f UN □AMENTAlS Of
`
`TH IRD ED IT ION
`
`•
`
`~ana ~ Vaet Ju~it~ ~- Vaet L~ar atte W. rratt
`
`Page 1 of 61
`
`KELONIA EXHIBIT 1022
`
`

`

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`Edm;sn O.gr.ufa llon
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`i C
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`I Prelssbo 2Yt1tr?!l l
`i Pccl«!Yei Outtfun •
`[ Po~ffiifl 0l!!1~n 'i
`
`With Ch11pt1r
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`Ch 1pttrS, Protein, : Pri
`Ch1pter 5, Proteins: Pri
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`Prepare & Present
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`using a wealth of resources such as
`enhanced art, PowerPoint slides contain(cid:173)
`ing text art optimized for presentation,
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`Page 2 of 61
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`

`

`. . ;·,
`
`I
`
`,
`
`THIRD EDITION
`
`FUNDAMENTALS OF
`
`LIFE AT THE M LECULAR LEV L
`
`Donald Voet
`University of Pennsylvania
`
`Judith G. Voet
`Swarthmore College, Emeritus
`
`Charlotte W. Pratt
`Seattle Pacific University
`
`,.
`
`ffi WILEY
`
`John Wiley & Sons, Inc.
`
`Page 3 of 61
`
`

`

`scholar, teacher, friend
`
`Vice-President & Executive Publisher
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`Marketing Manager
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`Amanda Wainer
`Alyson Rentrop
`Sandra Dumas
`Dorothy Sinclair
`Harry Nolan
`Madelyn Lesure
`Laura C. Ie rardi
`Hilary Newman
`Hilary Newman, Sheena Goldstein
`Sigmund Malinowski
`Wendy Wray
`Thomas Kulesa
`Suzanne Ingrao/Ingrao Associates
`
`Background Photo Cover Credit: Lester Lefkowitz/Getty Images
`
`Inset Photo Credits: Based on X-ray structures by (left to right) Thomas Steitz, Yale
`University; Daniel Koshland, Jr., University of California at Berkeley; Emrnanual
`Skordalakis and James Berger, University of California at Berkeley; Nikolaus G rigorieff
`and Richard Henderson, MRC Laboratory of Molecular Biology, U.K.; Thomas Steitz, Yale
`University.
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`This book was set in 10/12Times Ten by Aptara and printed and bound by
`Courier/Kendallville. The cover was printed by Phoenix Color Corporation.
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`This book is printed on acid free paper. oo
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`Copyright © 2008 by Donald Voet, Judith G. Voet, and Charlotte W. Pratt. All rights
`reserved.
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`No part of this publication may be reproduced, stored in a retrieval system or transmitted
`in any form or by any means, electronic, mechanical, photocopying, recording, scanning or
`otherwise, except as permitted under Sections 107 or 108 of the 1976 United States
`Copyright Act, without either the prior written permission of the Publisher, or authoriza(cid:173)
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`Inc., 222 Rosewood D rive, Danvers, MA 01923, website www.copyright.com. Requests to
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`To order books or for customer service, please call 1-800-CALL WILEY (225-5945).
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`ISBN-13 978-0470-12930-2
`
`Printed in the United States of America
`
`10 9 8 7 6 5 4 3 2 1
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`Page 4 of 61
`
`

`

`About the Authors
`
`Donald Voet received a B.S. in Chemistry from the
`California Institute of Technology, a Ph.D. in Chemistry
`from Harvard University with William Lipscomb, and did
`postdoctoral research in the Biology Department at MIT
`with Alexander Rich. Upon completion of his postdoctoral
`research, Don took up a faculty position in the Chemistry
`Department at the University of Pennsylvania where, for
`the past 38 years, he has taught a variety of biochemistry
`courses as well as general chemistry. His major area of
`research is the X-ray crystallography of molecules of bio(cid:173)
`logical interest. He has been a visiting scholar at Oxford
`University, the University of California at San Diego, and
`the Weizmann Institute of Science in Israel. Together with
`Judith G. Voet, he is Co-Editor-in-Chief of the journal
`Biochemistry and Molecular Biology Education. He is a
`member of the Education Committee of the International
`Union of Biochemistry and Molecular Biology. His hob(cid:173)
`bies ·include backpacking, scuba diving, skiing, travel, pho(cid:173)
`tography, and writing biochemistry textbooks.
`
`Judith ("Judy") Voet received her B.S. in Chemistry from
`Antioch College and her Ph.D. in Biochemistry from
`Brandeis University with Robert H. Abeles. She has done
`postdoctoral research at the University of Pennsylvania,
`Haverford College, and the Fox Chase Cancer Center. Her
`main area of research involves enzyme reaction mechanisms
`and inhibition. She taught Biochemistry at the University of
`Delaware before moving to Swarthmore College. She taught
`
`there for 26 years, reaching the position of James H.
`Hammons Professor of Chemistry and Biochemistry before
`going on "permanent sabbatical leave." She has been a visit(cid:173)
`ing scholar at Oxford University, University of California,
`San Diego, University of Pennsylvania, and the Weizmann
`Institute of Science, Israel. She is Co-Editor-in-Chief of the
`journal Biochemistry and Molecular Biology Education. She
`has been a member of the Education and Professional
`Development Committee of the American Society for
`Biochemistry and Molecular Biology as well as the
`Education Committee of the International Union of
`Biochemistry and Molecular Biology. Her hobbies include
`hiking, backpacking, scuba diving, and tap dancing.
`
`Charlotte Pratt received her B.S. in Biology from the
`University of Notre Dame and her Ph.D. in Biochemistry from
`Duke University under the direction of Salvatore Pizzo.
`Although she originally intended to be a marine biologist, she
`discovered that Biochemistry offered the most compelling
`answers to many questions about biological structure-function
`relationships and the molecular basis for human health and
`disease. She conducted postdoctoral research in the Center for
`Thrombosis and Hemostasis at the University of North
`Carolina at Chapel Hill. She has taught at the University of
`Washington and currently teaches at Seattle Pacific University.
`In addition to working as an editor of several biochemistry
`textbooks, she has co-authored Essential Biochemistry and
`previous editions of Fundamentals of Biochemistry.
`
`Page 5 of 61
`
`

