BioeINTERNATIONAL SEVENTH EDITION

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errustrv

Jeremy M. Berg

John L. Tymoczko

Lubert Stryer

withGregory J. Gatto, Jr.• ; w. H. Freeman and Company' New York

palgravemacmillan

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BRIEF CONTENTS

Part I THE MOLECUIJ\R DESIGN OF LIFE1 Biochemistry: An Evolving Science 1

2 Protein Composition and Structure 25

3 Exploring Proteins and Proteom es 67

4 DNA, RNA, and the Flow of Genetic Information 113

5 Exploring Genes and Genomes 145

6 Exploring Evolution and Bioinformatics 181

7 Hemoglobin: Portrait of a Protein in Action 203

8 Enzymes: Basic Concepts and Kinet ics 227

9 Catalytic Strategies 261

10 Regulatory Strategies 299

11 Carbohydrates 329

12 Lipids and Cell Membranes 357

13 Membrane Channels and Pumps 383

14 Signal-Transduction Pathways 415

Part II TRANSDUCING AND STORING ENERGY15 Metabolism: Basic Concepts and Design 443

16 Glycolysis and Gluconeogenesis 469

17 The Citric Acid Cycle 515

18 Oxidative Phosphorylation 543

19 The Light Reactions of Photosynthesis 585

20 The Calvin Cycle and the Pentose PhosphatePathway 609

21 Glycogen Metabolism 637

22 Fatty Acid Metabolism 663

23 Protein Turnover and Amino Acid Catabolism 697

Part III SYNTHESIZING THE MOLECULES OF LIFE24 The Biosynthesis of Amino Acids 729

25 Nucleotide Biosynthesis 761

26 The Biosynthes is of Membrane Lipids andSteroids 787

27 The Integration of Metabolism 821

28 DNA Replication, Repair, and Recombination 849

29 RNA Synthesis and Processing 883

30 Protein Synthesis 921

31 The Control of Gene Expression in Prokaryotes 957

32 The Control of Gene Expression in Eukaryotes 973

Part IV RESPONDING TO ENVIRONMENTAL CHANGES33 Sensory Systems 99S

34 The Immune System 1017

35 Molecular Motors 1049

36 Drug Development 1073

CON TENTS

Preface

Part I THE MOLECULAR DESIGN OF LIFE

Chapter I Biochemistry: An Evolving Science

1.1 Biochemical Unity UnderliesBiological Diversity

1.2 DNA Illustrates the Interplay BetweenForm and FunctionD NA is constructed from four building blocks

Two single strands of DNA combine to form adou ble helix

D NA str uctur e explains heredity and the storageof informat ion

1.3 Concepts from Chemistry Explain theProperties of Biological MoleculesThe double helix can form from its component strands

Covalent and noncovalenr bonds are important for thestructure and stability of biological molecules

T he double helix is an expression of the rulesof chemistry

The laws of thermodynamics govern the behavior ofbiochem ical syst ems

Heat is released in th e formation of the double helix

Acid -base reactions are central in many biochemicalprocesses

Acid-base reactions can disrupt the double helix

Buffers regula te pH in organisms and in the laboratory

1.4 The Genomic Revolution Is TransformingBiochemistry and MedicineThe sequencing of the human genome is a landmarkin human history

Genome sequences encode protei ns and pattern s ofexpression

Individuality depends on the interp lay between genesand environment

APPENDIX: Visualizing Molecular Structures I:Small Mo lecules

Chapter 2 Protein Composition and Structure

2.1 Proteins Are Built from a Repertoire of20 Am ino Acids

2.2 Primary Structure: Amino Acids Are Linked byPeptide Bonds to Form Polypeptide ChainsProteins have unique amino acid sequences specifiedby genes

Polypeptide chains are flexible yet conformationallyrestric ted

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2.3 Secondary Structure: Polypeptide Chains Can 3.2 Amino Acid Sequences of Proteins CanFold into Regular Structures Such As the Alpha Be Determined Experimentally 81Helix, the Beta Sheet, and Turns and Loops 38 Peptide sequences can be determined by automatedT he alpha helix is a coiled structure stabilized Edmandegradation 82by intrachain hydrogen bonds 38 Proteins can be specifically cleaved into smallBeta sheets are stabilized by hydrogen bonding between peptides to facilitate analysis 84polypeptide strands 40 Genomic and proteomic methods are complementa ry 86Polypeptide chains can change direction by 3.3 Immunology Provides Important Techniquesmakin g reverse turns and loops 42 with Which to Investigate Proteins 86Fibrou s proteins provide structural support for Antibodies to specific proteins can be generated 86cells and tissues 43

2.4 Tertiary Structure: Water-Soluble ProteinsMonoclonal antibodies with virtua lly anydesired specificity can be readily prepared 88

Fold into Compact Structures with Proteins can be detected and quantified by using anNonpolar Cores 45 enzyme- linked immunosorbent assay 90

2.5 Quaternary Structure: Polypeptide Chains Western blott ing permits the detection of

Can Assemble into Multisubunit Structures 48 proteins separated by gel electrophoresis 91

2.6 The Amino Acid Sequence of a Protein Fluorescent markers make the visualization of

Determines Its Three-Dimensional Structure 49 proteins in the cell possible 92

Amino acids have different propensities for 3.4 Mass Spectrometry Is a PowerfulTechniqueforming alpha helices, beta sheets, and beta turns 50 for the Identification of Peptides and Proteins 93

Protein folding is a highly cooperative process 52 The mass of a protein can be precisely determined

Prot eins fold by progressive stabilization of by mass spectrometry 93

intermediates rather than by random search 52 Peptides can be sequenced by mass spectrometry 95

Prediction of three-dimensional structure from Individual proteins can be identified by

sequence remains a great challenge 54 mass spectrometry 96

Some proteins are inherently unstructured and 3.5 Peptides Can Be Synthesized bycan exist in multiple conformations 54 Automated Solid-Phase Methods 97Protein misfolding and aggregation are associated 3.6 Three-Dimensional Protein Structurewith some neurological diseases 55 Can Be Determined by X-ray CrystallographyProtein modification and cleavage confer and NMR Spectroscopy 100new capabilities 57

X-ray crystallography reveals three-dimensionalAPPENDIX:VisualizingMolecular Structures 11: Proteins 60 structure in atomic detail 100

Nuclear magnetic resonance spectroscopy can revealthe structures of proteins in solution 103

Chapter 3 Exploring Proteins and Proteomes 67

The proteome is the functional representation of Chapter 4 DNA, RNA, and the Flow ofthe genome 68 Information 1133.1 The Purification of Proteins Is an Essential 4.1 A Nucleic Acid Consists of Four Kinds ofFirst Step in Understanding Their Function 68 Bases Linked to a Sugar-Phosphate Backbone 114The assay: How do we recognize the protein RNAand DNA differ inthe sugar component andthat we are looking for? 69

one of the bases 114Proteins must be released from the cell to be purified 69

Nucleotides are the monomeric units of nucleic acids 115Proteins can be purified according to solubility, size,

DNA molecules are very long 117charge , and binding affinity 70Proteins can be separated by gel electrop horesis and 4.2 A Pair of Nucleic Acid Chains withdisplayed 73 Complementary Sequences Can Form aA protein purifi cation scheme can be quantitat ively Double-Helical Structure 117evaluated 77 Thedouble helixis stabilized by hydrogen bonds andUltracen trifugat ion is valuab le for separating van der Waals interactions 117

biomolecules and determining their masses 78 DNA can assume a variety of structural forms 119

Protein purification can be made easier with the use Z-DNAisa left-handed doublehelixinwhichof recombinant DNA technology 80 backbone phosphates zigzag 120

