS: The Svedberg 345
Box 16.2 Macromolecular Inhibitory Complexes 352
Appendix 359
1. Mathematical Ideas 360
Vectors 360
Logarithms 360
Geometric Mean 361
2. Chemical Fundamentals 362
3. Derivation of the Henderson–Hasselbalch
Equation 364
4. Derivation of the General Free Energy Equation 366
5. Lipids 366
Fatty Acids 366
Phospholipids 366
6. Aspects of Enzyme Kinetics 367
Derivation of the Michaelis–Menten Equation 367
Derivation of Equations for Reversible Enzyme Inhibition 370
The Problem with Double Reciprocal Plots 371
The Lipid–Water Interface 372
7. Vitamins and Cofactors 373
8. The RS System of Stereochemistry 375
9. Reactive Oxygen Species 377
10. Enzyme Mechanisms 378
Aconitase 378
Prenyltransferase 379
11. Metabolic Pathways 381
Glyoxylate Cycle 381
Odd Chain Number Fatty Acids 382
Later Steps in Cholesterol Synthesis 383
The Purine Biosynthesis Pathway 384
References 385

GLOSSARY 386
INDEX 403

Contents xv

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 Preface

Considering Metabolism
Metabolic diseases such as diabetes and others associated with the current obesity
crisis have thrust metabolism into the forefront of popular thinking. In many ways,
metabolism is the central science of biochemistry. This is the view I have adopted as
the core concept of this textbook.
Having a research background in metabolism, a long-standing interest in the
fundamental topics of biochemistry—including kinetics and thermodynamics—and
having taught a one-semester biochemistry course for over 25 years, I have long
wanted to write a book that reflects the whole of the subject with the unifying theme
of metabolism.

Brevity
A key consideration when writing this text was to keep the book short enough and
approachable enough that a student can read it in one semester. The alternative
approach—having a book far too long for continuous reading and having the instructor
suggest which portions to omit—is already well represented. In my experience, for
students who are not biochemistry majors, the fragmentation resulting from parsing
longer texts leads to less reading and, therefore, less understanding. The areas of
special interest to the instructor can be readily augmented with primary sources,
while the textbook provides continuity and context.
I have emphasized recurring ideas such as commonalities in chemical reaction
mechanisms and pathway construction as much as possible. The decision of whether
the book is for teaching or reference is decidedly in favor of teaching; for example,
only a few protein domains are presented. The wealth of information available on
the Web (notably ncbi.nlm.nih.gov) can substitute for a more extensive collection.
The present text will provide students with an introduction to the foundations of
biochemistry.

Organization
The presentation of biochemistry topics is mostly a classical one, with a slight
divergence: the introduction to lipids directly follows the chemistry of water. This
is in keeping with presenting molecular classes in the order of increasing chemical
complexity: water, lipids, carbohydrates, nitrogen compounds. It also has the virtue
of contrasting water solubility with water insolubility in the case of lipids.

Image © Dr. Mark J. Winter/Photo Researchers, Inc.

xvi

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 When using this book for medically oriented courses, the chapter on photosynthesis
may be omitted. In that case, however, the photosynthetic “dark reactions” should
at least be referenced, as they are similar to those in the pentose cycle; this analogy
is made explicit in the chapter on carbohydrate pathways.

Key Features
• Dual diagrams of enzymatic reactions. A unique method of presenting electron
flow for reaction mechanisms was devised for this book. For each mechanism,
the substrate, intermediates, and product are presented on the top line. Below
a separator (dotted line), the molecules are redrawn with their electron flows,
using the traditional curved arrows. This separation allows the student to
visualize the result of the electron flow, which is commonly obscured by the
need to show the electron arrows for the next transformation.
• Word Origins feature box. Included in most chapters is a box that provides a
short history of certain words that are rich in meaning, without which it is often
more difficult to understand the underlying concept. Providing an explanation
of their origins helps students become familiar with these important terms and
achieve a better understanding of what is being described.
• Thermodynamics treatment. The development of thermodynamics for
metabolic purposes leads to the distinction between two classes of enzymes:
near-equilibrium and metabolically irreversible. This allows a simplification,
as near-equilibrium reactions are not sites of cellular regulation. The roles of
standard, actual, and near-equilibrium states for free energy are distinct and
consistently presented to aid student understanding.
• Chemical mechanisms. A study of biochemistry should impart a viewpoint
enriched by understanding the underlying chemistry of events in living systems.
This extended view of biology is best achieved by understanding how enzymatic
reactions function. All of the background chemistry needed for this text should
be covered by prerequisite courses of chemistry. Some further information is
presented in the appendix; a review of organic chemistry reaction mechanisms
(most critically, nucleophilic reactions) may be necessary for those who are less
comfortable with the material.
• Enzyme kinetics treatment. The text emphasizes direct plots of substrate
concentration against initial velocity, introducing double-reciprocals only after
a complete development of the subject. While in widespread use, the double-
reciprocal form is difficult to visualize and leads to the false impression that
memorizing patterns of lines for enzyme inhibition provides insight into how
inhibitors work. Instead, direct plots, with an emphasis on the behavior of
reaction velocity at different substrate concentrations, deliver the message
clearly. Coupled with everyday descriptions of the different types of inhibition,
these critical ideas are easily grasped. A further distinct notion is the use of the
kinetic term Vmax/Km rather than Km in developing kinetics. Too often, “Km”
becomes a focal point and is treated as an equilibrium constant rather than a
steady-state constant. This common misuse of Km versus Vmax/Km is part of the
reason that many students have difficulty understanding enzyme kinetics, and
it is a problem this text carefully avoids.
• Minimalist molecular biology treatment. The essence of molecular biology is
included in the final two chapters. The emphasis is on providing an overview
with a chemical perspective. For example, stacking interactions in DNA, the
basis for forming the double helix, are explained in simple, chemical terms.

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 • The pathway view. The distinction between a reaction view and a pathway
view is clearly emphasized to facilitate student comprehension. For example,
the distinction between a bound cofactor like FADH2 from a free cofactor
like NADH becomes obvious: only NADH can transfer electrons between
metabolic reactions.
• Appendix. The appendix of this text contains both entries for students
needing a little extra help and more advanced material that, while perhaps not
appropriate for the level of this particular text, is nonetheless important to the
field of biochemistry as a whole. For remediation, basic ideas of mathematics
and chemistry with which students traditionally have difficulty can be found in
the appendix, as can certain extended pathways like amino acid and cholesterol
routes. The advanced material includes the mechanism of aconitase and the
role of fluoroacetate, which represent milestone achievements in biochemistry.
These may be of interest to the more inquisitive student wishing to go beyond
the fundamentals.

Resources
For Instructors
An Instructor’s Media CD, compatible with Windows® and Macintosh® platforms,
provides instructors with the following resources:
• The PowerPoint® ImageBank contains all of the illustrations, photographs,
and tables (to which Jones & Bartlett Learning holds the copyright or has
permission to reproduce electronically). These images are inserted into
PowerPoint slides. Instructors can quickly and easily copy individual images
into existing lecture slides.
• The PowerPoint Lecture Outline presentation package provides lecture notes
and images for each chapter of Biochemistry. Instructors with the Microsoft®
PowerPoint software can customize the outlines, art, and order of the
presentation.
To receive a copy of the Instructor’s Media CD, please contact your sales
representative.
Also available for qualified instructors to download from the Jones & Bartlett
Learning website, www.jblearning.com, are the text files of the Testbank.
For Students
To further enhance the learning experience, Jones & Bartlett Learning offers the
following ancillary materials:
The Student Companion Website (http://science.jbpub.com/biochemistry)
provides content exclusively designed to accompany Biochemistry. The site hosts an
array of study tools including chapter outlines, study quizzes, an interactive glossary,
animated flashcards, crossword puzzles, and web links for further exploration of
the topics discussed in this book.

xviii Preface

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 Acknowledgments
This book has come a long way from my original, draft manuscript. It has gone
through several rounds of reviews and edits, and it benefitted from the feedback of
many individuals to whom I owe great thanks.

Sergio Abreu, Fordham University

Lois Bartsch, Graceland University
Sajid Bashir, Texas A&M University—Kingsville
Mrinal Bhattacharjee, Long Island University
Debra Boyd-Kimball, University of Mount Union
Barbara Bowman, University of California—Berkeley
Jeanne Buccigross, College of Mount St. Joseph
Mickael Cariveau, Mount Olive College
James Cheetham, Carleton University
Zhe-Sheng Chen, St. John’s University
David Eldridge, Baylor University
Susan Evans, Ohio University
John Fain, University of Tennessee Health Science Center
Sue Ford, St. John’s University
Matthew Gage, Northern Arizona University
Eric Gauthier, Laurentian University
Neil Haave, University of Alberta, Augustana Campus
David Hilmey, St. Bonaventure University
Blaine Legaree, Keyano College
Lisa Lindert, California State University—Sacramento
Meagan Mann, Austin Peay State University
Nick Menhart, Illinois Institute of Technology
Abdel Omri, Laurentian University
Gordon Rule, Carnegie Mellon University
Mary Railing, Wheeling Jesuit University
Gerald Reeck, Kansas State University
Abbey Rosen, Marian College of Fond du Lac
Frank Schmidt, University of Missouri
Michael Sehorn, Clemson University
Kavita Shah, Purdue University
Andrew Shiemke, West Virginia University
Amruthesh Shivachar, Texas Southern University
Todd Silverstein, Willamette University
Madhavan Soundararajan, University of Nebraska—Lincoln
Salvatore Sparace, Clemson University
Vicky Valancius-Mangel, Governors State University
David Watt, University of Kentucky
Wu Xu, University of Louisiana—Lafayette

I would also like to thank the entire team at Jones & Bartlett Learning: Shoshanna
Goldberg, former editor Molly Steinbach, Erin O’Connor, Cathleen Sether, Rachel
Isaacs, Lauren Miller, Scott Moden, and Louis Bruno. Without all of your support
and guidance, this book would never have come to fruition.

Ray Ochs
St. John’s University
[email protected]

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57366_FMxx_i_xx.indd 20 9/7/12 1:48 PM
 1
Foundations
CHAPTER Outline

1.1 Origins of Biochemistry 1.4 Cell Theory

1.2 Some Chemical Ideas 1.5 The Species Hierarchy and Evolution

Reactions and Their Kinetic Description 1.6 Biological Systems

Equilibrium Key terms

The Steady State References
1.3 Energy BOX 1.1: Word Origins: Organic

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 B
iochemistry is the study of the chemical nature of biology.
Biochemists use chemical ideas and tools to understand living
systems. We begin with a review of the chemical concepts of
equilibrium, kinetics, steady state, and energy. Additional chemical
principles are discussed in the appendix. Some foundational ideas of
biology complete the chapter, namely, the cell theory, evolution, and
species hierarchies.

1.1 Origins of Biochemistry

Compared to its component sciences, biochemistry is a young disci-
pline. The word biochimie was introduced by the German scientist
Hoppe-Seyler in 1877. He also edited the first biochemistry journal,
Biological Chemistry, still in existence today. It was during this period,
the later part of the 19th century, in which two erroneous ideas—
spontaneous generation and vitalism—were dispelled, clearing the
way for a discipline that required new thinking.
According to the hypothesis of spontaneous generation, living
organisms arise from nothingness, such as bacteria appearing in a
nutrient-rich broth. In the 1860s, however, Louis Pasteur demonstrated
that bacteria exist in the air; no bacteria appear in the broth if the
container is isolated from the atmosphere. This led to the cell theory,
which states that cells are the fundamental unit of living systems, arising
BOX 1.1: Word Origins from other cells. Despite this advance, Pasteur was himself a vitalist;
that is, he believed that living systems do not obey the same chemical
Organic principles as inert materials.
Among its rich meanings, the word organic implies Two challenges to vitalism bracketed the work of Pasteur. In 1828,
a sense of the whole, retained in the word organ- Wohler discovered that urea (formed in living systems) could be syn-
ism or organ. Historically, however, it was used by thesized in the laboratory from ammonia and bicarbonate. This in vitro
vitalists to identify substances that could be pro- synthesis of an organic compound therefore did not need the “aid of
duced only by a living organism. After vitalism was a kidney” as Wohler put it (Box 1.1). In 1897, the German chemists
disproved, organic was redefined, rather than cast (and brothers) Eduard and Hans Buchner showed that fermentation
aside. Today, organic chemistry simply identifies
could exist in an extract from ruptured cells, thus dispelling the notion
a branch of chemistry that specifically deals with
that cellular organization is required for processes that occur in living
compounds of carbon. Strictly speaking, inorganic
chemistry refers to the study of all other types of
systems.
molecules. Yet another meaning for organic has In the 20th century, biochemistry was dominated first by organic
emerged that is closer to its historical roots. That chemistry, as metabolic pathways were discovered, then by enzymol-
is, it describes farming methods that do not use syn- ogy, then bioenergetics, and later by molecular biology as the role
thesized chemicals (e.g., fertilizers and pesticides of DNA and information molecules emerged. As biochemistry plays
for plants and hormones for animals). Thus, growing an increasingly significant role in both the physical and chemical
plants and raising animals in this way is said to pro- sciences today, all of these disciplines overlap to some extent. What
duce organic foods. Whether this is a definite health remains, however, is the distinctive viewpoint of perceiving biology
benefit is debatable; for example, the absence of from a chemical perspective. While both the chemical and the biologi-
pesticides can lead to a greater bacterial content cal understanding of many areas of study have greatly expanded in
in food. Moreover, this use of organic is less strict
recent times, principles of biochemistry have emerged that are unique
and may vary from one producer to another. Despite
to this discipline and have been invaluable in elucidating a large num-
the three distinct definitions of organic, we are con-
cerned in this book only with the middle one, the
ber of biological phenomena. These underpinnings are presented in
chemistry of carbon compounds. subsequent chapters. Presently, though, we consider some fundamental
concepts of chemistry and biology.

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 1.2 Some Chemical Ideas
In order to determine whether you need a basic review, or can instead
skip to the next section, take the following self-test:
• Without specifying a value, what is the meaning of Avogadro’s
number?
• Distinguish between atoms, electrons, molecules, and moles.
• When is it appropriate to use mol units as opposed to grams?
• Why is the equilibrium constant for a reaction equal to the
products multiplied together, divided by the substrates multi-
plied together?
• How are equilibrium and kinetics related?
Mastering the ideas of the mole, Avogadro’s number, atoms, and
molecules is the first step in understanding more complex informa-
tion in biochemistry. We consider here the notions of kinetics and
thermodynamics with the assumption that the more elementary ideas
are well in hand.