`

`Brief Contents
`
`PART I
`INTRODUCTION
`1
`Introduction to the Chemistry of Life 1
`2 Water 22
`BIOMOLECULES
`3 Nucleotides, Nucleic Acids, and Genetic Information 39
`4 Amino Acids 74
`5 I Proteins: Primary Structure 91
`6 I Proteins: Three-Dimensional Structure 125
`7
`Protein Function: Myoglobin and Hemoglobin, Muscle Contraction, and Antibodies 176
`8 Carbohydrates 219
`9 Lipids and Biological Membranes 245
`10 Membrane Transport 295
`PAAT Ill ENZVMES
`11 I Enzymatic Catalysis 322
`12 I Enzyme Kinetics, Inhibition, and Control 363
`13 Biochemical Signaling 405
`P PT \i METABOLISM
`14
`Introduction to Metabolism 448
`15 Glucose Catabolism 485
`16 Glycogen Metabolism and Gluconeogenesis 530
`17 Citric Acid Cycle 566
`18 Electron Transport and Oxidative Phosphorylation 596
`19 Photosynthesis 640
`20 Lipid Metabolism 677
`21 Amino Acid Metabolism 732
`22 I Mammalian Fuel Metabolism: Integration and Regulation 791
`PART
`GENE EXPRESSION AND REPLICATION
`23
`Nucleotide Metabolism 817
`24 I
`Nucleic Acid Structure 848
`25
`DNA Replication, Repair, and Recombination 893
`26
`Transcription and RNA Processing 942
`27 Protein Synthesis 985
`28 1 Regulation of Gene Expression 1037
`
`Solutions to Problems SP-1
`Glossary G-1
`Index I-1
`
`vi
`
`Page 6 of 61
`
`

`

`Contents
`
`Preface
`
`Acknowledgments
`
`xvm
`
`XXI
`
`Instructor and Student Resources
`
`xxm
`
`Guide to Media Resources
`
`XXV
`
`PART I INTRODUCTION
`
`D. Water Moves by Osmosis and Solutes Move by
`Diffusion
`29
`2 Chemical Properties of Water
`A. Water Ionizes to Form H+ and OH -
`B. Acids and Bases Alter the pH
`32
`C. Buffers Resist Changes in pH
`34
`BOX 2-1 BIOCHEMISTRY IN HEALTH AND DISEASE
`The Blood Buffering System
`36
`
`30
`30
`
`PART II BIOMOLECULES
`
`Introduction to the
`Chemistry of Life
`
`1
`
`Nucleotides, Nucleic Acids,
`and Genetic Information
`
`39
`
`2
`1 The Origin of Life
`A. Biological Molecules Arose from Inorganic Materials
`B. Complex Self-replicating Systems Evolved from Simple
`3
`Molecules
`2 Cellular Architecture
`5
`A . Cells Carry Out Metabolic Reactions
`5
`B. There Are Two Types of Cells: Prokaryotes and
`7
`Eukaryotes
`C. Molecular Data Reveal Three Evolutionary Domains of
`Organisms
`9
`D. Organisms Continue to Evolve
`3 Thermodynamics
`11
`A. The First Law of Thermodynamics States That Energy Is
`Conserved
`12
`B. The Second Law of Thermodynamics States That Entropy
`13
`Tends to Increase
`C. The Free Energy Change Determines the Spontaneity of a
`14
`Process
`D. Free Energy Changes Can Be Calculated from Equilibrium
`15
`Concentrations
`E. Life Obeys the Laws of Thermodynamics
`BOX 1-1 PATHWAYS OF DISCOVERY
`Lynn Margulis and the Theory of Endosymbiosis
`BOX 1-2 PERSPECTIVES IN BIOCHEMISTRY
`Biochemical Conventions
`13
`
`2
`
`11
`
`17
`
`10
`
`22
`
`IJ Water
`
`1
`2
`
`3
`
`43
`
`43
`
`47
`
`47
`
`58
`
`40
`Nucleotides
`Introduction to Nucleic Acid Structure
`A. Nucleic Acids Are Polymers of Nucleotides
`44
`B. The DNA Forms a Double Helix
`C. RNA Is a Single-Stranded Nucleic Acid
`Overview of Nucleic Acid Function
`A. DNA Carries Genetic Information
`48
`B. Genes Direct Protein Synthesis
`49
`4 Nucleic Acid Sequencing
`50
`A. Restriction Endonucleases Cleave DNA at Specific
`51
`Sequences
`B. Electrophoresis Separates Nucleic Acid According to
`52
`Size
`C. DNA Is Sequenced by the Chain-Terminator Method
`D. Entire Genomes Have Been Sequenced
`57
`E. Evolution Results from Sequence Mutations
`5 Manipulating DNA
`59
`A. Cloned DNA Is an Amplified Copy
`60
`B. DNA Libraries Are Collections of Cloned DNA
`62
`C. DNA Is A.'Tiplified by the Polymerase Chain Reaction
`D. Recombinant DNA Technology Has Numerous Practical
`67
`Applications
`BOX 3-1 PATHWAYS OF DISCOVERY
`Francis ~ollins and the Gene for Cystic Fibrosis
`BOX 3-2 PERSPECTIVES IN BIOCHEMISTRY
`DNA Fingerprinting
`66
`BOX 3-3 PERSPECTIVES IN BIOCHEMISTRY
`Ethical Aspects of Recombinant DNA Technology
`
`53
`
`65
`
`56
`
`70
`
`74
`
`vii
`
`1 Physical Properties of Water
`A. Water Is a Polar Molecule
`23
`B. Hydrophilic Substances Dissolve in Water
`25
`C. The Hydrophobic Effect Causes Nonpolar Substances to
`Aggregate in Water
`26
`
`23
`
`Amino Acids
`
`1 Amino Acid Structure
`A. Amino Acids- Are Dipolar Ions
`
`74
`75
`
`Page 7 of 61
`
`