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Some DNA molecules are circular and supercoiled 121 5.2 Recombinant DNA Technology HasSingle-stranded nucleic acids can adopt Revolutionized All Aspects of Biology 154elaborate structures 121 Restriction enzymes and DNA ligase are key tools in

4.3 The Double Helix Facilitates the Accurate forming recombinant DNA molecules 154

Transmission of Hereditary Information 122 Plasmids and lambda phage are choice vectors for

Differences in DNA density established the validityDNA cloning in bacteria 155

of the semiconservative-replication hypothesis 123 Bacterial and yeast artificial chromosomes 157

The double helix can be reversibly melted 124 Specific genes can be cloned from digests of

4.4 DNA Is Replicated by Polymerasesgenomic DNA 157

That Take Instructions from Templates 125 Complementary DNA prepared from mRNA can be

DNA polymerase catalyzes phosphodiester-bridgeexpressed in host cells 160Proteins with new funct ions can be created through

formation 125directed changes in D NA 162

The genes of some viruses are made of RNA 126Recombinant methods enable the exploration of the

4.5 Gene Expression Is the Transformation of functional effects of disease-causing mu tations 163DNA Information into Functional Molecules 127 5.3 Complete Genomes Have BeenSeveral kinds of RNA play key roles in gene expression 127 Sequenced and Analyzed 163All cellular RNA is synthesized by RNA polymerases 128 The genomes of organisms ranging from bacteria toRNA polymerases take instructions from DNA templates 130 multicell ular eukaryotes have been sequenced 164Transcription begins near promoter sites and ends at T he sequencing of the human genome hasterminator sites 130 been finished 165T ransfer RNAs are the adaptor molecules in protein Next-generation sequencing methods enable the rapidsynthesis 131 determination of a whole genome sequence 166

4.6 Amino Acids Are Encoded by Groups of Comparative genomics has become a powerful

Three Bases Starting from a Fixed Point 132 research tool 166

Major features of the genetic code 133 5.4 Eukaryotic Genes Can Be Quantitated andMessenger RNA contains star t and stop signals for Manipulated with Considerable Precision 167protein synthesis 134 Gene-expression levels can be comprehensivelyThe genetic code is nearly universal 135 examined 167

4.7 Most Eukaryotic Genes Are Mosaics of New genes inserted into eukaryotic cells can be

Introns and Exons 135 efficiently expressed 169

RNA processing generates mature RNA 136 T ransgenic animals harbor and express genes

Many exons encode protein domains 137introduced into their germ lines 170Gene disruption prov ides clues to gene function 170RNA interference provides an addi tional tool fordisrupting gene expression 171

Chapter 5 Exploring Genes and Genomes 145 T umor-inducing plasmids can be used to introduce

5.1 The Exploration of Genes Relies on new genes into plant cells 172

Key Tools 146 Hu man gene therapy holds great promise for medicine 173

Restriction enzymes split D NA into specific fragments 147Restriction fragments can be separated by gel Chapter 6 Exploring Evolution andelectrophoresis and visualized 147 Bioinformatics 181DNA can be sequenced by cont rolled termination of 6.1 Homologs Are Descended from areplication 149

DNA probes and genes can be synthesized byCommon Ancestor 182

automated solid -phase me thods 150 6.2 Statistical Analysis of Sequence

Selected DNA sequences can be greatly amplified Alignments Can Detect Homology 183by the polymerase chain reaction 151 T he stati stical significance of alignments can be

peR is a powerful technique in medical diagnos tics, estimated by shuffling 185

forensics, and studies of molecular evolution 152 Distant evolutionary relations hips can be detected

The tools for recombinan t DNA technology through the use of subst itution matrices 186

have been used to identify disease-causing Databases can be searched to identify homologousmutations 153 sequences 189

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6.3 Examination of Three-Dimensiona lStructure Enhances Our Understanding ofEvolutionary RelationshipsTertiary structure is more conserved than primarystructureKnowledge of three-dimensional structures canaid in the evaluation of sequence alignments

Repeated motifs can be detected by aligningsequences with themselves

Convergent evolution illust rates common solutionsto biochemical challenges

Comparison of RNA sequences can be a source ofinsight into RNA secondary structures

6.4 Evolutionary Trees Can Be Constructedon the Basis of Sequence Informati on

6.5 Modern Techniques Make the ExperimentalExploration of Evolution PossibleAncient DNA can sometimes be amplifiedand sequenced

Molecular evolution can be examined experimentally

Chapter 7 Hemoglobin: Portra it of aProtein in Action

7.1 Myoglobin and Hemoglobin Bind Oxygenat Iron Atoms in HemeChanges in heme electron ic structure upon oxygenbinding are the basis for func tional imaging studies

The structure of myoglobin prevents the release ofreactive oxygen species

Human hemoglobin is an assembly of fourmyoglobin -like subunits

7.2 Hemoglobin Binds Oxygen CooperativelyOxygen binding markedly changes the quaternarystructure of hemoglobin

Hemoglobin cooperativity can be potentially explainedby several mode ls

Struc tural changes at the heme groups aretransmitted to the a l 13 t- 0:2132 interface2 ,3~Bisphosphoglycerate in red cells is crucial indetermining the oxygen affinity of hemoglobin

Carbon monoxide can disrupt oxygen transport byhemoglobin

7.3 Hydrogen Ions and Carbon Dioxide Promotethe Release of Oxygen: The Bohr Effect

7.4 Mutations in Genes Encoding HemoglobinSubunits Can Result in DiseaseSickle-cell anemia results from the aggregation ofmutated deoxyhemoglobin molecules

T halassemia is caused by an imbalanced production ofhemoglobin chains

T he accumu lation of free alpha-hemoglobinchains is prevented

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Additional globins are encoded in the human genome

APPENDIX: Binding Models Can Be Formulated inQuantitative T erms: the Hill Plot and the Concerted Model

Chapter 8 Enzymes : Basic Concepts andKinetics

8.1 Enzymes Are Powerful and HighlySpecific CatalystsMany enzymes require cofactors for activity

Enzymes can transform energy from one forminto another

8.2 Free Energy Is a Useful ThermodynamicFunction for Understanding EnzymesThe free-energ y change prov ides information aboutthe spontaneity but not the rate of a reaction

The standard free-energy change of a reaction isrelated to the equilibrium constant

Enzymes alter only the reaction rate and not thereaction equilibrium

8.3 Enzymes Accelerate Reactions by Facilitatingthe Formation of the Transition StateT he formation of an enzyme-substrate complex isthe first step in enzymatic catalysis

The active sites of enzymes have somecommon features

The binding energy between enzyme and subst rateis important for catalysis

8.4 The Michaelis-Menten Equation Describesthe Kinet ic Properties of Many EnzymesKinetics is the stud y of reaction rates

The steady-state assumption facilitates a descriptionof enzyme kinetics

Variation s in KM can have physiological consequences

KM and Vmax values can be determined byseveral means

KJ:""f and Vmax values are important enzymecharacteristics

kcatl KM is a measure of catalytic efficiency

Most biochemical reactions include multiple substrates

Allosteric enzymes do not obeyMichae1is-Menten kinetics

8.5 Enzymes Can Be Inhibited by SpecificMol eculesReversible inhibitors are kinetically distinguishable

Irreversible inhibitors can be used to mapthe active site

Transition-state analogs are potent inhibitorsof enzymes

Catalytic antibodies demonstrate the importance of selectivebinding of the transition state to enzymatic activity

Penicillin irreversibly inactivates a key enzyme inbacterial cell ~wall synthesis

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8.6 Enzymes Can Be Studied One Moleculeat a TimeAPPENDI X: Enzymes are Classified on the Basisof the T ypes of Reactions That T hey Catalyze