Reactions and Their Kinetic Description

If substances A and B react to form substances C and D, then the
generic reaction for this transformation can be written as follows:

A+B  C+D (1.1)

(1.1)

A and B are called substrates, whereas C and D are called products.

Each is a molecule, but each can also be called a compound or a metab-
olite. In order to visualize what is happening, let us relax our molecular
thinking and represent the molecules schematically as shown below.

B
A

B
A
A B C D
B
Based on this representation, the reaction involves removing a
piece of molecule A and placing it onto molecule B, thus creating A
molecules C and D. This is a “mechanistic” view. To more fully char- B
acterize the reaction, we need to know the rates in both the forward
and reverse directions. Consider first the forward direction, which
proceeds from left to right as the reaction is written: FIGURE 1.1 Collision Theory of Reaction Rates.
Three A molecules react with four B molecules
A+B →C+D (1.2)
(1.2) and each possible interaction of an A with a
B is indicated. There are a total of 3 × 4 = 12
possible collisions. In general, the rate is
Suppose there are three A and four B molecules, as shown in Fig­ proportional to the number of A molecules
ure 1.1. Each A can combine with any of 4 B’s, so there are 12 possible times the number of B molecules in a fixed
collisions (3 × 4) between the three A molecules and the four B molecules. volume; that is, rate is proportional to [A] × [B].

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 According to collision theory, the rate of a reaction is proportional to
the number of collisions. In this example, the rate is proportional to
3 × 4. In general, the rate is proportional to [A] × [B], where [A] and [B]
are the concentrations of A and B, respectively.
The rate under consideration, the forward rate, can be designated
as ratef. This rate is equal to a constant multiplied by the product of
[A] and [B]:

ratef = kf [ A][B], (1.3)

where kf is the constant of proportionality between the rate and the

concentrations and is called the rate constant.
For the reverse reaction, C + D → A + B, we can follow the same
derivation and arrive at a similar expression:

rater = kr [C][D] (1.4)

where rater represents the reverse reaction rate. The expressions for
reaction rate shown in Equations 1.3 and 1.4 can be generalized to
any reaction. The rate constant, while independent of changes in
concentration, can vary with conditions such as temperature or ionic
strength. Experimentally, reaction rates are measured by determining
the decrease in substrate concentration or the increase in product
concentration with time. Equations 1.3 and 1.4 summarize the results
of those experimental studies. Thus, the reaction rate has units of con-
centration per time.
A rate, by definition, has only one direction, yet chemical reactions
are commonly written with double arrows between substrates and
products. This notation, which indicates that both forward and reverse
reactions occur, is commonly used when a reaction attains a position
of equilibrium.

Equilibrium
Perhaps the most important fundamental idea in chemistry is that of
equilibrium. A state of equilibrium exists when the forward and reverse
rates of a reaction are equal. Once a reaction achieves equilibrium, no
further observable change occurs in the substrate or product concen-
trations, unless there is a change in external conditions. Reactions not
yet at equilibrium have a driving force toward the equilibrium state,
just as a rolling ball eventually comes to rest as the forces acting on it
balance. To become familiar with the state of equilibrium, we examine
the origins of the equilibrium expression and the equilibrium constant.
According to the definition of equilibrium, ratef = rater, so we can
equate Equations 1.3 and 1.4:

kf [ A][B] = kr [C][D] (1.5)

Sometimes to emphasize the fact that we are describing an equilib-

rium, an “eq” subscript is added to the concentration terms (i.e., [A]eq,

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 [B]eq, etc.). In Equation 1.5, though, we will just assume the concen-
trations are those at equilibrium under our conditions. Rearranging,

kf kr = [C][D] [ A][B] = Keq , (1.6)

(1.6)

where Keq is the equilibrium constant. Thus, the rate constants (kf and kr)
and the equilibrium constant (Keq) are related.
Equation 1.6 relates kinetics (a rate process intrinsically tied to a
time element) to equilibrium (a process independent of a time element).
A single reaction may exist in equilibrium, but so, too, may multiple
reactions:

ABCDE (1.7)

Under biological conditions, though, multiply connected reactions are

better represented using the steady state.

The Steady State

One problem with applying the equilibrium model to living cells is that
living cells are never actually at equilibrium. Thus, a more elaborate
system must be used to model metabolism: the steady state. The steady
state applies when the intermediates of a process are constant with time,
yet the overall process is changing with time. To understand this con-
cept, consider just two components, a substrate (S) and a product (P),
which are the absolute minimum requirements for an equilibrium:

SP (1.8)

The equilibrium constant for this reaction is:

Keq = [ P] [S] (1.9)

To describe a steady state, we need a minimum of three components:

a substrate (S), an intermediate (I), and a product (P):

S→I→P (1.10)
(1.10)

Equation 1.10 is really two reactions, S → I and I → P, much in the

same way that an equilibrium reaction is really two reactions (i.e., a
forward reaction and a reverse reaction). In the steady state, there is a
net flow of material from S to P in Equation 1.10, so the system overall
is not constant with time. Commonly, multiple intermediate species
are present in a steady state rather than just one. In Equation 1.11,
for example,

S→I→ J→K →L →P (1.11)

(1.11)

all of the individual rates (e.g., S → I, I → J, etc.) are equal. Not only that,
but the overall rate, S → P, is the same. The result is that the intermediate

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 concentrations (i.e., [I], [J], [K], and [L]) do not vary with time. Instead,
the concentrations of the intermediates are constant because each one
is formed at the same rate that it is removed.
The concentrations of S and P need not be constant, however. Sup-
pose, for example, that S is saturating for the first reaction. Saturation
with a substrate means that its concentration is very high, effectively
unchanging during the reaction, thus fixing the rate of the reaction
S → I. According to Equation 1.11, the product P cannot revert back
to L. As a result, P can accumulate and its concentration has no effect
on the rate of its formation from L.
Metabolic pathways that are linear in structure, as in Equa-
tion 1.11, are readily modeled by a steady state. In order to clearly
picture the situation, consider an everyday example of a line of people
forced to move single-file through a gate. Suppose, as diagrammed in
Figure 1.2, that people are admitted at a rate that enables them to flow
without backup through an entry gate to a building, and then allowed
to exit through a gate that is also controlled to allow no buildup at the
exit. The number of people entering is analogous to [S], whereas the
number of those leaving is analogous to [P]. We can view the steady-
state intermediates (analogous to I, J, K, and L in Equation 1.11) by
imagining a window in the building that lets us look at the line. At
any given time there are eight people visible through the window. Each
time we look, there will be a different eight people in view, but the
number is the same every time. This is the essence of the steady state.
While the steady state is distinct from an equilibrium, equating the
two is a common scientific error. Often, an equilibrium is used for all
situations where there is an element of balance, not recognizing that
this is inappropriate when a series of chemical reactions produces a
net flow. In that situation, the steady-state model is more appropriate.
Finally, it is important to stress that both equilibrium and steady
state are models. Thus, while they often are appropriate to the situ-
ation, they are always approximations. In some instances they are
wildly inaccurate ones. For example, prior to an enzymatic reaction
or series of reactions reaching constant intermediate concentrations,

FIGURE 1.2 The Steady-State Window. People are moving through a

building at a constant rate. As long as the rate of entry and exit is the same,
the number of people visible through the window (the intermediate state)
will be the same (8). At any instant in time, though, the eight people in this
intermediate state will be different.

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 neither model applies. This is called a pre-steady state condition, which
requires a different model entirely.

1.3 Energy
Energy is a concept that is at once simple and complex. It is simple
because it is part of everyday parlance: a child knows about “hav-
ing a lot of energy,” the relative difficulty of walking uphill, and the
existence of friction. It is complex because all forms of energy, such as
electrical, gravitational, pressure–volume work, and heat flow, can be
interconverted. The energy of a waterfall, a galloping horse, a chemi-
cal reaction, or within a single molecule can be understood through a
study of thermodynamics, the science of energy changes.
Thermodynamics has two faces: one that is classical and one that
is statistical. The classical approach uses a few postulates and defini-
tions but makes no assumptions about the exact nature of the systems
under investigation; even the existence of molecules is unnecessary.
The statistical approach considers the behavior of large collections
of molecules and allows more mechanistic conclusions, but it is more
narrowly applicable. Both approaches lead to a consistent set of equa-
tions and together they provide a reasonable understanding of the
nature of energy. To start, we need strict definitions of three entities:
internal energy, enthalpy, and entropy.
Internal energy is the energy of the system under study, such as a
chemical reaction or a pot of boiling water. It is the sum of the work
and heat of the system under study. Work is an energy of motion, the
product of force and distance.
Enthalpy (from the Greek enthalpos, meaning “putting heat in”)
is closely related to internal energy. Enthalpy is the heat released or
absorbed by a reaction at constant pressure, a common condition in
the laboratory as well as in the chemistry of living systems. As a result,
values for reaction enthalpies rather than internal energies are listed
in tables of thermodynamic data.
The statistical approach to thermodynamics reveals entropy as
the number of ways that energy can be distributed as a result of a
process. For example, if we suddenly apply brakes to a speeding car,
the energy of motion will be redistributed to particles of tire rubber
on the street, as well as into frictional heat. Entropy increases with an
increase in energy dispersion.
When discussing energy in a biochemical context, we are invari-
ably referring to a combination of changes in enthalpy and entropy,
called free energy. The free energy change for a system can be used
to determine whether a reaction can proceed in the direction written.
Issues of thermodynamics, free energy, and the relationship between
free energy and equilibrium are discussed elsewhere in this book. Here,
we will just assume that chemical energy is equivalent to free energy.
We commonly speak of both molecules and portions of molecules
as having high energy. Two high-energy molecules of particular impor-
tance in biochemistry are the reduced form of nicotinamide adenine

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 dinucleotide (NADH) and adenosine triphosphate (ATP). Both NADH
and ATP are mobile cofactors that allow communication between hun-
Radiant dreds of different reactions within the cell. NADH transfers electrons;
energy
consider it a donor of high-energy electrons. ATP, on the other hand,
transfers a terminal phosphoryl group; think of it as a high-energy
NADP+ NADPH Sugar phosphate compound.
e –
The connection between electron flow and ATP formation is a
Plants
H 2O O2 CO2
profound one in biochemistry. In the global energy cycle (Figure 1.3),
Animals radiation from the sun induces the formation of high-energy electrons
e– by driving the formation of the reduced form of nicotinamide adenine
NAD+ NADH Sugar dinucleotide phosphate (NADPH), a close analog of NADH. NADPH
then donates electrons to convert atmospheric carbon dioxide (CO2)
to sugars and other molecules. Subsequently, animals consume those
ATP
sugars, converting their electrons to NADH, which is used to form
ATP. In the process, sugars and other molecules form CO2, which is
FIGURE 1.3 The Global CO2 Cycle. Radiation
from the Sun is used to energize electrons once again utilized by plants.
in the chloroplasts of plants, thus producing
high-energy electrons in the form of NADPH.

1.4 Cell Theory

These electrons can be used to drive the
photosynthesis of sugar from atmospheric
CO2 in plants. Subsequently, the plants are
eaten by animals, and the sugars (and other The cell—the smallest unit of life—is a key organizing principle in biol-
molecules) are broken down to CO2, which is ogy. Single-celled organisms, such as bacteria, yeasts, and protozoans
released to the atmosphere, completing the (e.g., the paramecium), comprise the largest number of species. Our
cycle. Energy is trapped as electrons in NADH
major focus, however, is on multicellular organisms, primarily human.
and is used to produce ATP for cell processes.
The features of a typical mammalian cell are illustrated in Fig­
ure 1.4, which shows internal organelles and their arrangement within

Nucleolus Peroxisome
Nucleus Lysosome

Endoplasmic
reticulum

Endosome

Secretory
granule

Plasma
membrane
Mitochondrion
Cytoplasm
Golgi apparatus

FIGURE 1.4 The Cell. A representative drawing of the cell shows the
compartments that are created by membranes. The cell itself is separated
from its exterior by a plasma membrane. Several interior membranes,
such as those for the mitochondria, the lysosome, and the endoplasmic
reticulum, define separate reaction spaces within the cell.

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 Cytosol

Mitochondrion

Nucleus

Endoplasmic reticulum

Plasma
membrane

FIGURE 1.5 The Cell as a Concept. The cell can be represented as separate
reaction spaces, set apart by semipermeable membranes. Specific exchanges
across the relatively few membrane-delimited spaces are indicated by the
arrows drawn across the membranes in both directions.

the cell. A much simplified functional representation is depicted in Fig­

ure 1.5, where the properties relevant to biochemical analysis can be
readily seen. Consider, for example, the outer plasma membrane that
encloses the cell, serving as its boundary with the outside world. The
plasma membrane, like all cell membranes, is semipermeable. Some mol-
ecules readily cross the membrane, such as O2, H2O, and CO2, whereas
many others can traverse the membrane only if there is a carrier protein
that selectively allows them to cross. From a chemical viewpoint, the
membranes create separate water spaces to isolate chemical reactions.
Only those molecules that can communicate across these spaces—those
which can diffuse, or those which have a specific transporter—can
participate in the reactions. The major water space within the cell
is called the cytosol. Other membrane-delimited organelles shown in
Figure 1.5 that define separate water spaces for reaction are the mito-
chondria, the endoplasmic reticulum, and the nuclear membrane. In
addition to defining reactive spaces, membranes are the sites of lipid
biosynthesis.

1.5 The Species Hierarchy and Evolution

Evolution is a fundamental principle of biology. It is also commonly
misunderstood, perhaps due to the popularization of the phrase “sur-
vival of the fittest.” It is ironic that this phrase is so strongly embedded
in the popular lexicon, because it does not exist in On the Origin of
the Species, Darwin’s landmark work on evolution.
Evolution was first suggested from the extremes of plant and ani-
mal species that exist on isolated islands, notably the Galápagos of
present day Ecuador. The idea was that species arose from other spe-
cies, and those that could adapt best to their environment were able to
survive because they lived to reproduce. Eventually, adaptive character-
istics emerged. It is now commonplace to apply evolutionary principles

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 to biochemistry, mapping the formation of numerous enzymes and
DNA sequences from early origins to divergent present forms.
In order to catalog the complexity of the immense number of known
species, currently believed to number in the tens of millions, scientists
have traditionally turned to the classification hierarchy. The classical
organization is kingdom, phylum, class, order, family, genus, and spe-
cies. While there are currently considered to be five kingdoms, we will
focus on just three: animals, plants, and prokaryotes. Our emphasis
is on mammalian species, although plant, bacterial, and occasionally
yeast examples will be included. Most discoveries in biochemistry have
come from only a very small sampling of the biological universe, largely
Organism
for practical purposes, but there are many indications that a unity of
Free living unit capable of reproduction pathways and mechanisms exists between different organisms. Some
differences between organisms will be considered to get a sense of how
biological variation is expressed.