`

`v111
`
`Contents
`
`B. Peptide Bonds link Amino Acids
`78
`C. Amino Acid Side Chains Are Nonpolar, Polar, or
`Charged
`78
`D. The pK Values of lonizable Groups Depend on
`Nearby Groups
`81
`E. Amino Acid Names Are Abbreviated
`2 Stereochemistry
`82
`86
`3 Amino Acid Derivatives
`A . Protein Side Chains May Be Modified
`B. Some Amino Acids Are Biologically Active
`BOX 4-1 PATHWAYS OF DISCOVERY
`William C. Rose and the Discovery of Threonine
`BOX 4-2 PERSPECTIVES IN BIOCHEMISTRY
`The R S System
`85
`BOX 4-3 PERSPECTIVES IN BIOCHEMISTRY
`Green Fluorescent Protein
`87
`
`81
`
`86
`
`86
`
`g Proteins: Primary Structure
`
`75
`
`91
`
`C
`
`6
`
`5
`
`1 Polypeptide Diversity
`91
`94
`2 Protein Purification and Analysis
`94
`A. Purifying a Protein Requires a Strategy
`B. Salting Out Separates Proteins by Their Solubility
`97
`C. Chromatography Involves Interaction with Mobile and
`98
`Stationary Phases
`D. Electrophoresis Separates Molecules According to
`Charge and Size
`101
`104
`3 Protein Sequencing
`104
`A . The First Step Is to Separate Subunits
`B. The Polypeptide Chains Are Cleaved
`107
`C. Edman Degradation Removes a Peptide's First Amino Acid
`Residue
`109
`D. Mass Spectrometry Determines t he Molecular
`11 o
`Masses of Peptides
`E. Reconstructed Protein Sequences Are Stored in
`Databases
`112
`4 Protein Evolution
`114
`A. Protein Sequences Reveal Evolutionary Relationships
`B. Proteins Evolve by the Duplication of Genes or
`Gene Segments
`117
`BOX 5-1 PATHWAYS OF DISCOVERY
`Frederick Sanger and Protein Sequencing
`
`105
`
`140
`2 Tertiary Structure
`A. Most Protein Structures Have Been Determined by X-Ray
`Crystallography or Nuclear Magnetic Resonance
`141
`B. Side Chain Location Varies with Polarity
`145
`C. Tertiary Structures Contain Combinations of Secondary
`Structure
`146
`D. Structure Is Conserved More t han Sequence
`150
`E. Struct ural Bioinformatics Provides Tools for Storing,
`Visualizing, and Comparing Protein Structural
`Information
`151
`3 Quaternary Structure and Symmetry
`4 Protein Stability
`156
`A. Proteins Are Stabilized by Several Forces
`B. Proteins Can Undergo Denat uration and
`Renaturation
`158
`161
`5 Protein Folding
`161
`A. Proteins Follow Folding Pathways
`B. Molecular Chaperones Assist Protein Folding
`C. Some Diseases Are Caused by Protein Misfolding
`BOX 6-1 PATHWAYS OF DISCOVERY
`130
`Linus Pauling and Structural Biochemistry
`BOX 6-2 BIOCHEMISTRY IN HEALTH AND DISEASE
`Proteins: Three-Dimensional
`Collagen Diseases
`137
`125 BOX 6-3 PERSPECTIVES IN BIOCHEMISTRY
`Structure
`- - -- - - - - - - - - - - - - - - - - -
`Thermostable Proteins
`159
`BOX 6-4 PERSPECTIVES IN BIOCHEMISTRY
`Protein Structure Prediction and Protein Design
`
`11 4
`
`1 Secondary Structure
`127
`A. The Planar Peptide Group limits Polypeptide
`Conformations
`127
`B. The Most Common Regular Secondary Structures Are the a
`Helix and the 13 Sheet
`129
`C. Fibrous Proteins Have Repeating Secondary
`134
`Structures
`D . Most Proteins Include Nonrepetitive Structure
`
`139
`
`154
`
`156
`
`165
`
`168
`
`163
`
`Page 8 of 61
`
`