Chapter 9 Catalytic Strategies

A few basic catalytic principles areused bymany enzymes

9.1 Proteases Facilitate a FundamentallyDifficult ReactionChymotrypsin possesses a highly reactive serine residue

Chymotrypsin action proceeds in two steps linkedby a covalently bound intermediate

Serine is part of a catalytic triad that also includeshistidineand aspartateCatalytic triads are found in other hydrolytic enzymes

The catalytic triadhas been dissected bysite-directed mutagenesis

Cy steine, aspartyl, and metalloproteases are othermajor classes of peptide -cleaving enzymes

Protease inhibitors are important drugs

9.2 Carbonic Anhydrases Make a FastReaction FasterCarbonic anhydrase contains a bound zinc ionessential for catalyt ic activity

Catalysis entails zinc activation of a water molecule

A proton shuttle facilitates rapid regenera tion ofthe active form of the enzyme

Convergent evolution has generated zinc -basedactive sites in different carbonic anhydrases

9.3 Restriction Enzymes Catalyze HighlySpecific DNA-Cleavage ReactionsCleavage is by in-line dis placement of3 '-oxygenfrom phosphorus by magnesium -activated water

Restriction enzymes requ ire magnesium forcatalytic activ ity

The complete catalytic apparatus is assembledonly within complexes of cognate DNA molecules ,ensuring specificity

Hos t-cell DNA is protected by the addition of methylgroups to specific bases

Type II restriction enzymes have a catalytic core incommon and are probably related by horizontalgene transfer

9.4 Myosins Harness Changes in EnzymeConformation to Couple ATP Hydrolysis toMechanical WorkATP hydrolysis proceeds by the attack ofwater onthe gamma-phosphoryl group

Formation of the transition state for ATP hydrolysisis associated with a substantial conformational change

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The altered conformation of myosin persists for asubstantial period of time

Myosins are a family of enzymes containing P-loopstructures

Chapter 10 Regulatory Strategies

10.1 Aspartate Transcarbamoylase IsAllostericallyInhibited by the End Product of Its PathwayAllosterically regulated enzymes do not followMichaelis-Menten kinetics

A TCase consists of separable catalytic and regulatorysubunits

Allosteric interactions in ATCase are mediated by largechanges in quaternary struct ure

Allosteric regulators modulate the T -to -R equilibrium

10.2 Isozymes Provide a Means of RegulationSpecific to Distinct Tissues and DevelopmentalStages10.3 Covalent Modification Is a Means ofRegulating Enzyme ActivityKinases and phosphatases control the extent of proteinphosphorylation

Phosphorylation is a highly effective means ofregulating the activities of target proteins

Cyclic AMP activates prote in kinase A by altering thequaternary structure

AT P and the target protein bind to a deep cleftin the catalytic subunit of protein kinase A

10.4 Many Enzymes AreActivated by SpecificProteolytic CleavageChy motrypsinogen is activated by specific cleavageof a single peptide bond

Proteolytic activation of chymotryps inogen leadsto the formation of a substrate-binding site

The generation of trypsin from trypsinogen leadsto the activation of other zymogens

Some proteolytic enzymes have specific inh ibitors

Blood clotting is accomplished by a cascade ofzymogen activations

Fibrinogen is converted by thrombin into afibrin clot

Prothrombin is readied for activation by a vitaminK-dependent modification

H emophilia revealed an early step in clotting

The clotting process must be precisely regu lated

Chapter 11 Carbohydrates

11.1 Monosaccharides Are the SimplestCarbohydratesMany common sugars exist in cyclic forms

Pyranose and furanose rings can assume differentconformations

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Glucose is a reducing sugar 335 A membrane lipid is an amphipathic molecule

Monosaccharides are jo ined to alcohols and containing a hyd rophilic and a hydroph obic moiety 363

amines through glycosidic bonds 336 12.3 Phospholipids and Glycolipids ReadilyPhosphorylated sugars are key intermediates in Form Bimolecular Sheets in Aqueous Media 364energy generation and biosyntheses 336 Lipid vesicles can be formed from phospholipids 36511.2 Monosaccharides Are Linked to Form Lipid bilayers are high ly impermeable to ions and

Complex Carbohydrates 337 most polar molecules 366

Sucrose, lactose, and maltose are th e common 12.4 Proteins Carry Out Most Membranedisaccharides 337 Processes 367Glycogen and starch are storage forms of glucose 338 Proteins associate with the lip id bilayer in aCellulose, a structural component of plants, is made variety of ways 367of chains of glucose 338 Proteins interact with membranes in a variety

11.3 Carbohydrates Can Be Linked to Proteins of ways 368

to Form Glycoproteins 339 Some proteins associate with membranes th rough

Carbohydrates can be linkedtoproteins through covalently attached hydrophobic groups 371

asparagine (N-linked ) or through serine or Transmembrane helices can be accurately

threonine (O-linked) residues 340 predicted from amino acid sequences 371

The glycoprotein erythropoietin is a vital hormone 340 12.5 Lipids and Many Membrane ProteinsProreoglycan s. composed of polysaccharides and Diffuse Rapidly in the Plane of thepro tein, have important st ructural roles 341 Membrane 373Proteoglycans are importa nt components of cartilage 342 T he fluid mosaic model allows lateral movementMucins are glycoprotein components of mucus 343 but no t rotation th rough the membrane 374Protein glycosylation takes place in th e lumen of the Membrane fluidity iscontrolled byfattyacidendoplasmic reticulum and in th e Golgi complex 343 composition and cholesterol content 374Specific enzymes are responsible for oligosaccharide Lipid rafts are highl y dynamic complexes formedassembly 345 between cho lesterol and specific lipids 375Blood gro ups are based on protein glycosylat ion All biological mem branes are asymmetric 375patterns 345 12.6 Eukaryolic Cells Contain CompartmentsErrors in glycosylation can result in patho logical Bounded by Internal Membranes 376conditions 346Ol igosaccharides can be "sequenced" 346

11.4 Lectins Are Specific Carbohydrate-Binding Chapter 13 Membrane Channels and Pumps 383Proteins 347

The exp ression of transporters largely defines theLectins promote interactio ns between cells 348 metabolic activities of a given cell type 384Lectins are organized int o different classes 348

13.1 The Transport of Molecules Across aInfluenza viru s binds to sialic acid residues 349 Membrane May Be Active or Passive 384

Chapter 12 Lipids and Cell Membranes 357Many molecules require protein transpor ters tocross membranes 384

Many common features underli e the diversity of Free energy stored in concentration gradi ents can be

bio logical membranes 358 qu antified 385

12.1 FattyAcids Are Key Constituents of 13.2 Two Families of Membrane ProteinsLipids 358 Use ATP Hydrolysis to Pump Ions and

Fatty acid namesare based ontheir parent hydrocarbons 358 Molecules Across Membranes 386

Fatty acids vary in chainlength anddegree of P-lypeATPases couplephosphorylation andunsaturation 359 conformational changes to pump calcium ions

across membranes 38612.2 There AreThree Common Types of Digitalis specifically inhibits theNa+- K+ pumpMembrane Lipids 360 by blocking itsdephosphorylation 389Phospholipids are the major class of membrane lipids 360 P- type ATPases are evolutionarily conserved andM embrane lipid s can include carbohydrate moieties 361 play a wide rang e of roles 390Cholesterol is a lipid based on a steroid nucl eus 362 Multidrugresistancehighlights afamilyofArchaeal membranes are built from ether lipids with membrane pumps with ATP-binding cassettebranched chains 362 domains 390

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13.3 Lactose Permease Is an Archetype ofSecondaryTransporters That Use OneConcentration Gradient to Power the Formationof Another 392