Organ system
A grouping capable of an overt
function, such as respiration

1.6 Biological Systems

Organ There is another hierarchy that identifies the viewpoint of the inves-
A collection of tissues having defined tigator toward biological systems. Figure 1.6 shows a ranking with
structure and function, such as the liver
organisms at the top level and subatomic particles at the bottom.
There are even higher levels of organization than organisms, such as
Views
populations, which have medical as well as scientific importance (as in
Holistic Tissue
A group of cells with a single function,
studies of the transmission of infections between organisms). However,
such as connective tissue levels beyond that of organism are usually of interest in other fields,
such as the social sciences.
The rankings in Figure 1.6 also can be used to exemplify two
Cell extremes in the analysis of biochemistry. A view close to the top, tak-
The smallest unit of life; some cells are ing in as wide a swath as possible, is called holistic. Those who favor
also organisms (unicellular)
the holistic view argue that it leads to answers that are physiologically
relevant. A view close to the bottom, examining specific chemicals
or molecular interactions, is called reductionist. Those who favor
Subcellular the reductionist view argue that it alone allows firm conclusions to
Organelles, extracts, complexes
be drawn because the number of variables is much smaller than in
the holistic approach. Both are essential, and we will move between
them in the text. We begin with a reductionist approach, examining the
Molecules chemical properties of water, the molecule most essential for the exis-
Large (e.g., proteins), and small (e.g., tence of life.
most metabolites)

Reductionist
FIGURE 1.6 Hierarchies of Biological Study. Different levels of investigation
Atoms are possible in the experimental study of biology. Physiologists typically
Molecular building blocks; the roughly study the higher levels, such as organisms, organ systems, and organs,
100 elements
whereas physicists typically study subatomic particles. Biochemists
usually examine the intermediate levels. If the study is closer to the top
of the hierarchy (i.e., if the approach is holistic), it is considered to be
Subatomic particles physiologically relevant, but there is greater uncertainty about the findings.
Electrons, neutrons, and protons If the study is closer to the bottom (i.e., if the approach is reductionist), it is
considered to be more exact, but less relevant. Both approaches, while in
conflict, require each other.

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 Key Terms
cell theory heat reductionist
collision theory high-energy electrons saturation
cytosol high-energy molecules semipermeable
endoplasmic reticulum high-energy phosphate species hierarchies
energy holistic spontaneous generation
enthalpy internal energy steady state
entropy mitochondria vitalism
equilibrium nuclear membrane vitalist
free energy rate constant work

References
1. Ord, M. G.; Stocken, L. A. Foundations of Modern Biochemistry. In Early Adven-
tures in Biochemistry, M. G. Ord, L. A. Stocken, Eds.; JAI Press: Greenwich, CT,
1995; Vol. 1.
Part of a multivolume history of biochemistry; the information in the present chapter
is found mostly in the first two chapters of Foundations of Modern Biochemistry.
2. Morowitz, H. J. Entropy for Biologists. An Introduction to Thermodynamics;
Academic Press: New York, 1970.
A gentle introduction to thermodynamics with fewer equations than the usual
introduction. Biological examples are emphasized.
3. Margulis, L.; Schwartz, K. V. Five Kingdoms. An Illustrated Guide to the Phyla of
Life on Earth, 2nd ed.; W. H. Freeman and Co.: New York, 1988.
In addition to a catalog displaying drawings and photographs of examples of the
major life forms, there is an introduction to the science of taxonomy, the hierarchies
of life.
4. Cells, 2nd ed.; Cassimeris, L., Lingappa, V. R., Plopper, G., Eds.; Jones and Bartlett
Publishers: Boston, 2011.
A recent cell biology textbook that provides broad introductions to life at the cel-
lular level.
5. Piontkivska, H.; Hughes, A. L. Evolution of vertebrate voltage-gated ion channel
alpha chains by sequential gene duplication. J. Mol. Evol. 56:277–285, 2003.
A study of the evolutionary relationship of a specific calcium ion channel.

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 2
Water
CHAPTER Outline

2.1 Structure of Water 2.8 The pH Scale

Gas Phase Water 2.9 The Henderson–Hasselbalch Equation

Partial Charges and Electronegativity 2.10 Titration and Buffering

Condensed Phase Water: Hydrogen Bonding Summary
2.2 Properties of Water Follow from the Key Terms
Hydrogen Bonded Structure
Review Questions
2.3 The Hydrophobic Effect
References
2.4 Molecules Soluble in Water
BOX 2.1: Covalent and Ionic: Discreet or
2.5 High Heat Retention: The Unusual Continuous Distinction?
Specific Heat of Liquid Water
BOX 2.2: Word Origins: Hydrophobic
2.6 Ionization of Water
BOX 2.3: A Thermodynamic Look at the
2.7 Some Definitions for the Study Hydrophobic Effect
of Acids and Bases

Image © Dr. Mark J. Winter/Photo Researchers, Inc.

12

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 H
umans are comprised mostly of water. Our daily weight fluc-
tuates largely because of a gain or loss of water. At a more
philosophical level, most feel an almost mystical connection
to water. This is why Ishmael’s claim in Moby-Dick that we all yearn
for the sea still stirs a sentiment in readers 150 years after it was
written.
In most cells, the number of water molecules relative to others
is even more impressive than its preponderance by weight. This is a
consequence of the low molecular mass of water (18 Daltons). In fact,
for every single protein molecule in cells, there are 75 lipid molecules,
100 Na+ ions, and 20,000 water molecules.
Although we generally refer to the molecule itself as water, each phase
has its own name: ice for the solid, water for the liquid, and steam or
vapor for the gas. While commonplace, water is curiously distinct from
other substances, especially in the liquid phase. One unique property of
water is its ability to dissolve so many other substances. It falls short
of being a “universal solvent,” but the number and type of substances
that dissolve in water is an important biological consideration. Water
also can retain an enormous amount of heat compared to other liquids.
Moreover, acid–base reactions in water are assisted by the ionization of
the water molecule itself. Finally, water has unusual phase transitions,
such as a very high boiling point, and unusual behavior at low tempera-
tures, such as the fact that the solid is less dense than the liquid. All of
these properties stem from the molecular structure of the water molecule,
which we consider next.
Phases

2.1 Structure of Water Fluid

Gas

Water vapor, like other substances in the gas phase, can be thought of
Liquid
as molecules in isolation. Distinct ways of viewing phases of substances
Condensed
are illustrated in Figure 2.1. The gas and liquid are called fluid phases;
liquid and solid alternatively can be grouped together as condensed Solid
phases. A study of each phase and the transitions between them pro-
vide insight into both the behavior of water and its interaction with FIGURE 2.1 Liquid water is a condensed
other molecules. fluid. The three phases of matter can be
alternatively characterized as fluid or
condensed (incompressible). The liquid state
Gas Phase Water of water (as with other substances) shares the
properties of being both fluid and condensed.
The essential feature of the gas phase is that there is effectively no
interaction with other molecules. Many properties of gases (regardless
of their chemical identity) are essentially the same, as long as they are
studied under conditions we would consider “average.” One way of
determining such conditions and ensuring that they are the same for
all observers is to establish them by committee. This has been done
by the International Union of Pure and Applied Chemists (IUPAC): a
pressure 1 atm, and a temperature of 0°C is called standard tempera-
ture and pressure (STP).
The properties of greatest biochemical consequence are those
that arise from the arrangement of electrons and nuclei within the
water molecule. It is evident from the H2O formula that two atoms of

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 hydrogen are attached to a single atom of oxygen, and the molecule
O is neutral overall. When the atoms are drawn on paper as they are
known to be arranged geometrically, the two-dimensional structure
H 104.5° H in Figure 2.2 is the result. The H–O–H bond angle is about 104°.
The underlying reason water adopts this structure is only apparent
FIGURE 2.2 Two-dimensional structure of when we consider the three-dimensional representation in Figure 2.3.
water. The three atoms of water can be drawn An oxygen atom contains eight electrons: two inner electrons (which
in a plane; the two bonded hydrogens make are not involved in bonding) and six valence electrons. The number
an obtuse angle, the value of which can only
of valence electrons corresponds to the number of the column oxygen
be explained by a consideration of its three-
dimensional structure. occupies in the periodic table (Figure 2.4).
In the water molecule, the six valence electrons on oxygen mix with
the two from the hydrogen atoms, recombining into four molecular
(a) (b) orbitals that are oriented roughly as a tetrahedron, as in Figure 2.3.
This tetrahedral orientation results from the mutual repulsion of the
electrons in these orbitals. Because they are all attached to a central
O
oxygen atom, and thus in forced proximity, the orbitals assume a
H
geometrical arrangement in which they can be as far apart from one
another as possible. In water, the two nonbonding orbitals contain a
H H “lone pair” of electrons, and occupy a somewhat greater volume than
H the orbitals with bonded electrons. As a result, the H–O–H angle is
somewhat less (i.e., 104°) than it would be in a perfect tetrahedron
FIGURE 2.3 Three-dimensional structure of
gas-phase water. The four orbitals of the water
(i.e., 109.5°), such as occurs in methane (CH4).
molecule are shown; water has a tetrahedral
structure. (a) The space-filling diagram shows
Partial Charges and Electronegativity
bonded hydrogen orbitals coming out of the
page and nonbonded electron pairs behind A covalent bond is by definition a sharing of electrons between the nuclei
the plane of the page. (b) The tetrahedral of two atoms, but the sharing is usually unequal. In fact, the sharing is
orientation depicts the oxygen in the center of
the tetrahedron and the nonbonded orbitals
only truly equal in covalent bonds between identical atoms, as in H2,
and bonded hydrogen atoms at the vertices. N2, or O2. In the case of the single bond between O and H in water, the
electrons are located closer to the oxygen atom. This uneven sharing
leads to partial charges that can be assigned to each atom involved in
Period
the bond: the O is partially negative and the H partially positive.
I II III IV V VI VII VIII
In general, atoms differ in their inherent ability to attract the electrons
1 H that are involved in bonding. The ability of an atomic nucleus to attract
electrons in a bond to itself is called electronegativity. Values of electro-
2 Li Be B C N O F negativity can be directly assigned to each atom, based upon measure-
ments of bond energies involving different pairs of atoms. A normalized
3 Na Mg Al Si P S Cl scale runs from 0 (no electronegativity) to 4 (greatest electronegativity).
A clear trend in electronegativity values is present in the arrangement of
4 K Ca the elements in the periodic table. Those elements in the top right (e.g.,
N, O, and F) are the most electronegative, whereas those in the bottom
left (e.g., Fr, Ra, and Cs) are the least electronegative. These periodic
trends indicate the different powers atoms have in attracting bonding
FIGURE 2.4 An abbreviated periodic table. electrons to them. Elements on the right side are more stable when they
The periods IA through VIIIA are shown attract electrons, in part because these electrons complete their outer
without the traditional intervening transition shells. Elements on the top of the table have fewer electrons to shield the
elements. Those elements towards the charge of the nucleus. Thus, the nuclei of these atoms have greater power
right and towards the top have the greatest
of attracting bonding electrons. The electronegativity values for the most
electronegativity. Only the elements N, O, and
F (shaded) participate in hydrogen bonding. important elements in biochemistry are as follows: oxygen (3.5), nitrogen
Elements of biological importance are (3.0), carbon (2.5), sulfur (2.5), hydrogen (2.1), and phosphorus (2.1);
highlighted in blue. the element with the highest electronegativity overall is fluorine (4.0).

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 We are now in a position to examine the electronegativity values
for the O–H bond in water. Because hydrogen has a value of 2.1, and O

oxygen 3.5, the electronegativity difference is 1.4. It has been estimated + +

that this makes the bond about 39% ionic. This merely quantifies H H
the previous point that the electrons in this bond are more strongly
Net vector sum
attracted to the O than to the H. Thus, while the bond is in one view
covalent, it is in fact a polar bond, or a partially ionic bond. FIGURE 2.5 The net polarity of water. The
A symbolism used to indicate the polar bond is a vector (i.e., a vectors resulting from electronegativity
differences are indicated with plus annotations
directed line segment) drawn with the origin at the H and the arrow- at their positive ends. The sum of these
head at the O. The vector is further embellished with a little “plus vectors is the overall polarity of the molecule.
sign” at the origin to denote the relatively positive (electron deficient)
part of the distribution. Using the vector notation for the water mol-
ecule in three dimensions, it is possible to take a vector sum of all of
the individual polar bonds (Figure 2.5). Because the molecule has a + +
nonzero net sum, it has a net polarity. The two orbitals that are not O C O
bonded (i.e., those containing electrons only) do not contribute to the
overall polarity of the molecule. Not all molecules with polar bonds Net sum = 0
have a net polarity; for example, CO2 has polar bonds, but the vectors FIGURE 2.6 The lack of polarity in carbon
cancel out, as shown in Figure 2.6. dioxide. Despite having electronegativity
Because water has a net polarity due to the overall vector sum of differences within the molecule, the sum of
its bonds, it is a polar molecule. We can assign partial charges to the the vectors in carbon monoxide is zero, so
atoms within the molecule. By convention, polarity is indicated by it is a nonpolar molecule.
the Greek letter sigma, superscripted with a negative or positive sign
to indicate the partial charges as in Figure 2.7. These features of the
water molecule in the gas phase give rise to the unusual interactions δ−
that occur between water molecules in the condensed phases, and
provide an explanation for the distinct properties of water. O

δ+ δ+
Condensed Phase Water: Hydrogen Bonding H H

Just as people change their behaviors in social settings, molecules FIGURE 2.7 Partial charges in gas-phase
in the condensed phases (i.e., the liquid and solid phases) display water. The differences in electronegativity
new properties. The molecules are in such close proximity in these are indicated by partial positive and partial
states that they are also known as incompressible states, which means negative charges within water. As a result,
the bonding is only partly covalent.
that external pressure cannot cause them to move perceptively closer
together. Most of our interest will be in the liquid state. Still, some
consideration of solid phase water as well as the transitions between
states (phase changes) will enhance our understanding of water. δ− δ+
The manner in which neighboring water molecules are held δ−
together is illustrated for two water molecules in Figure 2.8. The
δ+
hydrogen atom between the two O nuclei in the figure has one bond
indicated as a solid line and the other as a dotted line. The solid δ+
line represents a covalent bond, whereas the dotted line represents a δ+
hydrogen bond, one of the most important interactions in biochem- FIGURE 2.8 The hydrogen bond. As a result of
istry. Because hydrogen has only one electron to share in the covalent the charge interactions, two water molecules
bond, the hydrogen bond can be thought of as an electrostatic attrac- are shown interacting through a hydrogen
tion to one of the lone pairs of the other water molecule. See Box 2.1 bond. The bond consists of one hydrogen
atom attracted to two oxygen nuclei at once.
for a discussion on covalent and ionic bonds.
Colloquially, the dotted portion of the bond is
Covalent bonds are much stronger than hydrogen bonds. The often identified as the hydrogen bond, while
average bond energy for a covalent O–H bond is 467 kJ/mol whereas in fact the entire structure contained in the
a hydrogen bond is on the order of 10 kJ/mol. Despite the relative loop in the figure is the hydrogen bond.