`

`Protein Function: Myoglobin and
`Hemoglobin, Muscle Contraction,
`and Antibodies
`
`176
`
`177
`181
`
`1 Oxygen Binding to Myoglobin
`177
`and Hemoglobin
`A . Myoglobin Is a Monomeric Oxygen-Binding Protein
`B. Hemoglobin Is a Tetramer with Two Conformations
`C. Oxygen Binds Cooperatively to Hemoglobin
`184
`D. Hemoglobin's Two Conformations Exhibit
`Different Affinities for Oxygen
`186
`E. Mutations May Alter Hemoglobin's Structure
`and Function
`194
`197
`2 Muscle Contraction
`A. Muscle Consists of lnterdigit ated Thick and
`Thin Filaments
`198
`B. Muscle Contraction Occurs When Myosin Heads Walk Up
`205
`Thin Filaments
`C. Actin Forms Microfilaments in Nonmuscle Cells
`209
`3 Antibodies
`A. Antibodies Have Constant and Variable Regions
`B. Antibodies Recognize a Huge Variety of Antigens
`BOX 7-1 PERSPECTIVES IN BIOCHEMISTRY
`181
`Other Oxygen-Transport Proteins
`BOX 7-2 PATHWAYS OF DISCOVERY Max Perutz and the
`182
`Structure and Function of H emoglobin
`BOX 7-3 BIOCHEMISTRY IN HEALTH AND DISEASE
`192
`High-Altitude Adaptation
`BOX 7-4 PATHWAYS OF DISCOVERY
`H ugh Huxley and the Sliding Filament Model
`BOX 7-5 PERSPECTIVES IN BIOCHEMISTRY
`213
`Monoclonal Antibodies
`
`207
`
`2 10
`212
`
`200
`
`Carbohydrates
`
`ix
`21~
`
`220
`
`220
`1 Monosaccharides
`A. Monosaccharides Are Aldoses or Ketoses
`B. Monosaccharides Vary in Configuration and
`221
`Conformation
`C. Sugars Can Be Modified and Covalently Linked
`226
`2 Polysaccharides
`227
`A . Lactose and Sucrose Are Disaccharides
`B. Cellulose and Chitin Are Structural Polysaccharides
`C. Starch and Glycogen Are Storage Polysaccharides
`D. Glycosaminoglycans Form Highly Hydrated Gels
`234
`3 Glycoproteins
`A. Proteoglycans Contain Glycosaminoglycans
`B. Bacterial Cell Walls Are Made of Peptidoglycan
`c. Many Eukaryotic Proteins Are Glycosylated
`238
`D. Oligosaccharides May Determine Glycoprotein Structure,
`240
`Function, and Recognition
`BOX 8-1 BIOCHEMISTRY IN HEALTH AND DISEASE
`227
`L actose Intolerance
`BOX 8-2 PERSPECTIVES IN BIOCHEMISTRY
`228
`Artificial Sweeteners
`BOX 8-3 BIOCHEMISTRY IN HEALTH AND DISEASE
`238
`Peptidoglycan-Specific Antibiotics
`
`224
`
`228
`230
`232
`
`234
`235
`
`Lipids and
`Biological Membranes
`
`245
`
`248
`
`252
`
`257
`
`246
`1 Lipid Classification
`A. The Properties of Fatty Acids Depend on Their
`Hydrocarbon Chains
`246
`B. Triacylglycerols Contain Three Esterified Fatty Acids
`C. Glycerophospholipids Are Amphiphilic
`249
`D. Sphingolipids Are Amino Alcohol Derivatives
`254
`E. Steroids Contain Four Fused Rings
`F. Other Lipids Perform a Variety of Metabolic Roles
`260
`2 Lipid Bilayers
`A. Bilayer Formation Is Driven by the Hydrophobic
`Effect
`260
`B. Lipid Bilayers Have Fluidlike Properties
`263
`3 Membrane Proteins
`A. Integral Membrane Proteins Interact with Hydrophobic
`Lipids
`263
`B. Lipid-Linked Proteins Are Anchored to the Bilayer
`C. Peripheral Proteins Associate Loosely with
`Membranes
`269
`4 Membrane Structure and Assembly
`A. The Fluid Mosaic Model Accounts for Lateral
`270
`Diffusion
`B. The Membrane Skeleton Helps Define Cell Shape
`C. Membrane Lipids Are Distributed Asymmetrically
`D. The Secretory Pathway Generates Secreted and
`278
`Transmembrane Proteins
`
`261
`
`269
`
`267
`
`272
`274
`
`Page 9 of 61
`
`