13.4 Specific Channels Can Rapidly TransportIons Across Membranes 394Action potentials are mediated by transient changesin Na+ and K+ permeability 394

Patch-clamp conductance measurements revealthe activit ies of single channels 395

T he structure of a potassium ion channel is anarchetype for many ion -channel structures 395

The structure of the potassium ion channel revealsthe basis of ion specificity 396

The structure of the potassium ion channel explainsits rapid rate of transport 399

Voltage gating requires substantial conformationalchanges in specific ion -channel domains 399

A channel can be activa ted by occlusion of the pore :the ball -and -chain model 400

The acetylcholine receptor is an archetype forligand-gated ion channels 401

Action potentials integrate the activities of several ionchannels working in concert 402

Disruption of ion channels by mutations orchemicals can be potentially life threatening 404

13.5 GapJunctionsAllow Ions and SmallMoleculesto Flow Between Communicating Cells 405

13.6 Specific Channels Increase the Permeabilityof Some Membranes to Water 406

Insulin binding results in the cross -phosphorylationand activation of the insulin receptor

The activated insulin-receptor kinase initiates akinase cascade

Insulin signaling is terminated by the action ofphosphatases

14.3 EGF Signaling: Signal-TransductionPathways Are Poised to RespondEGF binding results in the dimerization of theEGF receptor

The EGF receptor undergoes phosphorylation ofits carboxyl-terminal tail

EGF signaling leads to the activation of Ras, asmall G protein

Activated Ras initiates a protein kinase cascade

EGF signaling is terminated by protein phosphatasesand the intrinsic GTPase activity of Ras

14.4 Many Elements Recur with Variationin Different Signal-TransductionPathways

14.5 Defects in Signal-TransductionPathways Can Lead to Cancer and OtherDiseasesMonoclonal antibodies can be used to inhibitsignal -transduction pathways activated in tumors

Protein kinase inhibitors can be effective anticancerdrugs

Cholera and whooping cough are due to alteredG cprotein activity

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Chapter 14 Signal-Transduction Pathways

Signal transduction depends on molecular circuits

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Part II TRANSDUCING ANDSTORING ENERGY

14.1 Heterotrimeric G Proteins TransmitSignals and Reset Themselves 417Ligand binding to 7T M recep tors leads to theactivation ofheterotrimeric G proteins 419

Activated G proteins transmit signa ls by bindingto other proteins 420

Cyclic AMP stimulates the phosphorylation of manytarget proteins by activating protein kinase A 420

G proteins spontaneously reset themselves throughGT P hydrolysis 421

Some 7TM receptors activate the phosphoinositide cascade 422

Calcium ion is a widely used second messenger 423

Calcium ion often activates the regulatory proteincalmodulin 424

14.2 Insulin Signaling : PhosphorylationCascades Are Central to ManySignal-Transduction Processes 425The insu lin receptor is a dimer that closes arounda bound insulin molecule 426

Chapter 15 Metabolism: Basic Conceptsand Design

15.1 Metabolism Is Composed of ManyCoupled, Interconnecting ReactionsMetabolism consists of energy -yield ing andenergy -requiring reactions

A thermodynamically unfavorable reaction can bedriven by a favorable reaction

15.2 ATP Is the Universal Currency of FreeEnergy in Biological SystemsATP hydrolysis is exergonic

ATP hydrolysis drives metabolism by shifting theequilibrium of coupled reactions

The high phosphoryl potential of ATP resultsfrom structural differences between ATP and itshydrolysis products

Phosphoryl-transfer potential is an important formof cellular energy transformation

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15.3 The Oxidation of Carbon Fuels Is an Many adults are intolerant of milk because they

Important Source of Cellular Energy 451 are deficient in lactase 487

Compounds with high phosphoryl-t ransfer potential Ga lactose is highly toxic if the transferase is missing 488

can couple carbon oxidation to AT P synthesis 452 16.2 The Glycolytic Pathway Is TightlyIon gradients across membranes provide an Controlled 488important form of cellular energy th at can be Glycolysis in mu scle is regulated to meet the needcoupled to ATP synthesis 453 for ATP 489

Energy from foods tuffs is extracted in th ree stages 453 The regu lation of glycolysis in the liver illustrates

15.4 Metabolic Pathways Contain Many the biochemical versatili ty of the liver 490

Recurring Motifs 454 A family of transporters enab les glucose to ente r

Act ivated carriers exem plify the modular design and and leave animal cells 493

economy of metabolism 454 Cancer and exercise training affect glycolysis in a

M any activated carrier s are derived from vitamins 457 similar fashion 494

Key reactions are reite rated throughout metabolism 459 16.3 Glucose Can Be Synthesized from

M etab olic proce sses are regulated in three Noncarbohydrate Precursors 495

principal ways 461 Gluconeogenesis is not a reversal of glycolysis 497

Aspects of metabolism may have evolved from an The conversion of pyruvate into phosphoenolpyru vateRNA world 463 begins with the formation of oxaloacetate 498

Oxaloacetate is shu tt led into the cytoplasm andconverted into phosphoenolpyruvate 499

Chapter 16 Glycolysis and Gluconeogenesis 469 The conversion of fructose Ln-bisphcsphate into

Glucose is generat ed from dietar y carbohydrates 470 fructose 6-phosphate and ort hophosphate is an

Glucose is an import ant fuel for most organisms 471irreversible step 500

16.1 Glycolysis Is an Energy-ConversionT he generation of free glucose is an importantcontrol point 500

Pathway in Many Organisms 47 1 Six high-transfer-potential phosphoryl groups areH exokinase traps glucose in the cell and begins spent in synt hesizing glucose from pyruvate 501

glycolysis 47116.4 Gluconeogenesis and Glycolysis Are

Fructose L o-bisphcephate is generated from glucose Reciprocally Regulated 5026-phosphate 473

The six-carbon sugar is cleaved into twoEnergy charge determines whether glycolysis or

three-carbon fragment s 474gluconeogenesis will be most active 502

M echanism: T riose phos phate isomerase salvages aThe balance between glycolysis and gluconeo genesis

three-carbon fragment 475in the liver is sensitive to blood -glucose concentration 503

The oxidation of an aldehyde to an acid powersSubstrate cycles amplify metabolic signals and

the formation of a compound with highproduce heat 505

phosphoryl -transfer potential 476 Lactate and alanine formed by cont ract ing mu scle

M echanism: Phosphorylation is coupl ed to theare used by other organs 505

oxidation of glyceraldehyde 3-phosphate by aGlycolysis and gluconeogenesis are evolutionarily

thioester inte rmediate 478 intertwined 507

ATP is formed by phosphoryl transfer fromChapter 17 The Cit ric Acid Cycle 515

1,3-bisphosphoglycerate 479

Additional ATP is generated with the formation of The citr ic acid cycle harvests high -energy electrons 516pyruvate 480

Pyruvate Dehydrogenase Links GlycolysisT wo ATP molecules are formed in the conversion

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of glucose into pyru vate 481 to the Citric Acid Cycle 517

NAD + is regenerat ed from the metaboli smMechanism: The synthesis of acetyl coenzyme a from

of pyru vate 482 pyruvate requires three enzymes and five coenzymes 518

Fermentations provide usable energy in the abse nceFlexible linkages allow lipoamide to move between

of oxygen 484 different active sites 520

The binding site for NAD+ is simi lar in many 17.2 The Citric Acid Cycle Oxidizesdehydrogenases 485 Two-Carbon Units 52 1

Fructose and galactose are converted into glycolytic Citrate synthase forms citrate from oxaloacetate and

inte rmed iates 485 acetyl coenzyme A 522

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Mechanism: The mechanism of citrate synthase Ubiquinol is the entry point for electrons from FADH 2

prevents undesirable reactions 522 of flavoproteins 553

Citrate is isomerized into isocitrate 524 Electrons flow from ubiquinol to cytochrome c