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 BOX 2.1: Covalent and Ionic: Discreet or Continuous Distinction?
In your first encounters with chemistry, a bond is defined as being either ionic
or covalent. The division is important in distinguishing chemical behavior. For
example, an ionic solid has a much higher melting point than a solid of a cova-
lently bonded compound, because the forces that must be overcome in ionic
solids involve numerous species in a crystal. Yet, ionic compounds dissolve
readily in water and separate completely into ions, as opposed to covalently
bonded compounds, which may or may not dissolve readily in water, but retain
their molecular identity when they do. In order to understand deeper problems
in chemistry—beginning, say, with why some organic solvents dissolve in
water and others don’t—we need to explore whether the bonding qualities
of these types of compounds are entirely discreet or whether there is a con-
(a) tinuum that extends from strictly ionic to strictly covalent. The notion that the
continuous situation must be the answer is not true of all physical principles.
δ− δ− For example, the fundamental changes of quantum physics are discreet steps.
δ+ δ+ However, bonding characteristics are a macroscopic quality that appears as
δ+ δ+
a continuous process, involving partial ionic bonds. We could consider water,
in fact, from the opposite extreme as it is normally viewed: namely, as a com-
δ− pound of O2- associated with two H+ ions that are attached on one side, so
that the molecule has a preponderance of negative charge on one side and
δ+ δ+ a preponderance of positive charge on the other. Because of the incomplete
dissociation of water in its liquid state, we would conclude that water is not
actually an ionic compound but rather a partially covalent one.
δ− δ−

δ+ δ+ δ+ δ+

weakness of individual hydrogen bonds, in the aggregate they become

a dominant force and largely explain the peculiar properties of water.
(b)
O O O
The three-dimensional view depicted in Figure 2.9 applies to both
H H H H liquid and solid water. The latter is the regular crystal from which the
figure is taken. The liquid state is sometimes considered to be a flicker-
O O O O
ing crystal; the distinguishing fluid property, conforming to the shape
H H H H of any vessel, is due to the greater motion of the molecules in liquid
water and their ability to exchange positions in the liquid crystal-like
O O O O
structure. Another way to view the liquid state is to consider that the
H H H H structure, while largely resembling the crystal, has an occasional defect
that allows the water molecules to rearrange themselves.
O O O O
Molecules in the solid state are usually more dense than they are in
H H H the liquid state. For example, liquid ethanol has a density of 790 kg/
m3, whereas the solid form is 950 kg/m3. This is because molecules are
FIGURE 2.9 Condensed phase water. Two usually at their closest approach in a crystalline solid, and an increase
views of condensed phase water are shown.
(a) The oxygen atoms are shown to bond
in temperature (which is needed to convert a solid to a liquid) tends to
to four positions throughout the structure. cause the molecules to move further apart (which decreases their den-
(b) A side view of condensed phase water sity). Liquid water, however, is already highly ordered, and the small
showing a hexagonal structure that results amount of motion at temperatures close to the freezing point causes
from a plane of water molecules in a regular water molecules to move closer to one another on the average than in
array. This structure accurately portrays ice.
ice. As ice melts to water, its density increases, reaching a maximum
Liquid water approximates this structure, but
continuously breaks and reforms bonds so at 4°C. At higher temperatures, the increased motion does reduce the
that the structure that results is both irregular density of liquid water (Figure 2.10). Thus, water has a maximum
and changing. density at 4°C, which explains why ice floats on water.

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 2.2 Properties of Water Follow from the
Hydrogen Bonded Structure
1

Density
One of the anomalous properties of water compared to other common 0.998

liquids is its relatively high boiling point (Table 2.1).

The extensive hydrogen bonding in water produces a cohesiveness 0.996

that can resist the tendency of molecules to escape into the gas phase 0 10 20 30
as the temperature is increased. Thus, a higher temperature (and a (a) Temperature (°C)
correspondingly greater energy) is needed to boil water.
Another way of thinking about water is to view it as a hydride of
oxygen. Other hydrides of closely related elements are HF (hydrogen
fluoride), H2S (hydrogen sulfide), and NH3 (ammonia). HF does not 0.9999

Density
occur biologically; H2S is a product of bacterial respiration; and ammo-
nia, an intermediate in mammals, is excreted as a final waste product 0.9998
of nitrogen metabolism in fish. The boiling points of these substances
0.9997
are shown in Table 2.2.
Two factors—electronegativity differences and molecular geom- 0 2 4 6 8 10
etry—can be used to explain the striking differences between the boil- (b) Temperature (°C)
ing points of water and these other polar hydrides. FIGURE 2.10 How the density of water varies
The electronegativity of F (4.0) is greater than the electronega- with temperature. The density of water has
tivity of O (3.5). The fact that HF has a considerably lower boiling a maximum at 4°C. The variation of density
point than water is due to a difference in spatial arrangement. Three- with temperature is shown over a range of
(a) zero to 30°C and (b) zero to 10°C. The
dimensional views of these molecules are shown in Figure 2.11.
change is modest but significant. There are
We have seen how water interacts with other water molecules, two opposing effects as energy (temperature)
creating an extensive network of hydrogen bonds. It is not possible for is increased: closer approach of more active
either HF or NH3 to form such extensive hydrogen bonded networks; molecules and increased separation as the
they can form only limited intermolecular hydrogen bonds. Oxygen temperature is increased further.
and sulfur are in the same column of the periodic table, so you might
expect hydrogen sulfide to have properties that are very similar to
those of water. The S–H bond is insufficiently polar, however, because TABLE 2.1 Boiling Points
the electronegativities of S (2.5) and H (2.1) are so similar. As a result, of Common Liquids
hydrogen sulfide (indeed, any SH-containing molecule) does not form Fluid Boiling Point (°C)
hydrogen bonds. Accordingly, H2S has an extraordinarily low boiling
Water 100
point compared to that of H2O. Indeed, in our everyday experience
both H2S and NH3 occur only as a gas. Benzene 80
Thus, the uniqueness of water stems from its combination of Carbon tetrachloride 77
electronegativity differences and the geometry of its hydrogen-bonded Chloroform 61
interactions. This leads to a well-oriented and extensive lattice that Ethanol 79

H
TABLE 2.2 Boiling Points of Hydrides
O S N Hydride Boiling Point (°C)
H F
H2O 100
H H H H H H
HF 20
H 2O H2S NH3
NH3 -33
FIGURE 2.11 Comparing water to similar structures. Three-dimensional
H2S -61
structures of the hydrides of the atoms F, O, and S indicate that NH3 and
H2S are very similar to water, yet they do not exhibit water’s extensive
hydrogen bonding due to geometric differences (NH3) and lack of sufficient
electronegativity differences (H2S).

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 is not shared even by other very similar molecules. This combination
of properties is the key to understanding how water interacts with
other substances. At one extreme are molecules with virtually no
interactions with water. This is the basis of the hydrophobic effect,
a concept discussed in the next section. At the other extreme are
molecules that strongly interact with water, in which case they tend
to dissolve in water.

2.3 The Hydrophobic Effect

The aphorism that “oil and water don’t mix” can be readily under-
stood as a direct consequence of the condensed state of water. Consider
the molecule decane:

H + C
CH3−CH 2−CH 2−CH 2−CH 2−CH 2−CH 2−CH 2−CH 2−CH3

C It is composed entirely of C–C and C–H bonds, which are nonpolar

+ (C–C; the electronegativity difference is 2.5 - 2.5 = 0) or barely polar
C H (C–H; the electronegativity difference is 2.5 - 2.1 = 0.4). Even this
FIGURE 2.12 The lack of polarity in methylene small polarity is offset by the geometry of the structure, as the polarity
(–CH2–) residues. Using the method of vector vectors (pointing to the carbon chain) offset each other (Figure 2.12).
sums, the small polarities due to C–H bonds Hence, decane and compounds with similar chemical compositions
cancel out, explaining the nonpolar nature of are nonpolar and cannot form hydrogen bonds with water. Another
methylene groups in lipids.
nonpolar substance is the oil in vinegar-and-oil dressing. It is common
experience that the dressing settle into separate layers, even after they
have been vigorously mixed.
The finding that nonpolar molecules separate from water is called
BOX 2.2: Word Origins the hydrophobic effect (Box 2.2). This term should be taken liter-
ally: an effect rather than an accurate description of the underlying
Hydrophobic
chemistry. Although hydrophobic means “water hating,” alkanes
The word hydrophobic was in use as a medical term such as decane do not hate water at all. In fact, decane has a stronger
for hundreds of years as a synonym for the disease affinity for water molecules than it has for other decane molecules!
rabies. A consequence of late-stage rabies infection The water–alkane attraction results from water inducing a dipole in
is an inability to swallow, so those afflicted have a the electrons of the alkane. The induced dipole attraction, however,
“fear of water,” or hydrophobia. The use of “hydro-
is a minor factor. Focus should be trained instead on the water itself,
phobic” for the exclusion of water from nonpolar
because water prefers to interact with other water molecules far more
substances is more recent, stemming from the early
part of the 20th century. Despite the fact that the
than it does with lipids. This is sometimes described as water squeezing
scientific usage is well established and that there is out nonpolar molecules so that the latter form their own phase. For a
no debate about what it means, its strict translation more thorough consideration of the forces underlying the hydrophobic
does imply that water and lipid molecules display effect, see Box 2.3.
repulsive forces, which is not the case at all. The
term only describes the phenomenon that water
and nonpolar substances form separate phases as
if they had some antipathy for each other. Ironi-
cally, as an archaic medical term for rabies, it is
far removed from the underlying pathology. As an
2.4 Molecules Soluble in Water
embedded term for water–nonpolar interactions,
The hydrogen bonding between water molecules in pure solutions
it is similarly a description of the phenomenon, far of water is extensive. A large number of other molecules nonetheless
removed from the underlying chemistry. can dissolve in water if a stronger interaction can result from the
solute–water interaction than from the hydrogen bonds in pure water.

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 (a)
BOX 2.3: A Thermodynamic Look at the Hydrophobic Effect Water
molecule
In our discussion of the hydrophobic effect, we considered the formation
of two phases, colloquially an oil and water phase, and suggested that the Nonpolar
molecules
principal forces were due to the interactions of water with itself, rather
than with the oil. While this is true, the underlying reason for it is somewhat
subtle and requires that we apply the ideas of thermodynamics.

In particular, the free energy of a process is determined by two factors: the

enthalpy and the entropy. To apply these notions, consider the process of
moving from one state to the next. Suppose our process moves individual
lipid molecules (substrate) into coalesced lipid molecules (product). Stud-
ies of nonpolar molecules in water have shown that the hydrogen bond-
ing of water molecules still occurs when lipid molecules are forced into
water; a representative drawing of two such molecules in a water solution (b)
is shown in Figure B2.3a. The bonding energy (the enthalpy) of water
arranged around lipid molecules is similar to the bonding energy of water
molecules in the pure water solution itself. Thus, enthalpy is not the driv-
ing force for the hydrophobic effect. The “product,” which represents the
change that we know occurs, is modeled in Figure B2.3b, where the two
lipid molecules have coalesced and a cage of hydrogen-bonded waters
surrounds both of them.

The placement of water molecules around the lipids is believed to be far FIGURE B2.3 Hydrophobic effect.
more ordered than in pure water; alternatively we can say that water in (a) Two nonpolar molecules, introduced
this cage has less freedom of movement. In thermodynamic language, we into water, become individually surrounded
would say that we have increased the entropy of the system depicted in by hydrogen-bonded water molecules. The
enthalpy of these water molecules is similar
Figure B2.3b. Our picture of entropy requires a statistical view: an increase
to that of the bulk water (not shown, but
in entropy means molecules are more disperse in both space and in energy assumed as background in the graphic).
distribution. However, the entropy is less as these
waters are more ordered than bulk water.
(b) The same molecules are now shown but
associated together. The amount of water
surrounding the two of them is much less
than that in (a), so that the overall entropy
of this situation is greater than in (a) and is
thus favored.

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 δ+
δ−
δ− δ+
δ+
δ− Na+ Cl–
δ−
δ+ δ+
δ−
δ+

FIGURE 2.13 Solubilizing NaCl. Entry into solution involves water

molecules giving up their own hydrogen-bonded interactions in favor
of an ionic interaction between the partial charge of the oxygen atom
of water and the sodium ion and between the partial charge of the
hydrogen atom of water and the chloride ion. Thus, solubilized NaCl has
a different and literally separate identity from the solid.

Imagine you are trying to dissolve table salt (NaCl) in water. In the
solid form, NaCl is a regular array of interspersed Na+ and Cl- ions.
There is a considerable difference in the electronegativities of Na (0.9)
and Cl (3.0), so electrons are not shared between these ions. Instead,
Na+ bears a full charge of +1, Cl- bears a full charge of -1, and the
attraction is purely electrostatic. Once added to water, the Na+ ion
becomes surrounded by the negative ends of the water molecules and
the Cl- ion becomes surrounded by the positive ends of the water
molecules, as illustrated in Figure 2.13.
This can be represented as a reaction, in which solid NaCl is con-
verted to isolated Na+ and Cl- ions that are surrounded by water. The
process of surrounding ions with water molecules is called hydration and
the individual ions that are surrounded by water molecules are said to
be hydrated. It is customary to write the hydration of NaCl as follows:

NaCl → Na+ + Cl − (2.1)

Water is omitted from this chemical equation because it is not strictly a

reactant or product in the formal sense. Still, the reaction is impossible
without it. What is happening is that the energy of hydration—the
strength of the interaction of the ions for water—overcomes both
the strength of the interaction of water for other water molecules, as
well as the ionic bonding of the NaCl lattice, so the ions are brought
into solution.
In a similar way, many other compounds can dissolve in water
through the interactions of charges with the partial charges of water.
Alternatively, uncharged polar compounds such as alcohols (ROH,
where R = CH3– or CH3CH2–, for instance) can form hydrogen bonds
to water with their –OH groups, again displacing the interactions
between water molecules.