`

`PART Ill ENZYMES
`
`Enzymatic Catalysis
`
`322
`
`331
`333
`
`1 General Properties of Enzymes
`323
`A. Enzymes Are Classified by the Type of Reaction They
`324
`Catalyze
`B. Enzymes Act on Specific Substrates
`325
`C. Some Enzymes Require Cofactors
`326
`2 Activation Energy and the Reaction
`Coordinate
`328
`3 Catalytic Mechanisms
`330
`A. Acid-Base Catalysis Occurs by Proton Transfer
`B. Covalent Catalysis Usually Requires a Nucleophile
`c. Metal Ion Cofactors Act as Catalysts
`335
`D. Catalysis Can Occur through Proximity and Orientation
`336
`Effects
`E. Enzymes Catalyze Reactions by Preferentially Binding the
`Transition State
`338
`4 Lysozyme
`339
`A. Lysozyme's Catalytic Site Was Identified through Model
`340
`Building
`B. The Lysozyme Reaction Proceeds via a Covalent
`Intermediate
`343
`5 Serine Proteases
`347
`A. Active Site Residues Were Identified by Chemical
`348
`Labeling
`B. X-Ray Structures Provided Information about Catalysis,
`Substrate Specificity, and Evolution
`348
`C. Serine Proteases Use Several Catalytic Mechanisms
`D. Zymogens Are Inactive Enzyme Precursors
`357
`BOX 11-1 PERSPECTIVES IN BIOCHEMISTRY
`Effects of pH on Enzyme Activity
`332
`BOX 11 -2 PERSPECTIVES IN BIOCHEMISTRY Observing
`Enzyme Action by X -Ray Crystallography
`342
`BOX 11-3 BIOCHEMISTRY IN HEALTH AND DISEASE
`Nerve Poisons
`349
`BOX 11-4 BIOCHEMISTRY IN HEALTH AND DISEASE
`The Blood Coagulation Cascade
`358
`
`352
`
`Enzyme Kinetics,
`Inhibition, and Control
`------
`
`363
`
`1 Reaction Kinetics
`364
`A. Chemical Kinetics Is Described by Rate Equations
`B. Enzyme Kinetics Often Follows the Michaelis-Menten
`Equation
`366
`C. Kinetic Data Can Provide Values of Vmax and KM
`D. Bisubstrate Reactions · Follow One of Several Rate
`Equations
`375
`2 Enzyme Inhibition
`377
`A. Competitive Inhibition Involves Inhibitor Binding at an
`Enzyme's Substrate Binding Site
`377
`
`364
`
`372
`
`x
`
`Contents
`
`282
`
`E. Intracellular Vesicles Transport Proteins
`F. Proteins Mediate Vesicle Fusion
`287
`BOX 9-1 BIOCHEMISTRY IN HEALTH AND DISEASE
`Lung Surfactant
`250
`BOX 9-2 PATHWAYS OF DISCOVERY Richard Henderson and
`the Structure of B acteriorhodopsin
`266
`BOX 9-3 BIOCHEMISTRY IN HEALTH AND DISEASE Tetanus
`and Botulinurn Toxins Specifically Cleave SNAREs
`288
`
`Membrane Transport
`
`295
`
`297
`
`1 Thermodynamics of Transport
`296
`2 Passive-Mediated Transport
`297
`A . lonophores Carry Ions across Membranes
`B. Porins Contain 13 Barrels
`298
`C. Ion Channels Are Highly Selective
`299
`D. Aquaporins Mediate the Transmembrane Movement of
`306
`Water
`E. Transport Proteins Alternate between Two
`Conformations
`307
`3 Active Transport
`3 11
`A. The (Na+ -K+)-ATPase Transports Ions in Opposite
`Directions
`311
`B. The Ca2+ - ATPase Pumps ca2+ Out of the Cytosol
`C. ABC Transporters Are Responsible for Drug
`Resistance
`314
`D. Active Transport May Be Driven by Ion Gradients
`BOX 10-1 PERSPECTIVES IN BIOCHEMISTRY
`Gap Junctions
`308
`BOX 10-2 PERSPECTIVES IN BIOCHEMISTRY Differentiating
`Mediated and Nonmediated Transport
`309
`BOX 10-3 BIOCHEMISTRY IN HEALTH AND DISEASE
`The Action of Cardiac Glycosides
`313
`
`313
`
`316
`
`Glucose transport
`
`1 .
`
`c,~~ •• -~~ymp,_,_
`,..,,. __ ~....,-. . . 11,. Glucose uniport
`
`To capillaries
`
`~-=::::~-~:-► Na•
`J<+
`
`Microvilli
`
`Page 10 of 61
`
`