Isocitrate is oxidized and decarboxylated to through Q -cytochrome c oxidoreductase 553

alpha- ketoglutarate 524 The Q cycle funnels electrons from a two -electron

Succinyl coenzyme A is forme d by the oxidative carrier to a one-electron carrier and pumps protons 554

decarboxylation of alpha-ketoglutarate 525 Cytochrome c oxidase catalyzes the reduction of

A compound with high phosphoryl ~transfer potential molecu lar oxygen to water 555

is generated from succinyl coenzyme A 525 T oxic derivat ives of molecular oxygen such as

Mech anism: Succinyl coenzyme A synthetase superoxide radical are scavenged by protective enzymes 558

transforms types of biochemical energy 526 Electrons can be transferred between groups that are

Oxaloacetate is regenerated by the oxidation not in contact 560

of succinate 527 The conformation of cytochrome c has remained

The citric acid cycle produces high -transfer-potential essentially const ant for more than a billion years 561

electrons, AT P, and CO2 528 18.4 A Proton Gradient Powers the17.3 Entry to the Citric Acid Cycle and Synthesis of ATP 561Metabol ism Through It Are Controlled 530 ATP synthase is composed of a proton-conducting

T he pyru vate dehydrogenase complex is regulated unit and a catalytic unit 563

allosterically and by reversib le pho sphorylation 531 Proton flow through ATP synthase leads to the release

The citr ic acid cycle is controlled at several points 532 of tightly bound ATP, The binding-change mechanism 564

Defects in the citric acid cycle contribute to the Rotational catalysis is the world 's smallest molecular motor 565

development of cancer 533 Proton flow around the c ring powers AT P synthesis 566

17.4 The Citric Acid Cycle Is a Source of AT P synthase and G proteins have several common

Biosynthetic Precursors 534 features 568

T he citric acid cycle mu st be capable of being 18.5 Many Shuttles Allow Movement Acrossrapidly replenished 534 Mitochondrial Membranes 568The disruption of pyruvate metabolism is the cause Electrons from cytoplasmic NADH enterof beriberi and poisoning by merc ury and arsenic 535 mitochondria by shuttles 569

T he citric acid cycle may have evolved from The entry of ADP into mitochondria is coupled topreexisting pathways 536 the exit ofATP by ATP-ADP translocase 570

17.5 The Glyoxylate Cycle Enables Plants Mitochondrial transporters for metabolites have a

and Bacteria to Grow on Acetate 536 common triparti te structure 571

18.6 The Regulation of Cellular Respiration Is

Chapter 18 Oxidative Phosphorylation 54 3 Governed Primarily by the Need for ATP 572

18.1 Eukaryotic Oxidative PhosphorylationT he complete oxidation of glucose yields about30 molecules of ATP 572

Takes Place in Mitochondria 544T he rat e of oxida tive phosphorylation is determined

Mitochondria are bounded by a double membrane 544 by the need for AT P 573Mitochondria are the result of an Regulated uncoupl ing leads to the generation of heat 574endosymbiotic event 545

Oxidative phosphorylation can be inhibited at many stages 57618.2 Oxidative Phosphorylation Depends on Mitochondrial diseases are being discovered 576Electron Transfer 546 Mitochondria playa key role in apoptosis 577The electron-transfer potential of an electron is Power transmission by proton grad ients is a centralmeasured as redox potential 546 motif of bioenergetics 577A J.14-volt potential difference between NADH andmolecular oxygen dr ives electron transport through Chapter 19 The Light React ions ofthe chain and favors the formation of a proton Photosynthesis 58 5gradient 548

18.3 The Respiratory Chain Consists of Photosynthesis converts light energy into chemical energy 586

Four Complexes: Three Proton Pumps and 19.1 PhotosynthesisTakes Place in Chloroplasts 587a Physical Link to the Citric Acid Cycle 549 T he primary events of photosynthesis take place in

The high -potential electrons ofNADH enter the thylakoid mem branes 587

respiratory chain at NAD H -Q oxidoreductase 551 Chloroplasts arose from an endosymbiotic event 588

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19.2 Light Absorption by Chlorophyll InducesElectron TransferA special pair of chlorophylls init iate charge separation

Cyclic electron flow reduces the cytochrome of thereaction center

19.3 Two Photosystems Generate a ProtonGradient and NADPH in OxygenicPhotosynthesisPhotosystem II transfers electrons from water toplastoquinone and generates a proton gradient

Cytochrome bilinks photosystem II to photosystem I

Photosystem I uses light energy to generate reducedferredoxin , a powerful reductant

Ferredoxin- NADP+ reduc tase converts NADP+intoNADPH

19.4 A Proton Gradient Across the ThylakoidMembrane Drives ATP SynthesisThe ATP synthase of chloroplasts closely resemblesthose of mit ochondria and prokaryotes

Cyclic electron flow through photo system I leads tothe production of ATP instead ofNADPH

The absorption of eight photons yields one 0 2, twoNADPH, and three ATP molecules

19.5 Accessory Pigments Funnel Energy intoReaction CentersResonance energy transfer allows energy to movefrom the site of init ial absorbance to the reactioncenter

Light -harvesting complexes contain additionalchlorophylls and carotinoids

T he components of photosynthesis are highly organized

Many herbicides inhibit the light reactions ofphotosynthesis

19.6 The Ability to Convert Light into ChemicalEnergy Is Ancient

Chapter 20 The Calvin Cycle and PentosePhosphate Pathway

20.1 The Calvin Cycle Synthesizes Hexosesfrom Carbon Dioxide and WaterCarbon dioxide reacts with ribulose 1,S-bisphosphateto form two molecules of 3-phosphoglycerate

Rubisco activity depends on magnesium andcarbamate

Rubisco also catalyzes a wasteful oxygenase reaction:Cata lytic imperfection

Hexose phosphates are made from phosphoglycerate,and ribu lose 1,5-bisphosphate is regenerated

Three ATP and two NADPH molecules are used tobring carbon dioxide to the level of a hexose

Starch and sucrose are the major carbohydratestores in plants

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20.2 The Activity of the Calvin Cycle Dependson Environmental Conditions 617Rubisco is activated by light-driven changes in protonand magnesium ion concentrations 618

Thioredoxin plays a key role in regulating theCalvin cycle 618

The C4 pat hway of tropical plants acceleratesphotosynthesis by concentrating carbon dioxide 619

Crassulacean acid metabolism permits growth inarid ecosystems 620

20.3 The Pentose Phosphate PathwayGenerates NADPH and SynthesizesFive-Carbon Sugars 621T wo molecules of NADPH are generated in theconversion of glucose n-phosphate into ribulose5-phosphate 621

T he pentose phosphate pathway and glycolysis arelinked by transketolase and transaldolase 621

Mechanism: T ransketolase and transaldolase stabilizecarbanionic intermediates by different mechanisms 624

20.4 The Metabolism of Glucose 6-phosphateby the Pentose Phosphate Pathway IsCoordinated with Glycolysis 626T he rate of the pentose phosphate pathway is controlledby the level ofNADP+ 626

The flow of glucose e-phosphare depends on theneed for NADPH, ribose Scphosphare, and ATP 627

Through the looking-glass: The Calvin cycle and thepentose phosphate pathway are mirror images 629

20.5 Glucose 6-phosphate DehydrogenasePlays a Key Role in Protection Against ReactiveOxygen Species 629Glucose o-phosphate dehydrogenase deficiency causesa drug-induced hemolytic anemia 629

A deficiency of glucose 6-phosphate dehydrogenaseconfers an evolutionary advantage in somecircumstances 631