20 Chapter 2 WATER

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 2.5 High Heat Retention: The Unusual Specific
Heat of Liquid Water
Another feature of liquid water that results from hydrogen bonding
is its exceptionally high specific heat. Specific heat is the amount of
energy needed to increase the temperature of 1 g of a substance by
1°C. Effectively, the high specific heat of water means that water
acts as a “temperature buffer”; that is, heat loss or gain is smaller in
water compared to other substances. This stems from the strength of
the hydrogen bonds. As the temperature is increased, the bonds bend
but do not break (i.e., the water molecules adhere to each other very
tightly). Heat goes into vibrational energy of the bonds, but the lattice
structure remains; that is, it resists translational changes. Hence, the
temperature rise is minimal in water. In the solid form (ice), the bend-
ing modes are unavailable, so ice does not share the high specific heat
of water. The specific heat of ice is more similar to that of an alcohol
such as ethanol (CH3CH2OH).

2.6 Ionization of Water

Pure water dissociates to a very small extent into ions. The reaction
can be understood as a reaction between two water molecules, in
which a proton migrates from one to the other as in Figure 2.14.
In solution, the protonated water molecule —H3O+— exists, but
there is very little of the H+ form. However, it is customary to rep-
resent protonated water as just H+, so the dissociation equation is
written as:

H 2O  H + + OH − (2.2)
(2.1)

Although the ionization of water takes place to only a very slight

extent, it is nonetheless an extremely important aspect of biochem­
istry. With pure water, the dissociation produces an equal amount
of H+ and OH-. However, many substances dissolve in water and
alter this balance, which leads us to the subject of acids, bases,
and pH.

H
–
H—O—H + H—H—O—H H—O
H +H O H
+

FIGURE 2.14 Water equilibrium. A different view of water dissociation in

which ions are produced from pure water by removing a hydrogen ion from
one water and attaching it to the other. The hydrogen ion moves without its
electrons, leaving behind a negatively charged hydroxide ion and creating
a positively charged hydronium ion with three hydrogens. This picture
is abbreviated in the text by using the simpler H+ rather than the more
elaborate hydronium ion (hydrated proton; H3O+).

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 2.7 Some Definitions for the Study of
Acids and Bases
While several definitions for acids and bases exist, the following simple
set suffices for our study of water solutions:
• Acids are species that increase the hydrogen ion concentration
when added to water.
• Bases are species that decrease the hydrogen ion concentration
when added to water.
Based on these definitions, we can define neutral, acidic, and basic
solutions as follows:
• In a neutral solution, [H+] = [OH-].
• In an acidic solution, [H+] > [OH-].
• In a basic solution, [H+] < [OH-].
Species such as NaCl dissociate completely in water, but do not affect
the concentration of H+ or OH-. Hence, NaCl dissolves in water to
form a neutral solution.
Hydrochloric acid (HCl, the acid in your stomach that helps
digest food) and acetic acid (CH3COOH, the principal component
of vinegar) dissolve in water according to the following chemical
equations:

HCl → H+ + Cl− (2.3)

(2.2)

CH3COOH  CH3COO− + H+ (2.4)

(2.3)

Equation 2.2 for HCl is similar to the dissociation of NaCl in that

both species dissociate completely into ions in water. Unlike NaCl, the
dissociation of HCl leads to an increase in [H+], thus making HCl an
acid. The reaction in Equation 2.2 is essentially irreversible, so HCl
is said to be a strong acid.
The dissociation of CH3COOH in Equation 2.3 also meets our
definition of an acid; that is, [H+] increases. Because CH3COOH is
only partially dissociated, which is indicated by the double arrows in
Equation 2.3, CH3COOH is said to be a weak acid.
Sodium hydroxide (NaOH) and ammonia (NH3) are bases:

NaOH → Na+ + OH − (2.5)

(2.4)

NH3 + H 2O → NH 4+ + OH − (2.6)
(2.5)

NaOH dissociates completely in water, making it a strong base,

whereas NH3 reacts with water to a limited extent, making it a
weak base. The OH - produced in both Equations 2.4 and 2.5
will react with any H+ present to form H2O. Thus, by displacing
the water dissociation equation (Equation 2.1) in the direction of
H2O formation, bases such as NaOH and NH3 lower the concen-
tration of H+.

22 Chapter 2 WATER

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 2.8 The pH Scale TABLE 2.3 pH and [H1] Values
[H1] in Scientific
The pH scale is used to represent the very small numbers that occur pH [H1] (mol/L) Notation (mol/L)
for the values of [H+]. By definition,
5 0.00001 10-5
pH = − log [ H+ ] (2.6)
(2.7) 7 0.0000001 10-7
9 0.000000001 10-9
The log term in Equation 2.6 is the common (base-10) log. Some typi-
cal pH values and the corresponding hydrogen ion concentrations,
[H+] are shown in Table 2.3.
One useful feature of pH is obvious: it is a compact way of describ-
ing the concentration of hydrogen ions. However, there are some clear
pitfalls. The pH is a double transformation of hydrogen ion concen-
tration. First, it is a negative value, so that increasing pH means less
hydrogen ion. Second, it is a logarithm, so a change of one unit of pH
is equivalent to a 10-fold change in [H+]. Thus, a solution with a pH
of 2 ([H+] = 0.01 mol/L) has 10 times more H+ than a solution with a
pH of 3 ([H+] = 0.001 mol/L).
To become more familiar with pH, consider the range of the pH
function shown in Figure 2.15. Scale A shows pH values typically
encountered in the human body fluids. The values range from about
2 to about 8. Scale B is the readout of the pH meter. This is the most
familiar representation, and many have come to regard this as the actual
range of pH itself. It is important to understand that it is simply another
representation of the pH concept, this time based on how we measure
it. In fact, scale B is somewhat generous, because the electrode of this
instrument is poorly selective above a pH of about 12. Scale C is the
actual range of the pH function, from negative infinity to positive infin-
ity. This corresponds to the true range of [H+], which varies from zero to
infinity. It is important to recognize the artificiality of the middle scale
as merely the markings on the pH meter. For example, the pH of a 2 M
solution of HCl has a negative value (pH = -log 2 = -0.30).

Stomach Small
(a) acid Blood intestine
2 7.4 8

(b)

Acidic Neutral Basic

o 1 2 3 4 5 6 7 8 9 10 11 12 13 14
(c)

–∞ +∞

o 7 14

FIGURE 2.15 Three pH scales. The range of the pH function depends upon your interest. (a) In human physiology, the range
is about 2 to 8, with some of the key values indicated. (b) Measurements of pH using the pH electrode and meter are typically
marked from zero to 14, giving the popular conception that this is the range of pH. (c) The actual range of the pH function is
from negative infinity to positive infinity. The value of 7 appears to be in the center only because pure water at STP has this
value; otherwise, even that entry is arbitrary.

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 2.9 The Henderson–Hasselbalch Equation
Most biological acids and bases are weak rather than strong. As an
example, the equilibrium of acetic acid:

CH3COOH  CH3COO− + H+ (2.8)

(2.7)

We may represent CH3COOH as HAc and CH3COO- as Ac-. Equa-

tion 2.7 can be characterized by the following equilibrium constant
expression:

Ka = [ Ac − ][ H + ] [ HAc ] (2.8)
(2.9)

Taking the log of both sides of Equation 2.8 yields Equation 2.9:

log Ka = log ([ Ac − ][ H + ] HAc ) (2.9)

(2.10)

Using properties of logarithms, Equation 2.9 becomes:

log Ka = log [ H +] + log [ Ac − ] [ HAc ] (2.10)

(2.11)

In the previous section (see Eq. 2.6), pH was defined as,

pH = − log [ H +] (2.12)
(2.11)

In an analogous way, we can define the negative log of the equilibrium

constant as,

pKa = −log Ka (2.12)

(2.13)

which has advantages for representing the equilibria of weak acids in

a similar way to those for hydrogen ion. For example, consider the
two equations for the acetic acid dissociation:

Ka = 1.8  10−5
pKa = 4.7

Using the definitions for pH (Eq. 2.6) and pKa (Eq. 2.12), rearranging
Eq. 2.10 produces the Henderson–Hasselbalch equation:

pH = pKa + log [ Ac− ] [ HAc ] (2.13)

(2.14)

As a sample problem that makes use of this equation, suppose that

acetic acid (pKa = 4.7) was present at a pH of 7.4 (the value for
normal blood). Using the Henderson–Hasselbalch equation, we can
immediately determine that most of the acetic acid would be in the
salt form, that is, as Ac-. Inserting the values for the pH and pKa into
Equation 2.13, we get:
7.4 = 4.7 + log ([ Ac − ] [ HAc ]) (2.14)
(2.15)

24 Chapter 2 WATER

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 Thus,

log [ Ac− ] [ HAc ] = 2.7 (2.15)

(2.16)

Raising each side of Equation 2.17 to the power of 10 (i.e., taking

anti-logarithms), we get:
[ Ac − ] [ HAc ] = 102.7 = 500 (2.16)
(2.17)

It is evident that despite the less than intuitive nature of a negative

logarithm transformation, as discussed in the prior section, using this
equation simplifies calculations. We need only to perform arithmetic to
subtract pKa from pH. From the last equation, even if we didn’t know the
exact value of 102.7, we know 102 is 100, and this must be much greater
than 100 (but less than 1000), so we can immediately say the species in
the anionic form, Ac-, greatly outnumber those in the acid form, HAc.
In fact, there are 500 ions of Ac- for every 1 molecule of HAc. To a very
close approximation, Ac- prevails; thus the overall molecular charge is -1.
The Henderson–Hasselbalch equation applies to weak bases, too.
A weak base, such as ammonia, can be written as a dissociation in the
same form as acetic acid:

NH 4+  NH3 + H + (2.18)
(2.17)

Written in this way, the protonated form—the ammonium ion, NH4+—

is an acid. It is a weak acid, as it is only partially dissociated, and can
be characterized by the following equilibrium constant expression:

Ka = [ NH3 ][ H + ] [ NH 4+ ] (2.19)
(2.18)

The corresponding form of the Henderson–Hasselbalch equation:

pH = pKa + log [ NH3 ] [ NH 4+ ] (2.20)

(2.19)

A more general form of the Henderson–Hasselbalch equation, which

applies to both weak acids and weak bases, is:

pH = pKa + log [ X ] [ XH ] (2.21)

(2.20)

where X is the base (i.e., least protonated) form of the species and XH
is the acid (i.e., more protonated) form. Equation 2.20 is tremendously
useful in the study of the numerous weak acids and bases that we
encounter throughout our study of biochemistry. We can calculate the
ratio of the two forms of the species by merely subtracting the values
for the pH and pKa.

2.10 Titration and Buffering

The Henderson-Hasselbalch equation provides specific pH values, given
the ratio of the basic and acidic forms of a weak acid and the constant
pKa. A different view of pH as a function of the same ratio is provided

chapter 2 WATER 25

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 14 by a titration curve. Figure 2.16 shows a titration of acetic acid, start-
ing with the fully protonated form (CH3COOH) and ending with the
12 completely anionic form (acetate ion, CH3COO-). In this titration, the
strong base NaOH is added in small increments, and the pH is recorded
10
continuously. Note the relatively flat buffering region centered in the
midpoint of the titration, where pH changes very little as NaOH is
8
added. The center of the buffer region—where pH changes the least—
corresponds to the pKa value. All weak acids and weak bases are buffers,
pH

and thus effectively blunt the response to added acid or base. The reason
6
pKa
for the behavior can be explained mathematically as follows. When
pH = pKa, the Henderson–Hasselbalch equation reduces to
4

0 = log [ Ac− ] [ HAc ] (2.22)

(2.21)
2
Taking the antilog of both sides yields
0
0 0.5 1.0 [ Ac − ] [ HAc ] = 1 (2.23)
(2.22)
NaOH equivalents
FIGURE 2.16 Acetic acid titration curve. A small amount of added NaOH will only slightly raise this ratio,
Acetic acid is placed in solution and NaOH because substantial and nearly equal amounts of Ac- and HAc are
added until its amount in solution reaches
present. However, once the ratio becomes a factor of 10 larger or
the same number of equivalents, which is
moles per charge. As both species have a unit smaller, the same addition of NaOH will more profoundly change the
charge, equivalents and moles are the same ratio, and hence the pH.
in this case. The middle, relatively flat region Perhaps the most significant physiological buffer is the blood bicar-
shows buffering, that is, a minimal response bonate buffer that maintains the extracellular pH in mammals. This
of pH to added acid or base. The center of the system has two equilibria:
buffering region, at 0.5 equivalent volumes,
corresponds to the pKa on the ordinate.
CO2 + H 2O  H 2CO3  H + + HCO3− (2.24)
(2.23)

and is maintained by having a relatively high concentration of CO2.

The actual concentration of CO2 can be adjusted by changes in res-
-
piration. The concentration of the bicarbonate ion, HCO3, can be
adjusted by excretion in the kidney. Note that our definition of acids
as species that increase the hydrogen ion concentration in solution
also applies to CO2, which itself has no protons, because it causes an
increase in [H+] in solution when it dissolves in water, thus making
it an acid.

Summary
Water is the most abundant molecule in biological systems and a
ubiquitous part of everyday life. However, compared to other liquids,
water has unusual properties, including an exceptionally high boiling
point indicative of intermolecular cohesiveness, and an ability to dis-
solve a wide variety of polar molecules.
The unusual properties of water are due to the hydrogen bond,
which is a consequence of the electronegativity difference between H
and O, and the geometry of the water molecule. An extensive hydrogen-
bonded network provides the bonding strength that explains the high
boiling point. Due to the fixing of molecules in a three-dimensional

26 Chapter 2 WATER

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 lattice, heat energy is stored in the bond vibrations of water rather
than in translational energy, accounting for its high specific heat.
The ready dissociation of water into protons and hydroxide ions,
and the ability to solvate ions accounts for the ability of water to
support the dissociation of acids and bases. Weak acids, which are
partially dissociated, are particularly important biologically. These can
be profitably analyzed using the Henderson–Hasselbalch equation, a
logarithmic transform of the equilibrium expression for acid dissocia-
tion. This allows quick calculations of pH or the ratio of dissociated
to undissociated forms of weak acids, given the pKa. Finally, a full
titration of weak acids reveals a buffering region, in which changes
in acidity have only small effects on solution pH.