`

`B. Uncompetitive Inhibition Involves Inhibitor Binding to the
`381
`Enzyme-Substrate Complex
`C. Mixed Inhibition Involves Inhibitor Binding to Both the Free
`382
`Enzyme and the Enzyme-Substrate Complex
`386
`3 Control of Enzyme Activity
`A. Allost eric Control Involves Binding at a Site Other Than the
`386
`Active Sit e
`B. Control by Covalent Modification Often Involves Protein
`390
`Phosphorylation
`394
`4 Drug Design
`394
`A . Drug Discovery Employs a Variety of Techniques
`B. A Drug's Bioavailability Depends on How It Is Absorbed and
`396
`Transported in the Body
`C. Clinical Trials Test for Efficacy and Safety
`396
`D. Cytochromes P450 Are Often Implicated in Adverse Drug
`398
`Reactions
`BOX 12-1 PERSPECTIVES IN BIOCHEMISTRY
`Isotopic Labeling
`367
`BOX 12-2 PATHWAYS OF DISCOVERY
`J.B.S. Haldane and Enzyme Action
`BOX 12-3 PERSPECTIVES IN BIOCHEMISTRY
`Kinetics and Transition State Theory
`372
`BOX 12-4 BIOCHEMISTRY IN HEALTH AND DISEASE
`HIV Enzyme Inhibitors
`384
`
`369
`
`I Biochemical Signaling
`
`405
`
`407
`
`1 Hormones
`406
`A. Pancreatic Islet Hormones Control Fuel Metabolism
`B. Epinephrine and Norepinephrine Prepare the
`409
`Body for Action
`C. Steroid Hormones Regulate a Wide Variety of Metabolic and
`41 O
`Sexual Processes
`D. Growth Hormone Binds to Receptors in Muscle,
`411
`Bone, and Cartilage
`412
`2 Receptor Tyrosine Kinases
`A. Receptor Tyrosine Kinases Transmit Signals across the Cell
`413
`Membrane
`B. Kinase Cascades Relay Signals to the Nucleus
`416
`C. Some Receptors Are Associated with Nonreceptor
`422
`Tyrosine Kinases
`D. Protein Phosphatases Are Signaling Proteins in
`425
`Their Own Right
`428
`3 H eterotrimeric G Proteins
`A. G Protein-Coupled Receptors Contain Seven Transmembrane
`429
`Helices
`B. Heterotrimeric G Proteins Dissociate on Activation
`430
`C. Adenylate Cyclase Synthesizes cAMP to Activate Protein
`432
`Kinase A
`D. Phosphodiesterases Limit Second Messenger Activity
`436
`4 The Phosphoinositide Pathway
`A. Ligand Binding Results in the Cytoplasmic Release of the
`437
`Second Messengers IP3 and ca2+
`B. Calmodulin Is a Ca2+ -Activated Switch
`438
`C. DAG Is a Lipid-Soluble Second Messenger That Activates
`440
`Protein Kinase C
`
`435
`
`Contents
`
`xi
`
`D. Epilog: Complex Systems Have Emergent Properties
`BOX 13-1 PATHWAYS OF DISCOVERY
`Rosalyn Yalow and the Radioimmunoassay (RIA)
`BOX 13-2 PERSPECTIVES IN BIOCHEMISTRY
`Receptor- Ligand Binding Can Be Quantitated
`BOX 13-3 BIOCHEMISTRY IN HEALTH AND DISEASE
`Oncogenes and Cancer
`421
`BOX 13-4 BIOCHEMISTRY IN HEALTH AND DISEASE
`Drugs and Toxins That Affect Cell Signaling
`BOX 13-5 BIOCHEMISTRY IN HEALTH AND DISEASE
`444
`Anthrax
`
`442
`
`408
`
`414
`
`435
`
`PART IV METABOLISM
`
`Introduction to Metabolism
`
`448
`
`450
`
`460
`
`449
`1 Overview of Metabolism
`449
`A. Nutrition Involves Food Intake and Use
`B. Vitamins and Minerals Assist Metabolic Reactions
`C. Metabolic Pathways Consist of Series of Enzymatic
`451
`Reactions
`D. Thermodynamics Dictates the Direction and Regulatory
`455
`Capacity of Metabolic Pathways
`E. Metabolic Flux Must Be Controlled
`457
`459
`2 "High-Energy" Compounds
`A . ATP Has a High Phosphoryl Group-Transfer Potential
`462
`B. Coupled Reactions Drive Endergonic Processes
`C. Some Other Phosphorylated Compounds Have High
`464
`Phosphoryl Group-Transfer Potentials
`468
`D. Thioesters Are Energy-Rich Compounds
`469
`3 Oxidation- Reduction Reactions
`469
`A . NAO+ and FAD Are Electron Carriers
`B. The Nernst Equation Describes Oxidation-Reduction
`470
`Reactions
`C. Spontaneity Can Be Determined by Measuring Reduction
`472
`Potential Differences
`4 Experimental Approaches to the Study of
`475
`Metabolis,m
`475
`A. Labeled Metabolites Can Be Traced
`B. Studying Metabolic Pathways Often Involves Perturbing the
`477
`System
`C. Systems Biology Has Entered the Study of
`477
`Metabolism
`BOX 14-1 PERSPECTIVES IN BIOCHEMISTRY
`Oxidation States of Carbon
`453
`BOX 14-2 PERSPECTIVES IN BIOCHEMISTRY
`454
`Mapping Metabolic Pathways
`BOX 14-3 PATHWAYS OF DISCOVERY
`Fritz Lipmann and "High-Energy" Compounds
`BOX 14-4 PERSPECTIVES IN BIOCHEMISTRY
`ATP and t:,,G
`462
`
`460
`
`Page 11 of 61
`
`