Chapter 21 Glycogen Metabolism 637

Glycogen metabolism is the regulated release andstorage of glucose 638

21.1 Glycogen Breakdown Requires theInterplay of Several Enzymes 639Phosphorylase catalyzes the phosphorolytic cleavageof glycogen to release glucose 1-phosphate 639

Mechanism: Pyridoxal phosphate participates in thephosphorolytic cleavage of glycogen 640

A debranching enzyme also is needed for thebreakdown of glycogen 641

Phosphoglucomutase converts glucose l -phosphateinto glucose e-phosphate 642

T he liver contains glucose 6-phosphatase, ahydrolytic enzyme absent from muscle 643

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21.2 Phosphorylase Is Regulated by Allosteric The complete oxidation of palmitate yields

Interactions and Reversible Phosphorylation 643 106 molecules ofATP 671

}..1uscle phosphory lase is regu lat ed by the int race llular 22.3 Unsaturated and Odd-Chain Fatty Acidsenerg y charge 643 Require Additional Steps for Degradation 672Liver phosphorylase prod uces glucose for use by other An isomerase and a redu ctase are required fortissues 645 the oxidation of unsaturated fatt y acids 672Phosphorylase kina se is activated by phosphorylation Odd-chain fatty acids yield propionyl Co A in theand calcium ions 645 final thi olysis step 67321.3 Epinephrine and Glucagon Signal the Vitamin B12 contains a corrin ring and a cobalt atom 674Need for Glycogen Breakdown 646 Mechanism: Methylmalonyl e oA mutase catalyzes aG proteins transmi t the signal for the initiation of rear rangement to form succinyl e oA 675glycogen breakdown 646 Fa tty acids are also oxidized in peroxisomes 676Gl ycogen breakdown must be rapidly turned off Ketone bodies aTe formed from acety l eoA whenwhen necessary 648 fat breakdown pr edominates 677The regula tion of glycogen phosphoryla se became Ketone bod ies are a major fuel in some tissues 678more sophisticated as the enzyme evolved 649 Animals cannot convert fatt y acids into glucose 68021.4 Glycogen Is Synthesized and Degraded 22.4 Fatty Acids Are Synthesized by Fattyby Different Pathways 649 Acid Synthase 680UD P-glucose is an activated form of glucose 649 Fatly acids are synthesized and degraded by differentG lycogen syn thase catalyzes th e transfer of glucose pathways 680from UD P·g lucose to a growing chain 650 The form ation of malonyl eoA is the committed stepA branching enzyme forms « - f .b linkages 651 in fatty acid synthesis 681Glycogen synthase is the key regulatory enzy me in Intermediates in fatty acid synthesis are att ached toglycogen synthesis 651 an acyl carri er prot ein 681Glycogen is an efficient storage form of glucose 651 Fatty acid synthesis consists of a series of condensation,21.5 Glycogen Breakdown and Synthesis Are reduction , dehydration, and reduction reaction s 682Reciprocally Regulated 652 Fatty acids are synthesized by a multifunctional

Protein phosphatase 1 rever ses the regulatory effects enzyme complex in animals 683of kinases on glycogen metabolism 653 T he synthesis of palmitate requires 8 molecules of acetyl

Insulin stimulates glycogen synthesis by inactivating CoA, 14 moleculesof NADPH, and 7 molecules ofATP 685glycogen synthase kinase 654 Citrate carries acetyl groups from mitochondria to

G lycogen metabolism in the liver regulates the the cytoplasm for fatt y acid synthesis 686blood -glucose level 655 Several sources supply NAD PH for fatty acid synthesis 686A biochemical understanding of glycogen -storage Fatty acid syn thase inhibito rs may beuseful drugs 687diseases is possible 656 22.5 The Elongation and Unsaturation of

Chapter 22 Fatty Acid Metabolism 663Fatty Acids Are Accomplished by AccessoryEnzyme Systems 687

Fatty acid deg rad ation and synthesis m irror each Membrane-bound enzymes generate unsaturated fatty acids 688other in their chemical reactions 664 Eicosanoid hormon es are derived from polyunsaturated

22.1 Triacylglycerols Are Highly Concentrated fatty acids 688

Energy Stores 665 22.6 Acetyl CoA Carboxylase Plays a Key RoleDietary lipids are digested by pancreatic lipases 665 in Controlling Fatty Acid Metabolism 690Dieta ry lipids are transported in chylomicrons 666 Acetyl eoA carboxylase is regulated by conditions in

22.2 The Use of Fatty Acids As Fuel Requires the cell 690

Three Stages of Processing 667 Acetyl e oA carbox ylase is regulated by a variety of

Triacylglycerol s are hydrolyzed by hormo ne-st imulat edhormones 690

lipases 667Chapter 23 Protein Turnover and Amino

Fatty acids are linked to coenzyme A before theyAcid Catabolism 697are oxid ized 668

Carn itine carries lon g-chain activated fatty acids 23.1 Proteins Are Degraded to Amino Acids 698into the mitocho ndrial matrix 669 The digestion of dietary proteins begins in theAcetyl CoA, NADH, and FADH 2 are generated in stomach and is completed in the intestine 698each round of fatty acid oxidation 670 Cellular proteins are degraded at di fferent rates 699

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23.2 Protein Turnover Is Tightly RegulatedUbiquitin tags proteins for destruction

T he proteasome digests the ubiquitin-taggedproteins

The ubiquitin pathway and the proteasomehave prokaryotic counterparts

Protein degradation can be used to regulatebiological function

23.3 The First Step in Amino Acid DegradationIs the Removal of NitrogenAlpha-amino groups are converted intoammonium ions by the oxidative deaminationof glutamate

Mechanism: Pyridoxal phosphate forms Schiff-baseintermediates in aminotransferases

Aspartate aminotransferase is an archetypalpyridoxal-dependent transaminase

Pyridoxal phosphate enzymes catalyze a wide arrayof reactions

Serine and threonine can be directlydeaminated

Peripheral tissues transport nitrogen to theliver

23.4 Ammonium Ion Is Converted into Ureain Most Terrestrial VertebratesThe urea cycle begins with the formation ofcarbamoyl phosphate

The urea cycle is linked to gluconeogenesis

Urea-cycle enzymes are evolutionarily related toenzymes in other metabolic pathways

Inherited defects of the urea cycle causehyperammonemia and can lead to brain damage

Urea is not the only means of disposing ofexcess nitrogen

23.5 Carbon Atoms of Degraded AminoAcids Emerge As Major MetabolicIntermediatesPyruvate is an entry point into metabolism for anumber of amino acids

Oxaloacetate is an entry point into metabolism foraspartate and asparagine

Alpha-ketoglutarate is an entry point into metabo lismfor five-carbon amino acids

Succinyl coenzyme A is a point of entry for severalnonpolar amino acids

Methionine degradation requires the formation of akey methyl donor, S -adenosylmethionine

T he branched-chain amino acids yield acetyl CoA,acetoacetate, or propiony l CoA

O xygenases are required for the degradation ofaromatic amino acids

23.6 Inborn Errors of Metabolism CanDisrupt Amino Acid Degradation

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Part III SYNTHESIZING THE MOLECULESOF LIFE

Chapter 24 The Biosynthesis of Amino Acids 729

Amino acid synthesis requires solutions to threekey biochemical problems 730

24.1 Nitrogen Fixation: Microorganisms UseATP and a Powerful Reductant to ReduceAtmospheric Nitrogen to Ammonia 730The iron - molybdenum cofactor of nitrogenase bindsand reduces atmospheric nitrogen 731

Ammonium ion is assimilated into an amino acidthrough glutamate and glutamine 733