Key Terms
buffering region hydrated strong acid
condensed phases hydrogen bond strong base
electronegativity hydrophobic effect titration curve
enthalpy ionization of water translational
entropy partially ionic bond weak acid
fluid phases polar bond weak base
free energy polar molecule

Review Questions
1. Gas-phase water (i.e., water vapor) has properties similar to most other gases,
yet condensed water (i.e., liquid and solid water) is unusual.
a. Why are the properties the same in the gas phase?
b. What are the unusual phase transitions of water?
c. What accounts for the unusual properties of water in general?
2. In a solution of pure water, it is possible to calculate the concentration of water
itself. What is its value?
3. Electronegativity values are assigned to individual elements, and yet the concept
of electronegativity applies only to bonds. Explain this disparity.
4. Oxygen and sulfur are both nucleophiles, they have the same valence, and both
form dihydrides. Yet, H2S does not form hydrogen bonds to other molecules of
H2S; indeed, sulfur does not participate in hydrogen bonding at all. Why is that?
5. Oxygen and nitrogen appear to be very different. Whereas oxygen appears in
acidic compounds and tends to assume a negative charge, nitrogen appears in
basic compounds and tends to assume a positive charge. Both elements, however,
participate in hydrogen bonding. Explain these facts.
6. Why is it that a molecule like CO2, which contains polar bonds but is not polar
overall, cannot attract polar molecules?
7. Ammonia is a polar molecule by virtue of its lone pair. When protonated to
ammonium, however, it is symmetrical and would seem, by vector addition, to
have no polarity. Yet, the ammonium ion readily dissolves in water. Why?
8. The hydrophobic effect is due to attractive forces only and not repulsive ones.
Rationalize this with the term hydrophobic.
9. A rule of thumb in chemistry is “like dissolves like.” Explain how this applies
differently to polar and nonpolar substances.
10. When enough NaCl is added to water, the salt no longer dissolves and solid NaCl
falls out of solution. At this point, the solution is said to be saturated. Explain
this phenomenon.

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 11. Water is a temperature buffer, which means that it resists changes in temperature
more than other liquids. Explain this based on the structure of water.
12. Water ionizes to a very small extent, although this can be increased with increas-
ing temperature. Provide a reasonable explanation.
13. Protons produced by the self-ionization of water have an unusually rapid mobility
in solution; they move faster than can be accounted for by diffusion. Provide a
possible mechanism to account for this proton jumping.
14. The definition of an acid as an entity that increases the proton concentration in
water (known as the Arrhenius definition) has the advantage that we can call
CO2 an acid. How could we handle this situation if instead we used the Brönsted
(proton donor) definition?
15. While useful, the pH scale can also be confusing because it is a double transform:
both the negative of the number and the log of the number are taken. How does
this affect your intuition about a change in proton concentration?

References
1. Johnson, J. L. H.; Yalkowsky, S. H. A three-dimensional model for water. J. Chem.
Ed. 79:1088–1091, 2002.
A model-building exercise that leads to the construction of a three-dimensional
water molecule that illustrates key properties of the condensed phase, such as the
“flickering crystal” quality of the liquid and the density change in going from liquid
to solid.
2. Pauling, L. The Nature of the Chemical Bond and the Structure of Molecules and
Crystals; an Introduction to Modern Structural Chemistry; Cornell University Press:
Ithaca, NY, 1960, p. 644.
Pauling’s classical treatise clearly describes the topics of electronegativity and hydro-
gen bonding, among many others.
3. Tanford, C. The Hydrophobic Effect: Formation of Micelles and Biological Mem-
branes; John Wiley & Sons: New York, 1980.
Another landmark publication is this monograph on Tanford’s expertise, the hydro-
phobic effect. The text includes detailed descriptions of the net forces in the water–
lipid interactions.
4. Tanford, C. How protein chemists learned about the hydrophobic factor. Protein
Sci. 6:1358–1366, 1997.
A historical introduction to the notion of hydrophobicity, which largely became a
controversy among protein chemists, but later was used to clearly explain lipid–
water interactions, which are much simpler.

28 Chapter 2 WATER

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 3
Lipids
CHAPTER Outline

3.1 Significance Summary

3.2 Fatty Acids Key Terms

3.3 Triacylglycerols Review Questions

3.4 Phospholipids References

3.5 Cholesterol BOX 3.1: On Steak and Fish: Polyunsaturated
Fats, Trans Fats, and Health Risks
3.6 Lipid–Water Interactions of
Amphipathic Molecules BOX 3.2: Lipid Composition of Pizza

3.7 Water Permeability of Membranes BOX 3.3: Lecithin and Emulsification

and Osmosis
BOX 3.4: Word Origins: Osmosis
3.8 Effect of Lipids on Membrane Composition

Image © Dr. Mark J. Winter/Photo Researchers, Inc.

29

57366_CH03_0029.indd 29 9/7/12 1:51 PM

 A
defining characteristic of lipids is their relative insolubility
in water. Chemically, lipids are relatively simple—consisting
mostly of unreactive hydrocarbons—making this topic an
appropriate next step in our study. Lipids play a role in virtually every
aspect of the cellular biology and in disease states of the body. The
myriad of forms that serve this purpose arise from relatively modest
variations in structure. Here, we consider the major types of lipid
molecules and their principal roles.

3.1 Significance
The two major functions of lipids are energy storage and membrane
formation. Beyond this, lipids can form micelles and serve as signal
molecules.
Distinct structures correspond to each of the two major functions.
For storing energy, the exclusion of lipid from the water phase is abso-
lute. The major chemical species involved are triacylglycerols, which
are classified as nonpolar lipids. For the formation of membranes, a
portion of the molecule interacts with water. These are polar lipids,
the most prominent class of which is the phospholipids. We will begin
by considering fatty acids, the building blocks of lipids.

3.2 Fatty Acids

Fatty acids are molecules with two distinct parts: a long hydrocarbon
segment, called a tail, and a smaller region that typically consists of a
carboxyl group, called the head (Figure 3.1). The hydrocarbon tail con-
sists mostly of chemically unreactive methylene groups with a variable
number of double bonds. Table 3.1 lists some examples and nomenclature
of the fatty acids.
Table 3.1 succinctly describes the fatty acids, each of which var-
ies in the number of carbon atoms and the number of double bonds.
Table 3.1 also introduces the delta notation, which designates the
position of the first carbon involved in the double bond, with the
carboxyl group taken as carbon number 1. Some of the common
names for fatty acids reflect their biological origins, such as butyric

CH3 CH2 CH2 CH2

CH2 CH2 CH2 COOH

Tail Head
FIGURE 3.1 Parts of a Fatty Acid. The hydrophobic portion is the tail; the
hydrophilic portion is the head. Numbering systems usually consider the
carboxyl group as carbon 1.

30 Chapter 3 LIPIDS

57366_CH03_0029.indd 30 9/7/12 1:51 PM

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hanno impulsività e fobìe nel paranoico, allucinazioni, deliri parziali
(megalomani, persecutivi, ecc.) negli epilettici, accessi impulsivi e
motori nei cretini; e poi sembra sia a tutti comune — secondo gli
studi di Roncoroni e di Pelizzi — l'atrofia degli strati superiori corticali
e la confusione degli strati tutti.
Anche qualche carattere biologico e psicologico è comune alle tre
categorie, come le ineguaglianze pupillari, la mancanza di affettività
e del senso morale, le vertigini, le impulsività, il mancinismo, la
sterilità, ecc.
Altre, come già abbiamo veduto, sono comuni soltanto all'epilettico
ed al cretino; altre, infine, all'epilettico ed al paranoico, come le
allucinazioni, le fobìe, le tendenze geniali.
Oltre a questo, la stessa anomalìa prende, in ciascuna delle tre
forme di degenerazione, appaparenze diverse: così nell'epilessia si
trovano sopratutto alterazioni della condotta, automatismo ed
impulsività; nella paranoia il carattere più saliente è l'originalità,
l'esercizio di un'attività inutile. L'alterazione dei sentimenti affettivi si
manifesta nella prima come una disaffettività generale, nella seconda
con avversione sopratutto per le persone più care, nel cretino con
l'apatia. Negli epilettici, però, la mancanza di senso morale è
raramente associata ad una completa o continua alterazione
dell'intelligenza, come nei cretini; e nel paranoico si complica spesso
con idee deliranti.
In questi degenerati parziali non si osserva sempre la stessa
sindrome completa di sintomi: molto spesso si ha soltanto qualcuna
di queste diverse manifestazioni psichiche, motorie o somatiche.
Queste forme di degenerazione dipendono da un arresto di sviluppo
embrionale che ha acquistato carattere atavico per l'eredità, come
provano per l'epilessia la frequenza della stenocrotafia, della
submicrocefalìa, della fossetta occipitale medianica, dell'oxicefalìa,
l'assenza dello strato granulare profondo, l'ipertrofia delle cellule
piramidali e la presenza di cellule nervose nella sostanza bianca,
trovata da Roncoroni. Tuttavia i gravi patemi nella paranoia, le
intossicazioni e le autointossicazioni nel cretinismo, i traumatismi
fisici e psichici nell'epilessia possono generare manifestazioni simili. È
ciò che spiega l'apparizione tardiva di forme epilettiche, paranoiche
e, qualche rara volta, cretinose (mixedema), che, se fossero sempre
solo congenite, dovrebbero manifestarsi solo nelle prime epoche
della vita.
Se noi ora applichiamo tali quadri sintetici del mondo degenerativo
allo studio del genio, vediamo che solo l'epilettico è a questo legato
strettamente.
Certamente anche in qualche genio si può trovare traccia della
degenerazione cretinosa, come in Nobili, Skoda, Garovaglio, con
aspetto completamente cretinoso; e certo anche la paranoia può
formare sostrato al genio, come vedemmo in Cardano, in Tasso, in
Colombo [59], in cui un parziale delirio fu veramente il punto di
partenza di vere creazioni e scoperte, come lo fu di delirî persecutivi
e megalomani, che, a loro volta, si convertirono in forme geniali; ma
anche in questi troviamo un elemento epilettoide che ne magnifica e,
forse, ne determina gli atti [60], come pure nei non gravi casi in cui il
genio è a base di melanconia e di alcoolismo, come Hotfmann e Poë.
E per ciò, anche accettando come credo si debba, l'appunto di
Roncoroni, Morselli e Sergi, secondo cui non deve limitarsi alla
degenerazione epilettica la base del genio, resta sempre che essa ne
è il fulcro principale, che interviene anche quando le altre forme
paiono in giuoco. Ed allora come non considerarla quale base del
genio una volta che eredità, anomalìe somatiche e funzionali
seguono le stesse linee, e che le principali manifestazioni sue, l'estro
e l'idea fissa, hanno nella epilessia psichica il gruppo psichiatrico che
più loro si avvicina?
 CAPITOLO XIV.
I fenomeni contraddittori nel genio.

A molti critici della mia teoria sulla nevrosi del genio, di cui tentavo
ricostrurre la figura classica sulla trama dell'epilessia, non parve vero
di afferrare non solo qualche eccezione, ma qualche completa
contraddizione con le linee che io ne tracciava; così il buon Galleani,
che fece notare esservi genî alti e grossi in contraddizione alla mia
affermazione della frequenza dei piccoli e magri.
L'obbiezione è vera; ma non scalza la base della teoria, fino ad un
certo punto potendo spiegarsi la diversità di forme, se non di
sostanza, del genio, per il fatto che, pur essendo sempre uguale
nell'intima struttura, presenta una differenza notevole nei fenomeni
che noi diremmo secondari.
Ma v'ha di più. Studiando i miei e i caratteri trovati nei genî, si trova
che questi presentano, in confronto all'uomo medio, i due estremi, i
due eccessi in più o in meno di sviluppo; mentre l'uomo medio, il
vero normale, è appunto tale, perchè evita ambo gli eccessi.
Osservazione questa che io devo al geniale aiuto del dott. Celesia.

1. Statura e peso. — Così, cominciando dalla statura, Havelock-Ellis

fece notare come prevalga nei genî, in confronto ai normali, la
statura ora piccolissima, ora grandissima, mentre nei normali prevale
la statura media; infatti, egli ebbe a trovare:
Nei normali inglesi di statura piccola 16%; Nei normali inglesi di
statura alta 16%; Nei normali inglesi di statura media 68%;
Nei genî inglesi di statura piccola 37%; Nei genî inglesi di statura
alta 41%; Nei genî inglesi di statura media 22% [61].
Così si dica per la magrezza e la grassezza. Kiernan credette fornire
una grande prova dell'assenza di degenerazione del genio, col dare
una lunga lista di genî che presentavano un eccesso di adipe, come
se la degenerazione grassa non fosse essa stessa una
degenerazione. Così egli annovera, fra gli eccessivamente adiposi,
Victor Hugo, Rénan, Sue, Maupassant, Flaubert, Gauthier, Sarcey,
Janin, A. Dumas, Sainte Beuve, Rossini, che non poteva vedere i
propri piedi, tanto era grasso, Balzac, cui tre persone con le mani
unite potevano appena contornare la cintura [62].
A nostra volta, poi, ricordiamo la ben più lunga lista dei genî
magrissimi: Erasmo, Pascal, Keplero, D'Auembert, Aristotele, Voltaire,
di cui dicevasi che il corpo non era più che un lieve, quasi
trasparente inviluppo, attraverso al quale potevasi quasi vedere
l'animo e il genio. Lammenais era un ometto quasi impercettibile;
diceva Lamartine: "È una fiammella che il soffio delle proprie
inquietudini caccia da un punto all'altro della camera".

2. Capacità cranica. — E così dicasi della capacità craniana e dello

sviluppo cerebrale, poichè mentre una buona parte, la maggior parte
dei genî, come Volta, Petrarca, Bodoni, Fusinieri, Kant, Cuvier,
Tackeray, Tourguenieff, ebbe capacità grandi da cmc. 1600 a 2013, e
mentre, nella media di 26 crani francesi geniali il Lebon trovò una
capacità di cmc. 1532, superiore di quasi cmc. 200 e più alla media,
non pochi però ebbero scarsa capacità, come Rasori, Descartes,
Foscolo, Tissot, G. Reni, Hoffmann, Schumann, e su 12 cervelli di
grandi tedeschi, studiati da Wagner e Bischoff, 8 avevano alte e 4
bassissime capacità,, come Bollinger 1207, Liebig 1352, ecc.
3. Sviluppo delle circonvoluzioni. — Mentre il maggiore sviluppo delle
circonvoluzioni e la maggior asimmetria si credettero caratteri
generali degli uomini di genio, pur qualche volta essi presentano
straordinarie atrofie, come in Bertillon, Gambetta, ecc., od anomalìe
ataviche [63], senza dire delle meningiti di Grossi, Donizetti, ecc. E
così alla bellezza della fisionomia e all'armonia delle forme craniane
celebrate come caratteri del genio (Helmoltz, Dante, Schopenhauer),
contrastano le enormi anomalìe ataviche di Nobili, Foscolo, Emery,
Mind, Skoda, che arrivano fino all'aspetto cretinoso.