`

`A ll
`
`'-Ontent s
`
`II Glucose Catabolism
`
`485
`
`501
`
`509
`
`1 Overview of Glycolysis
`486
`2 The Reactions of Glycolysis
`489
`A . Hexokinase Uses the First ATP
`489
`B. Phosphoglucose lsomerase Converts Glucose-6-Phosphate to
`Fructose-6-Phosphate
`490
`C. Phosphofructokinase Uses the Second ATP
`491
`D . Aldolase Converts a 6-Carbon Compound to Two 3-Carbon
`Compounds
`492
`E. Triose Phosphate lsomerase lnterconverts Dihydroxyacetone
`Phosphate and Glyceraldehyde-3-Phosphate
`494
`F. Glyceraldehyde-3-Phosphate Dehydrogenase Forms the First
`"High-Energy" Intermediate
`497
`G. Phosphoglycerate Kinase Generates the First ATP
`499
`H. Phosphoglycerate Mutase lnterconverts 3-Phosphoglycerate
`and 2-Phosphoglycerate
`499
`I. Enolase Forms the Second "High-Energy"
`Intermediate
`500
`J. Pyruvate Kinase Generates the Second ATP
`3 Fermentation: The Anaerobic Fate of
`Pyruvate
`504
`A. Homolactic Fermentation Converts Pyruvate to
`Lactate
`505
`B. Alcoholic Fermentation Converts Pyruvate to
`Ethanol and CO2
`506
`C. Fermentation Is Energetically Favorable
`4 Regulation of Glycolysis
`510
`A. Phosphofructokinase Is the Major Flux-Controlling Enzyme of
`Glycolysis in Muscle
`511
`B. Substrate Cycling Fine-Tunes Flux Control
`514
`5 Metabolism of Hexoses Other than Glucose
`A . Fructose Is Converted to Fructose-6-Phosphate or
`Glyceraldehyde-3-Phosphate
`516
`B. Galactose Is Converted to Glucose-6-Phosphate
`C. Mannose Is Converted to Fructose-6-Phosphate
`6 The Pentose Phosphate Pathway
`520
`A . Oxidative Reactions Produce NADPH in Stage 1
`522
`B. lsomerization and Epimerization of Ribulose-5-Phosphate
`Occur in Stage 2
`523
`C. Stage 3 Involves Carbon-Carbon Bond Cleavage and
`Formation
`523
`D. The Pentose Phosphate Pathway Must Be Regulated
`BOX 15-1 PATHWAYS OF DISCOVERY
`Otto Warburg and Studies of Metabolism
`488
`BOX 15-2 PERSPECTIVES IN BIOCHEMISTRY Synthesis of
`2,3-Bisphosphoglycerate in Erythrocytes and Its Effect
`on the Oxygen Carrying Capacity of the Blood
`502
`·BOX 15-3 PERSPECTIVES IN BIOCHEMISTRY
`Glycolytic ATP Production in Muscle
`510
`BOX 15-4 BIOCHEMISTRY IN HEALTH AND DISEASE
`Glucose-6-Phosphate D ehydrogenase D eficiency
`
`516
`
`518
`520
`
`524
`
`526
`
`Ii Glycogen Metabolis_m
`
`and Gluconeogenes1s
`
`530
`
`1 Glycogen Breakdown
`532
`A. Glycogen Phosphorylase Degrades Glycogen to Glucose-1-
`Phosphate
`534
`B. Glycogen Debranching Enzyme Acts as a
`Glucosyltransferase
`536
`C. Phosphoglucomutase lnterconverts Glucose-1-Phosphate and
`Glucose-6-Phosphate
`537
`2 Glycogen Synthesis
`540
`A. UDP-Glucose Pyrophosphorylase Activates Glucosyl
`Units
`540
`B. Glycogen Synthase Extends Glycogen Chains
`541
`C. Glycogen Branching Enzyme Transfers Seven-Residue
`Glycogen Segments
`543
`3 Control of Glycogen Metabolism
`545
`A. Glycogen Phosphorylase and Glycogen Synthase Are Under
`Allosteric Control
`545
`B. Glycogen Phosphorylase and Glycogen Synthase Undergo
`Control by Covalent Modification
`545
`c. Glycogen Metabolism Is Subject to Hormonal Control
`4 Gluconeogenesis
`552
`A. Pyruvate Is Converted to Phosphoenolpyruvate in Two
`Steps
`554
`B. Hydrolytic Reactions Bypass Irreversible Glycolytic
`Reactions
`557
`C. Gluconeogenesis and Glycolysis Are Independently
`Regulated
`558
`5 Other Carbohydrate Biosynthetic Pathways
`BOX 16-1 PATHWAYS OF DISCOVERY
`Carl and Gerty Cori and Glucose Metabolism
`BOX 16-2 BIOCHEMISTRY IN HEALTH AND DISEASE
`Glycogen Storage Diseases
`538
`BOX 16-3 PERSPECTIVES IN BIOCHEMISTRY
`Optimizing Glycogen Structure
`544
`BOX 16-4 PERSPECTIVES IN BIOCHEMISTRY
`Lactose Synthesis
`560
`
`550
`
`560
`
`533
`
`f p Citric Acid Cycle _____ 566
`
`1 Overview of the Citric Acid Cycle
`567
`2 Synthesis of Acetyl-Coenzyme A
`570
`A. Pyruvate Dehydrogenase Is a Multienzyme Complex
`B. The Pyruvate Dehydrogenase Complex Catalyzes Five
`Reactions
`572
`3 Enzymes of the Citric Acid Cycle
`A. Citrate Synthase Joins an Acetyl Group to
`Oxaloacetate
`577 ·
`B. Aconitase lnterconverts Citrate and lsocitrate
`578
`C. NAO+ -Dependent lsocitrate Dehydrogenase Releases
`CO2
`579
`
`576
`
`570
`
`Page 12 of 61
`
`