24.2 Amino Acids Are Made from Intermediatesof the Citric Acid Cycle and Other MajorPathways 735Human beings can synthesize some amino acids butmust obtain others from the diet 735

Aspartate, alanine, and glutamate are formed by theaddition of an amino group to an alpha-ketoaeid 736

A common step determines the chirality of allamino acids 737

The formation of asparagine from aspartate requiresan adenylated intermediate 737

Gl utamate is the precursor of glutamine, proline,and arginine 738

3-Phosphoglycerate is the precursor of serine ,cysteine, and glycine 738

T etrahydrofolate carries activated one -carbon unitsat several oxidation levels 739

S-Adenosylmethionine is the major donor ofmethyl groups 740Cysteine is synthesized from serine andhomocysteine 742

High homocysteine levels correlate withvascular disease 743

Shikimate and chorismate are intermediates in thebiosynthesis of aromatic amino acids 743

Tryptophan synthase illust rates substrate channelingin enzymatic catalysis 746

24.3 Feedback Inhibit ion Regulates AminoAcid Biosynthesis 747Branched pathways require sophisticatedregulation 747

An enzymatic cascade modulates the activity ofglutamine synthetase 749

24.4 Amino Acids Are Precursors of ManyBiomolecules 750Glutathione, a gamma-glutamyl pep tide, serves asa sulfhydryl buffer and an antioxidant 751

Nitric oxide, a short-lived signa l molecule, is formedfrom arginine 751

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Porphyrins are synthesized from glycine and succinyl

coenzyme Aporphyrins accumulate in some inherited disorders of

porphyrin metabolism

Chapter 25 Nucleotide Biosynthesis

Nucleotides can be synthesized by de novo or

salvage pathways

25.1 The Pyrimidine Ring Is Assembled deNovo or Recovered by Salvage PathwaysBicarbonate and other oxygenated carbon compoundsare activated by phosphorylation

The side chain of glutamine can be hydrolyzed to

generate ammoruaIntermediates can move between act ive sites bychanneling

Orotate acquires a ribose ring from PRPP toform a pyrimidine nucleotide and is convertedinto uridylate

Nucleotide mOTIO -, di- , and triphosphates areinte rconvertible

CTP is formed by amination of UT P

Salvage pathways recycle pyrimidine bases

25.2 Purine Bases Can Be Synthesized deNovo or Recycled by Salvage PathwaysThe purine ring system is assembled on ribosephosphate

T he purine ring is assembled by successi ve steps ofactivation by phosphorylation followed bydisplacement

AM P and GMP are formed from IMP

Enzymes of the pur ine synthesis pathway associatewith one another in vivo

Salvage pathways economize intracellular energyexpend iture

25.3 Deoxyribonucleotides Are Synthesizedby the Reduction of Ribonucleotides Througha Radica l MechanismMechanism : A tyrosyl radical is critical to the actionof ribonucleotide reductase

Stable radicals other than tyrosyl rad ical areemployed by other ribonucleotide reductases

Thymidylate is formed by the methylation ofdeoxyurid ylate

Dihydrofolate reductase catalyzes the regenerationof tetrahydrofolate, a one -carbon carrier

Several valuable anticancer drugs block the synthesisof thymidylate

25.4 Key Steps in Nucleotide Biosynthesis AreRegu lated by Feedback InhibitionPyrimidine biosynthesis is regulated by aspartatetranscarbamoylase

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The synthesis of purine nucleotides is controlled byfeedback inhibition at several sites 777

The synthesis of deoxyribonucleotides iscontrolled by the regulation of ribonucleotidereductase 778

25.5 Disruptions in Nucleotide Metabol ismCan Cause Pathological Conditions 778The loss of adenosine deaminase activity resultsin severe combined immunodeficiency 778

Gout is induced by high serum levels of urate 779

Lescb-Nyhan syndrome is a dramatic consequenceof mutations in a salvage-pathway enzyme 780

Folic acid deficiency promotes birth defects suchas spina bifida 781

Chapter 26 The Biosynthesis of MembraneLipids and Steroids 787

26.1 Phosphatidate Is a Common Intermediatein the Synthesis of Phospholipids andTriacylglycerols 788The synthesis of phospholipids requires an activatedintermediate 789

Sphingolipide are synthesized from ceramide 791

Gangliosides are carbohydrate-rich sph ingolipidsthat contain acidic sugars 792

Sphingolipide confer diversity on lipid structure andfunction 793

Respiratory distress syndrome and T ay-Sachs diseaseresult from the disruption of lipid metabolism 793

Phosphatiditic acid phosphatase is a key regu latoryenzyme in lipid metabolism 794

26.2 Cholesterol Is Synthesized from AcetylCoenzyme A in Three Stages 795The synthesis of meva lonate, which is activated asisopentenyl pyrophosphate, initiates the synthesis ofcholesterol 795Squalene (C30) is synthesized from six molecules ofisopentenyl pyrophosphate (Cs) 796Squalene cyclizes to form cholesterol 797

26.3 The Complex Regulation ofCholesterol Biosynthesis Takes Place atSeveral Levels 798Lipoproteins transport cholesterol and tr iacylglycerolsthroughout the organism 801

The blood levels of certa in lipoproteins can servediagnostic purposes 802

Low -density lipoproteins playa central role incholesterol metabolism 803

The absence of the LDL receptor leads tohypercholesterolemia and atherosclerosis 804

Mutations in the LDL receptor prevent LDL releaseand result in receptor destruction 805

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HDL appears to protect against arteriosclerosis 806 Metabolic adaptations in prolonged starvationThe clinical management of cholesterol levels can be minimize protein degradation 838understood at a biochemica l level 807 27.6 Ethanol Alters Energy Metabolism in26.4 Important Derivatives of Cholesterol the Liver 840Include Bile Salts and Steroid Hormones 807 Ethanol metabo lism leads to an excess ofNADH 840Letters identify the stero id rings and numbers Excess ethanol consumption disrupts vitaminidentify the carbon atoms 809 metabo lism 842Steroids are hydroxylated bycytochrome P450monooxygenases that use NADPH and O 2 809 Chapter 28 DNA Repl ication, Repair, andThe cytochrome P450 system is widespread and Recombination 849performs a protective function 810

28.1 DNA Replication Proceeds by thePregnenolone, a precursor of many other steroids, is Polymerization of Deoxyribonucleosideformed from cholesterol by cleavageof its side chain 811

Triphosphates Along a Template 850Progesterone and corticosteroids are synthesized from

DNA pclymerases requ ire a template and a primer 850pregnenolone 811Androgens and estrogens are synthesized from All DNA polymerases have structural features in

pregnenolone 812 common 851

Vitamin D is derived from cholesterol by the Two bound metal ions participate in the

ring-splitt ing activity oflight 813 polymerase react ion 851The specificity of replication is dictated by

Chapter 27 The Integration of Metabolism 821 complementarity of shape between bases 852

27.1 Caloric Homeostasis Is a Means ofAn RNA primer synthesized by primase enables DNAsynthesis to begin 853

Regulating Body Weight 822One strand of DNA is made continuously, whereas

27.2 The Brain Plays a Key Role in Caloric the other strand is synthesized in fragments 853Homeostasis 824 DNA ligase joins ends of DNA in dup lex regions 854

1Signals from the gastrointestinal tract induce feelings The separation of DNA strands requires specificof satiety 824 helicases and ATP hydrolysis 854

:/Leptin and insulin regulate long-term control 28.2 DNA Unwinding and Supercoiling Areover caloric homeostasis 825 Controlled by Topoisomerases 855Leptin is one of several hormones secreted by Thelinking number ofONA,atopological property,adipose tissue 826

determines the degree of supercoiling 856Leptin resistance may be a contributing factor