4. Filoneismo, ecc. — Al grande filoneismo, che è il carattere più

generale e che è la base del genio creativo, si contrappone il
frequente misoneismo, che ne fa i più terribili ostacoli ai progressi
nuovi, sorti nel loro tempo; Napoleone che respinse il vapore,
Richelieu che ne mandò all'ospedale dei pazzi il primo inventore,
Bacone che irrise a Copernico, Galileo che, dopo avere scoperto il
peso dell'aria, negava la teoria della pressione della colonna di aria
sui liquidi, Laplace che nega i metereoliti, Voltaire che non crede ai
fossili, Darwin e Wundt che irridono all'ipnotismo come Virchow che
irride alle immunizzazioni dei sieri, al darwinismo e all'antropologia
criminale.

5. Sensibilità ed equazione personale. — Più importanti ancora per la

nostra questione sono i fenomeni ora di anestesia, ora di iperestesìa
e, sopratutto, di ritardo o di celerità eccessiva nell'equazione
personale. Mentre otto sopra undici dei genî da me studiati [64]
hanno un'equazione molto più lenta della media, uno solo
rappresentava una cifra media, e due diedero un minimum del
tempo di equazione personale ad attenzione ordinaria. E mentre,
sopratutto in nove artisti, sotto il comando di massima attenzione si
ebbe una notevole diminuzione, che però non scendeva sotto alla
media, in quattro biologi questa diminuzione non si notò; e, mentre
uno diede brevi esponenti dell'oscillazione individuale, gli altri otto,
specialmente artisti, diedero un coefficiente fin doppio e più del
primo. Nei quali pure il suggerimento di massima attenzione provocò
una diminuzione notevole, quasi della metà. Ma questo coefficiente,
sotto il suggerimento della massima attenzione, mentre nei biologi
non si abbrevia che di pochi millesimi di secondi, da 3 a 4, negli
artisti varia quasi del doppio, 30 a 16, 24 a 15, e ciò per la vista.
Quanto all'udito, l'equazione personale presenta la massima brevità
in tre, ma molto scarsa in sei. L'esponente oscillatorio fu minimo in
quattro, massimo in sette, i quali erano dunque più pronti a
rispondere a un eccitamento acustico che al visivo, e assolutamente
e relativamente ai biologi.
Anche l'acuità visiva si trovò in alcuni superiore, in altri assai
inferiore. Il tatto, o normale o più acuto del normale, in cinque su
dodici, apparve più ottuso in sette.
Importantissimo sarebbe il contrasto tra i visivi o i tipi intellettuali
auditivi, che, secondo Saint-Paul, sarebbero infinitamente superiori,
come 72 a 12; ma e' non mi pare abbastanza chiarito. Meglio lo
chiarirono recentemente Patrizi e Cesarmi, che, su ottanta studenti
di Modena che si avvicinano ai tipi almeno degli studiosi, trovarono i
tipi acustici più frequenti del doppio dei visivi, 75% in confronto a
33, e gli indifferenti 1,3, aggiungendo l'osservazione curiosa che gli
acustici provocano nello studio sfigmografico reazioni più pronte e
più dolorose. E chi non vede che qui abbiamo fino ad un certo punto
la ragione del sorgere dei grandi maestri musicali, anch'essi
precocissimi, quasi fin dalla nascita?

6. Longevità. — E lo stesso dicasi della longevità dei genî.

Recentemente William Thayer nel Forum (febbraio 1900) tentò
dimostrare, come già io avevo fatto, con nuovi documenti la grande
longevità dei genî Anglo-Sassoni di un secolo preciso, dal 1800 al
1900; ma egli pure dimostrò la precoce mortalità di alcuni poeti.
Cominciando dai poeti, che fin dall'antichità si credevano destinati a
morire giovani per l'emotività eccessiva, trovò che in 46 poeti si ha
una vita media di 66 anni. Però 9 su 46 morirono giovani, da 37 a
26, e cioè 4 per consunzione e 5 per stravizi: Shelley 30 anni, Kints
26, Byron 37, Leopardi 39, Poë 40.
In 39 pittori e scultori la media è di 66 anni; però uno morì giovane
(Fortuny a 36 anni).
Di 30 musicisti la media è di 62 anni: Auber morì a 89 anni, Verdi a
86, Spontini a 77. Ma quattro morirono giovani: Bellini, Bizet,
Schubert e Mendelssohn.
Di 26 romanzieri la vita media è di 63 anni; nessuno morì giovane.
Di 40 letterati la media è di 67 anni; nessuno morì giovane.
Di 22 ecclesiastici la media è di 66 anni; uno solo morì giovane:
Robertson.
Di 35 donne celebri la media età è 69 anni: Somerville 92, Trollope
83, Staure 85, George Sand 72, Stern 71. Ma anche qui 2 morirono
giovani: le sorelle Brontë, 30 e 39 anni.
Su 18 filosofi la vita media è di 65 anni.
Su 38 storici la media è di 73 anni. Ma 3 morirono giovani.
Su 58 scienziati e inventori la vita media è di 72 anni.
La media età di 14 novatori e rivoluzionari fu di 69 anni; un solo
giovane.
Di 48 militari celibi la vita media è di 71 anni; due soli giovani:
Scobeleff e Jackson, 38 e 39 anni.
Di 112 uomini politici la media e di 71 anni.
Di 16 presidenti dell'America del Nord la media è di 68 anni.
La vita media di primi ministri è di 77 anni; però 4 giovani: Parnell
45, Cavour 51, Gambetta 44, Manin 51.
La regola è la longevità, ma con notevoli eccezioni per alcuni, morti
precocissimi.
E nei genî troviamo da una parte un'attività psichica esagerata fino
alla più tarda età (Humboldt a 80, Goëthe a 81 anni scrisse il Faust,
così Verdi, Linneo e Bismarck); dall'altra Beccarla, che cessa ogni
lavoro a 32 anni, ecc. E molti lasciano lavori incompleti, come pure
Leonardo da Vinci per lentezza nel comporle.
E mentre la precocità è il carattere generale del genio, non mancano
le genialità tarde (Alfieri, Wren, Flaubert, Klaorott).

7. Odio e amore per la musica nel genio. — Se noi studiamo la

bellissima monografia del Cuningham Moffet (Music, gennaio 1900),
vediamo che la maggior parte dei grandi pensatori, specialmente
storici, filosofi ed anche letterati, aveva un vero orrore per la musica.
André Lang osservò che il maggior numero dei poeti e letterati
odiava la musica. Johnson, Catterina II e V. Hugo la dicevano "il
meno spiacevole dei rumori". Lang confessa che può sentire una
cantata solo se le parole sono belle, ma non esiste per lui peggior
musica della nuova: "È la sola arte che vi s'impone per forza, perchè
non potete sfuggire i suoni come potreste sfuggire la pittura; il
vantaggio unico per noi è che la musica cattiva non ci fa soffrire".
Anche Grant odiò la musica; obbligato di sentirne a Parigi, considerò
quell'ora come la più triste della sua vita.
Napoleone preferiva la musica più stupida: Malboroug s'en va en
guerre, e diceva che la musica gli tormentava i nervi; e così
Napoleone III, Zola, Gambetta e Goncourt, che arricciavano il naso
quando vedevano aprire il piano.
Stook non conosceva altra musica che il God save the Queen;
Macaulay, parlando di un pranzo a Corte: "La musica copriva la
conversazione con i suoi accordi sonori, fra cui il canto: The
combat", ed il nipote aggiungeva che "questo era il solo caso in cui
abbia distinto un'aria da un'altra".
Fontenelle disse che non comprendeva quattro cose: il mondo, le
donne, la musica e i saltatori. Gauthier dichiarava che di tutti i
rumori la musica era il peggiore.
Max Müller non godè che il solo canto di Lind. "Sono — ci scriveva —
tardo ai suoni come altri ai colori". Anche Max Buckle, come
Macaulay, per quanto avesse meravigliosa memoria, non poteva
distinguere un'armonia dall'altra; e Humphrey Dawis sentiva così
poco la musica, che non poteva marciare in tempo quando era
soldato. E così Carlo Lamb e Jean Stanley.
Beaumarchais sentenziò: "Tutto ciò che non è atto a scriversi, lo è al
canto".
A tutti questi genî, odiatori di musica, opponiamo Aristotele, che fa
della musica il pernio dell'educazione morale: Musset, che dice: "È la
musica che mi fa credere in Dio". Daudet pare che amasse
qualunque specie di musica di Chopin; il Bethoven amava il
tamburino come l'organino perfino le campane; ogni suono parlava
per lui. "Ogni musica — diceva — mi ispira. Wagner m'ipnotizza, il
violino degli zingari mi ha fatto lavorare".
Nell'Uomo di genio dimostrai quanto Alfieri fosse sensibile alla
musica. Milton era eccellente musico. Coleridge diceva che "la
musica lo rinfrescava". Addison aveva "eccellente criterio musicale".
E così De Quincey e Gratry. Moore dice che "la musica è la giusta
interprete della religione; niente parla all'anima come essa". Sidney
Smith: "Ogni suonatore è un uomo felice".
Darwin amava la musica, e così Elliot e Kemble. Burns non solo era
un amante della buona musica, ma sapeva suonare il violino. I suoi
canti erano ispirati da canzoni musicate, popolari, ed amava
sentirsele suonare.
Carlo Reade, romanziere, ricorreva alla musica come alla più nobile
delle ricreazioni. Carlyle diceva che "la musica e la lingua degli
angeli".
"Molti luoghi della Commedia — scrive Graf [65] — mostrano che
Dante ebbe squisito senso musicale, e così Petrarca, che l'armonia di
liuti, canti e suoni rapivano fuor di sè stesso".
Metastasio non solo componeva, ma cantava i suoi versi. Goëthe
gustò l'arte di Mendelssohn. Byron non poteva udire musica
melanconica senza piangere. Moore, per perfezionare i propri versi,
usava cantarli, e diceva la parola povera a paragone della musica.
Leopardi preferì, è vero, la musica triste, ma gustò pure il Socrate
immaginario di Paesiello. "Notisi — con Graf — come quel rozzo
canto che passa nella via, e lontanando muore, subito sollevi la
mente del poeta alla considerazione di tutto ciò che passa e muore
nel mondo, ond'egli ricorda gli avi famosi e il grande impero di
Roma, e finalmente conclude:

"Tutto è pace e silenzio; e tutto posa

Il mondo, e più di lor non si ragiona".

"Errerebbe di grosso — conclude il fine critico — chi in tutto questo,

invece di un procedimento di associazioni, che nell'animo del
Leopardi è spontaneo e naturalissimo, non vedesse altro che una
velata lirica e un artificio retorico. Qui l'impressione musicale deriva
la massima parte del suo valore estetico dall'abituale contenuto della
coscienza.
"E così in molti altri casi. Nelle Ricordanze, udendo il suon dell'ora
che dalla torre del borgo gli arreca il vento, il poeta commenta;

"Era conforto
Questo suon, mi rimembra, alle mie notti,
Quando fanciullo, nella buia stanza,
Per assidui terrori io vigilava,
Sospirando il mattin".

Nella canzone: Alla sua donna, sono ricordate:

"Le valli ove suona

 Del faticoso agricoltor il canto";

e nel tramonto della luna, il canto del carrettiere che saluta

"Con mesta melodia

L'estremo albor della fuggente luce
Che dianzi gli fu duce...".

"Egli è certo, dunque, che nella musica il Leopardi dovette pregiare

non tanto i miracoli di una maestria consumata, la ostentazione di
una virtuosità rigogliosa, creatrice e vincitrice di ostacoli, le
complicazioni e le pompe teatrali, quanto l'arcano e dolce linguaggio
che parla alle anime, l'intima virtù suscitatrice di sentimenti ineffabili
e di estatici suoni" (Graf).

Noi vediamo dunque da tutti i caratteri dei genî, dalla statura fino
all'equazione personale, al senso musicale, ecc., che, pure
persistendovi un certo andazzo costante, non mancano per
eccezione linee in senso perfettamente opposto, come accade
appunto nell'epilessia, in cui si notano gli estremi opposti di statura,
di capacità cranica, di energia intellettuale e sensoria, pure
essendovi una maggioranza che ha statura piccola [66],
submicrocefalìa, ottusità sensoria ed intellettuale.
 CAPITOLO XV.
Anatomia patologica dei genî.