`

`Contents
`
`x iii
`
`583
`
`588
`588
`
`D. a-Ketoglutarate Dehydrogenase Resembles Pyruvate
`Dehydrogenase
`580
`E. Succinyl-CoA Synthetase Produces GTP
`F. Succinate Dehydrogenase Generates FADH2
`G. Fumarase Produces Malate
`583
`H. Malate Dehydrogenase Regenerates Oxaloacetate
`4 Regulation of the Citric Acid Cycle
`583
`A. Pyruvate Dehydrogenase Is Regulated by Product Inhibition
`and Covalent Modification
`585
`B. Three Enzymes Control the Rate of the Citric Acid
`Cycle
`585
`5 Reactions Related to the Citric Acid Cycle
`A . Other Pathways Use Citric Acid Cycle Intermediates
`B. Some Reactions Replenish Citric Acid Cycle
`Intermediates
`589
`C. The Glyoxylate Cycle Shares Some Steps with t he Cit ric
`Acid Cycle
`590
`BOX 17-1 PATHWAYS OF DISCOVERY
`569
`H ans Krebs and the Citric A cid Cycle
`BOX 17-2 BIOCHEMISTRY IN HEALTH AND DISEASE
`Arsenic Poisoning
`576
`BOX 17-3 PERSPECTIVES IN BIOCHEMISTRY
`E vol ution of the Citric Acid Cycle
`
`580
`
`582
`
`592
`
`Electron Transport and
`-Oxidative Phosphorylation
`
`596
`
`1 The Mitochondrion
`597
`A. M itochondria Contain a Highly Folded Inner
`Membrane
`597
`B. Ions and Met abolites Enter Mit ochondria via
`Transporters
`599
`600
`2 E lectron Transport
`A. Electron Transport Is an Exergonic Process
`601
`B. Electron Carriers Operate in Sequence
`602
`C. Complex I Accepts Electrons from NADH
`604
`D. Complex II Contributes Electrons to Coenzyme Q
`E. Complex Ill Translocates Protons via the Q Cycle
`F. Complex IV Reduces Oxygen to Water
`615
`3 Oxidative Phosphorylation
`618
`A . The Chemiosmotic Theory Links Electron Transport to ATP
`Synthesis
`618
`B. ATP Synthase Is Driven by the Flow of Protons
`622
`C. The P/O Ratio Relates t he Amount of ATP Synthesized to the
`Amount of Oxygen Reduced
`629
`D. Oxidative Phosphorylation Can Be Uncoupled from Electron
`Transport
`630
`4 Control of Oxidative Metabolism
`631
`A. The Rate of Oxidative Phosphorylation Depends on the ATP
`631
`and NADH Concentrations
`B. Aerobic Metabolism Has Some Disadvantages
`634
`BOX 18-1 PERSPECTIVES IN BIOCHEMISTRY Cytochromes
`Are Electron-Transport Heme Proteins
`610
`
`609
`61 1
`
`BOX 18-2 PATHWAYS OF DISCOVERY
`619
`Peter M itchell and the Chemiosmotic Theory
`BOX 18-3 PERSPECTIVES IN BIOCHEMISTRY B acterial Electron
`Transport and Oxidative Phosphorylation
`621
`BOX 18-4 PERSPECTIVES IN BIOCHEMISTRY Uncoupling in
`B rown A dipose Tissue Generates Heat
`632
`BOX 18-5 BIOCHEMISTRY IN HEALTH AND DISEASE
`Oxygen Deprivation in Heart Attack and Stroke
`
`635
`
`• Photosynthesis
`
`640
`
`643
`
`1 Chlo