I. — Teoria di Flechsig.

Come tutti i prodotti di grandi anomalìe psichiche, anche il genio ha

la sua speciale anatomia patologica. E già, quanto al volume, ora
eccessivo, ora scarso, del cranio, abbiamo accennato, e così
sull'anomalìa spesso atavica delle circonvoluzioni (Vedi L'uomo di
genio). Ed a quelli esposti allora aggiungeremo altri dati
importantissimi.
Ma prima ci conviene ribattere l'obbiezione del Flechsig, essersi,
cioè, trovata la base anatomica del genio non nell'anomalìa
involutiva, ma, al contrario, nel massimo sviluppo dei centri
associativi, obbiezione che continuamente ci si affaccia in Germania
e più in Italia — per quell'antiitalianismo che ci è tutto speciale —. A
quest'obbiezione risponderò con i recenti lavori di Grandis [67], di
Vogt [68], di Leonardo Bianchi [69], di Hitzig, di Monakow [70] e di
Leggiadri-Laura [71].
"Non è provata — scrive Grandis — l'energia specifica delle varie
zone della corteccia cerebrale, pretesa dal Flechsig; e l'idea sua che
non si possa avere una sostituzione delle funzioni di una parte della
corteccia cerebrale, per mezzo di un'altra dello stesso emisfero, è
dimostrata falsa dalla clinica e dall'anatomia patologica".
Il Flechsig ammette come cosa dimostrata e come assioma che le
fibre nervose non siano atte a trasmettere gii eccitamenti se non
quando si sono rivestite di guaina midollare. Ma ciò ha contro di sè
molti dati dell'anatomia comparata. Tutti i cefalopodi hanno fibre
nervose prive di guaina midollare, le quali, cionondimeno,
trasmettono molto bene gli impulsi che partono dal centro e quelli
che provengono dal mondo esterno alle loro estremità periferiche. E
il Birottau dimostrò, con numerose ricerche, come nei nervi dei
cefalopodi e di alcune specie di aplisìe, a fibre non mielinizzate, tutti i
fenomeni elettro-fisiologici decorrano perfettamente nello stesso
modo come nei nervi provvisti di guaina mielinica (Grandis).
Aggiungasi che, secondo Westphal, nessun fatto ci autorizza a
ritenere che sia necessaria detta guaina, perchè le fibre nervose
possano funzionare; anzi, lo stesso Westphal aveva già dimostrato
falso anche l'altro fatto fondamentale: che, cioè, i nervi motori si
rivestano di guaina mielinica prima dei nervi sensibili, come pretende
il Flechsig.
E poi, assai prima dell'età di tre anni, il bambino eseguisce tutti i
movimenti; ed è capace di percepire tutte le forme o impressioni
esterne di cui è capace l'adulto, assai prima, cioè, che le sue fibre
nervose siano rivestite di guaina mielinica; non solo, ma il bambino
di due anni, che ha da lungo tempo perfetti i nervi cerebrali, è assai
meno perfetto in tutte le funzioni dipendenti dai nervi cerebrali, di
quanto non sia nei movimenti dei nervi spinali.
"Assodato il fatto — conchiude Grandis — che le fibre nervose sono
capaci di trasmettere gli eccitamenti anche quando sono prive di
guaina mielinica, il risultato delle ricerche del Flechsig ci permette
soltanto di determinare il decorso seguito dalle fibre centripete per
arrivare alla corteccia e per delimitare ivi la loro area di distribuzione;
ma sono fondamentalmente deboli le conclusioni teoriche che egli ne
vuol derivare sulla distribuzione cerebrale delle più elevate funzioni
psichiche".
Anche il nostro Leonardo Bianchi — che onora così altamente la
Psichiatria italiana — trova che la teoria del Flechsig, spinta alle sue
ultime conseguenze, rappresenta una più o meno larvata
risurrezione del sistema di Fall.
"La deduzione più verisimile — osserva il Bianchi — che, se non è
nettamente formulata, si legge tra le righe delle diverse
comunicazioni fatte su questo argomento da Flechsig, è che ciascun
territorio corticale embriologico di ciascuno dei tre gruppi
(primordiale, intermediario e terminale) possegga proprietà
fisiologiche distinte; e si dovrà finir per conchiudere che i quaranta
territori, che da qui a qualche anno saranno cresciuti di numero,
servano ad altrettante specifiche attività dello spirito".
"Ora non è dimostrato — segue egli con quella finezza critica che è
tutta sua propria —, nè verisimile, che esistano nella corteccia
cerebrale centri della memoria distinti dai centri percettivi.
"La larga zona occipito-parietale in cui si troverebbe, secondo
Flechsig, l'area associativa posteriore, è quasi tutta di pertinenza
della funzione visiva; su parecchi punti di essa l'eccitazione elettrica
provoca movimenti oculari, la distinzione di essa, o di parte di essa,
se è solo corticale, produce fugaci disturbi visivi; se è profonda,
produce l'emiopìa permanente; se è bilaterale, la cecità psichica; nel
quale ultimo caso gli oggetti visti non sono più riconosciuti.
"Anche l'estremità anteriore terminale di detta area è nell'uomo
esclusivamente visiva, destinata, cioè, alla lettura; e nulla autorizza a
considerare questa zona come destinata ai più alti processi
intellettivi, consistente nell'associazione d'immagini fornite dalle
diverse aree percettive o sensoriali. Se le lesioni bilaterali di detta
zona, oltre la cecità psichica per gli oggetti, inducono uno stato
demenziale più o meno grave, è lecito supporre che la demenza in
tali casi sia l'espressione della perdita di una gran parte del
patrimonio intellettivo dell'uomo, dipendente dalla distinzione dei
registri delle immagini visive dal mondo esterno, le quali
costituiscono gran parte di tutta la somma dei componenti psichici
sensoriali dell'umana intelligenza. L'affermazione, poi, che
l'eccitazione della zona sensoriale dia per risultato l'allucinazione, e
quella della zona associativa induca la confusione mentale, è affatto
arbitraria. Basta infatti rammentare i casi in cui una sola
allucinazione visiva o uditiva turba profondamente la personalità
psichica, fino a produrre intensa confusione mentale.
"Nessun sussidio alla dottrina delle aree associative, intese nel senso
di Flechsig, apporta l'analisi istologica, la quale se dimostra — come
appare dai recenti lavori di R. y Cajal, che ha riconosciuto nove strati
nella zona visiva, in confronto dei sette già riconosciutivi dal Meynert
e dei cinque attribuiti alla zona motrice, e dalle recenti ricerche dello
stesso Cajal, dell'Hammarberg, dello Schlopp — una struttura
sempre più differente nelle varie zone corticali, non dimostra però
affatto, come fatto costante, una maggiore semplicità di struttura
nell'area percettiva rispetto alle aree associative, nel senso del
Flechsig.
"II fatto della frequente demenza che riscontrasi negli individui colti
da sordità verbale per focolaio distruttivo della prima circonvoluzione
temporale, e considerazioni di fatto tendenti a dimostrare che la
funzione dell'udito generico e quella dell'audizione verbale si
sovrappongono nella medesima area con grande prevalenza, a
sinistra, della funzione specifica del linguaggio, rispetto alla funzione
generale dell'udito, dimostrano che questa regione ha una funzione
specifica di alto valore intellettivo e associativo; invece, dal Flechsig,
sarebbe una zona primordiale e intermedia.
"Così alla zona motrice, somestetica di Flechsig, concorrono
necessariamente tutti i prodotti che si formano nelle singole zone
della corteccia cerebrale. Onde centripete, nel cervello, come nel
midollo spinale, si risolvono attraverso i centri motori sugli apparati
muscolari. E perciò la zona così detta motrice è una zona associativa
anche a maggior titolo della grossa zona associativa postero-inferiore
di Flechsig, perchè utilizza il prodotto di tutte le zone sensoriali poste
all'indietro e inferiormente.
"Lo stesso avviene per la zona che si estende sui piedi delle
circonvoluzioni frontali e che pure, essendo essenzialmente motrice,
è effettivamente la più genuina espressione della spiritualità,
essendo deputato alla funzione della scrittura e della parola parlata.
Queste aree debbono essere di necessità associative del più alto
valore, per le numerose relazioni con altre parti del cervello, pure
essendo comprese dalla maggior parte degli autori nella zona
motrice o di proiezione. Inoltre il rapporto tra la mielinizzazione e la
funzione non è confermato — come già osservava il Grandis ed ora
ripete il Bianchi — dalla fisiologia. I movimenti volitivi del bambino
per il cammino si compiono per la zona nº 1, che è la prima a
svilupparsi, mentre il cammino ed anche i movimenti volitivi più
semplici sono molto più tardivi dell'audizione della parola che si
compie dalle aree 7 e 23.
"E i lobi frontali non sono certamente centri di moto, nè di senso; ma
neppure si possono considerare come semplici aree associative,
inquantochè non servono solo alla fusione fisiologica dei percepiti
per la formazione dei concetti, ma sono anche l'organo della fusione
fisiologica dei sentimenti elementari dei singoli individui, da cui
nascono i più alti sentimenti umani che caratterizzano l'uomo
moderno civile. In ultima analisi, sono gli organi della direttiva
dell'individuo nell'ambiente sociale e cosmico".
"Cosa rimarrà — finisce Bianchi — della fantastica geografia psico-
anatomica del mantello cerebrale, di cui il Flechsig da parecchi anni,
in varie edizioni rivedute e mutate, ha arricchita la nostra
letteratura?".
Più di recente la C. Vogt, completando le ricerche anteriori del marito
O. Vogt, abbatte la teoria di Flechsig con nuovi documenti
esperimentali.
Il Flechsig vuole che il processo di mielinizzazione sia diverso negli
animali e nell'uomo. Ora la Vogt, dalle sezioni in serie dei cervelli di
più di 30 giovani gatti, di più di 20 giovani cani, di 12 conigli e di 6
bambini, trovò che vi ha identità completa nel processo della
mielinizzazione negli animali e nell'uomo.
E, ciò che più importa, la Vogt dimostrò che la mielinizzazione delle
fibre nervose non è punto in rapporto con le funzioni cerebrali, ma
dipende dallo sviluppo delle fibre di proiezione; ciò conferma quanto
il Grandis desumeva dalla clinica.
La Vogt ha infatti trovato che, tanto nell'uomo quanto negli animali,
le regioni non mielinizzate dalle fibre di proiezione sono
precisamente quelle che contengono, secondo i risultati della
degenerazione secondaria, le fibre dei centri non ancora mielinizzati.
Questi dati basterebbero da soli a togliere ogni importanza alle
conclusioni che il Flechsig vuole trarre specialmente in rapporto con
la psichiatria, e scalzano una legge — già negata da C. Vogt —,
secondo la quale l'insieme delle fibre di proiezione si mielinizza prima
della corteccia.
Secondo il Larionoff, che pure ammette i centri di associazione, il
centro per la percezione dei suoni nel cane sarebbe la parte postero-
neutrale del cervello; vale a dire la parte che si mielinizza più tardi,
secondo la Vogt; cioè, dovrebbe essere un centro di associazione,
secondo le vedute del Flechsig, mentre è invece un centro
sensoriale. Persino l'importanza che il criterio della mielinizzazione ha
nello studio della disposizione dei sistemi di fibre nervose, sarebbe
menomata dal fatto che, contrariamente all'opinione del Flechsig, lo
studio della mielinizzazione non contraddice allo studio delle
degenerazioni secondarie, ma lo conferma.
Ora, da questo studio risulta alla Vogt che tutte le regioni corticali
contengono fibre di proiezione e dovunque in numero abbastanza
grande, perchè non si possa fare di alcuna regione della corteccia un
puro centro di associazione.
Recentissimamente, poi, al Congresso di Parigi, Hitzig non solo non
credette confermare le idee del Flechsig sulla mielinizzazione
cronologica dei centri di proiezione e di associazione; ma osservava
che lo stesso Flechsig ha trovato differenze individuali ch'egli
attribuisce, è vero, ad influenze patologiche, ma che i suoi avversari
considerano, ad egual diritto, come fisiologiche.
Ora, veramente, questa obbiezione dell'Hitzig non mi pare molto
efficace, giacchè il Vulpius ha dimostrato che la mielinizzazione è
ostacolata dalle malattie della nutrizione, dal rachitismo; Tuchzeck,
Zacher ed altri hanno a loro volta dimostrato la influenza ostacolante
dell'idiozia e dell'epilessia. Ma l'Hitzig ha ragione quando afferma che
l'opinione dei varî autori è così diversa intorno alla differenza della
struttura anatomica dei centri di proiezione e di associazione, che è
assolutamente impossibile di formarsi a questo riguardo un'opinione
precisa. Infine l'Hitzig considera la teoria del Flechsig sulla sede dei
fatti di coscienza come puramente ipotetica.
"L'ipotesi — scrive Leggiadri-Laura — di immagini di memorie
depositate in particolari gruppi di cellule non è provata da alcun
fatto".
Ma più decisive appaiono le ricerche di Monakow comunicate allo
stesso Congresso, in quanto concordano con quelle della C. Vogt. Il
Monakow nega che si possa parlare di centri di associazione nel
senso del Flechsig, per la ragione che, se esistono su tutta la
superficie cerebrale spazi considerevoli più o meno estesi in
circonferenza in cui non sì trovano affatto fibre di proiezione e focolai
in cui si riuniscono tali fibre, non è però in nessun modo possibile di
limitare, in un modo un po' preciso, i territori che sono poveri in fibre
di proiezione e quelli che ne possegono abbondantemente. Il
Monakow non ha infatti constatato differenze anatomiche
fondamentali tra le due specie di territori degli emisferi cerebrali. Del
resto, esistono in altre regioni cerebrali (la sostanza grigia centrale)
parti che sono egualmente sprovviste di fibre di proiezione, e nelle
quali non si sogliono punto distinguere centri di proiezione e centri di
associazione. Queste le principali obbiezioni del Monakow, come
anche per lui il metodo di studio fondato sulla mielinizzazione è ben
lungi dall'essere sufficiente a risolvere il problema fisiologico della
fine organizzazione dei neuroni nel cervello.
"Tutto ciò che è lecito dire — così il Monakow — si è che è verisimile
e logico che lo sviluppo dei centri sensoriali preceda quello delle parti
corticali, che servirebbero di base all'intelligenza. Ma l'ipotesi che
stabilisce le funzioni psichiche superiori in focolai corticali
specialmente delimitati ed aventi una struttura particolare (i centri di
associazione o intellettuali), è insostenibile. Si devono piuttosto
rappresentare i diversi elementi che concorrono al lavoro psichico,
come sparsi in tutta la corteccia cerebrale, e benchè dobbiamo
ammettere per il lavoro psichico condizioni anatomiche necessarie, di
cui le strutture diverse predominano ora in questa, ora in quella
circonvoluzione, dobbiamo però riconoscere che tali condizioni
anatomiche ci sono tuttora ignote".
S'aggiunga che i casi di genî con straordinaria sviluppo dei centri di
associazione non sono che due o tre al più, mentre, come notava
Hansemann a proposito di Helmoltz, si riscontra questo sviluppo
eccessivo in numerosissimi casi di uomini volgarissimi, per cui da
ogni parte la teoria di Flechsig e le sue applicazioni sul genio cadono
nel nulla.
E quelli che continuamente ce la rinfacciano, dimostrano con quanto
poco criterio e calore seguano il movimento scientifico moderno.

II. — Anomalìe in crani e cervelli di genî.

Veniamo alle ultime scoperte fatte sui crani e cervelli di genî dopo il
mio Uomo di genio (volume I, cap. II).

Emilio Demi. — Nel cranio del geniale scultore livornese Emilio Demi,
morto a 65 anni, dopo però una vita dissipata di alcoolista e
vagabondo, l'egregio dott. A. Mochi [72] trovò seni e arcate
sopraciliari sporgenti, suture coronaria e sagitale ancora aperte a 65
anni. Enorme sporgenza degli zigomi, mandibola voluminosissima,
sutura medio-frontale, prognatismo alveolare, cortezza della faccia.
Nel Museo di anatomia di Padova sono conservati crani rarissimi di
alcuni grandi ingegni medici. Col mezzo del dott. Favaro ottenni su
questi le informazioni che qui riassumo [73]:
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