T opoisomerases prepare the double helix forto obesity 827 unwinding 858D ieting is used to combat obesity 827

T ype I topoisomerases relax supercoiled struc tures 85827.3 Diabetes Is a Common Metabolic Disease Type II topoisomerases can introduce negativeOften Resulting from Obesity 828 supercoils through coupling to ATP hydrolysis 859Insu lin initiates a complex signal -transduction 28.3 DNA Repl ication Is Highly Coordinated 861pathway in muscle 828

DNA replication requires highly processive polymerases 861Metabolic syndrome often precedes type 2 diabete s 830

The leading and lagging strands are synthesizedExcess fatty acids in muscle modify metabolism 830 in a coordinated fashion 862Insulin resistance in muscle facilitates pancreatic failure 831 DNA replication in Escherichia coli begins at aMetabolic derangements in type 1 diabetes result from unique site 864insulin insufficiency and glucagon excess 832 DNA synthesis in eukaryotes is initiated at multiple sites 86527.4 Exercise Beneficially Alters the Telomeres are unique structures at the ends ofBiochemistry of Cells 833 linear chromo somes 866Mitochondrial biogenesis is stimulated by muscular activity 834 T elomeres are replicated by telomerase, a specializedFuel choice during exercise is determined by the polymerase that carries its own RNA temp late 867intensity and duration of activity 835 28.4 Many Types of DNA Damage Can Be27.5 Food Intake and Starvation Induce Repaired 867Metabolic Changes 836 Errors can arise in D NA replication 867The starved-fed cycle is the physiological response Bases can be damaged by oxidizing agents , alkylatingto a fast 837 agents, and light 868

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Contents xxix

DNA damage can be detected and repaired by a Enhancer sequences can stimulate transcription at

variety of systems 869 start sites thousands of bases away 900The presence of thymine instead ofuracil in DNA

87129.3 The Transcription Products of Eukaryotic

perm its the repair of deaminated cytos ine Polymerases Are Processed 901Some genetic diseases are caused by the expansion RNA pol ymerase I produces three ribosomal RNAs 901of repeats of three nucleotides 872 RNApolymerase III produces transfer RNA 902Many cancers are caus ed by the defective repair Theproduct of RNA polymerase II, thepre-mRNAofDNA 872

transcript, acquires a 5' cap and a 3' poly(A ) tail 902Many potential carcinogens can be detected by their Small regulatory RNAs are cleaved from largermutagenic action on bacteria 873

prec ursors 90428.5 DNA Recombination Plays Important Roles RNA editingchanges theproteins encoded by mRNA 904in Replication, Repair, and Other Processes 874 Sequences at the ends of introns spe cify splice sitesRecA can initiate recombination by promoting strand in mRNA pre cursors 905invasion 874 Splicing consists of two sequential transesterificationSome recombination reactions proceed through reactions 906Holliday-junction intermediates 875 Small nuclear RNAs in spliceosomes catalyze the

splicing of mRNA precursors 907

Chapter 29 RNA Synthesis and Processing 883 Transcription and processing of m RNA are coupled 909Mutations that affect pre -mRNA splicing cause disease 909

RN A synthesis comprises three stages: Initiation , M ost human pre-mRNAS can be spliced in alternativeelongation, and termination 884 ways to yield different pro teins 910

29. 1 RNA Polymerases Catalyze Transcription 885 29.4 The Discovery of Catalytic RNA WasRNA chains are formed de novo and grow in the Revealing in Regard to Both Mechanism and5' -to-S' direction 886 Evolution 911RNA polymerases backtrack and correct errors 888RNA polymerase binds to promoter sites on the D NAtemplate to init iate transcription 888 Chapter 30 Protein Synthesis 921Sigma subunits of RNA polym erase recognize 30.1 Protein Synthesis Requires the Translationpromoter sites 889

of Nucleotide Sequences into Amino AcidRNA polymerases must unwind the templat e Sequences 922dou ble helix for transcrip tion to take place 890Elongat ion takes place at transcription bubbles

The synthesis of long pro te ins requires a low error

thatmovealong theDNAtemplate 890 frequency 922

Sequences within the newly transcribed RNA signalTransfer RN A molecules have a common design 923

termination 891 Some transfer RNA molecules recogn ize mo re than

Some messenger RNAs directly sense metaboliteone codon because of wobble in base-pairing 925

concentrations 892 30.2 Aminoacyl Transfer RNA SynthetasesThe rho protein helps to terminate the transcription Read the Genetic Code 927of some genes 892 Amino acids are first activated by adenylation 927Some antibiotics inhibit transcription 893 Aminoacyl-tRNA synthetases have highly discriminating

Precursors of tr ansfer and ribosomal RNA are amino acid acti vation sites 928cleaved and chemically modified aft er transcription Proofreading by aminoacyl-tRNA synthetases increasesin prokaryotes 895 the fidelity of protein synthesis 929

29.2 Transcription in Eukaryotes Is Highly Synthetases recognize variou s features of transfer RNA

Regulated 896 molecules 930

Three types ofRNApolymerase synthesize RNA in Aminoacyl-rk N z, synthetases can be divided into two

eukaryot ic cells 897 classes 931

Three common elements can be found in the RNA 30.3 The Ribosome Is the Site of Proteinpolymerase II promoter region 898 Synthesis 931The TFIID protein complex initiates the assembly of RibosomalRNAs (55, 165, and 235 rRNA)playa centralthe act ive transcription complex 899 role in protein synthesis 932M ultiple transcription factors interact with eukaryoti c Ribosom es have three tRNA-binding sites that bridgepromoters 900 the 30s and 50s subunit s 934

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The start signal is usually AUG preceded by severalbases that pair with 165 rRNA

Bacterial protein synthesis is initiated byformy lmethionyl transfer RNA

Formylmethionyl-tRNAris placed in the P site ofthe ribosome in the formation of the 70Sinitiation complex

Elongat ion factors deliver aminoacyl -tR NA to theribosome

Peptidyl transfera se catalyzes pep tide-bondsynthesis

T he formation of a peptide bond is followed by theGT P·driven translocation oftRNAs and mRN A

Protein synthesis is terminated by release factorsthat read stop codons

30.4 Eukaryotic Protein Synthesis Differsfrom Prokaryotic Protein Synthesis Primarilyin Translation InitiationMutat ions in initiation factor 2 cause a curiouspathological condition

30.5 A Variety of Antibiotics and Toxins CanInhibit Protein SynthesisSome antibiotics inhibit protein synthesis

Diphtheria toxin blocks protein synthesis in eukaryotesby inhibiting translocation

Ricin fatally modifi es 285 ribosomal RNA

30.6 Ribosomes Bound to the EndoplasmicReticulum Manufacture Secretory andMembrane ProteinsSignal sequences mark proteins for translocation acrossthe endoplasmic reticu lum membrane

Transport vesicl es carry cargo proteins to their finaldestination

Chapter 31 The Control of Gene Expressionin Prokaryotes

31.1 Many DNA-Binding Proteins RecognizeSpecific DNA SequencesThe helix -turn -helix motif is common to manyprokaryotic D NA-binding proteins

31.2 Prokaryotic DNA-Binding Proteins BindSpecifically to Regulatory Sites in OperonsAn operon consists of regulatory elements andprotein -encoding genes

The lac repressor protein in the absence of lactosebinds to the operator and blocks transcription

Ligand binding can induce structural changes inregulatory proteins

The operon is a common regulatory unit inprokaryotes

T ranscription can be stimulated by proteins thatcontact RN A polymerase

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31.3 Regulatory Circuits Can Result in SwitchingBetween Patterns of Gene ExpressionLambda repressor regulates its own express ion

A circuit based on lambda repressor and Cro forma genetic switch

Many prokaryotic cells release chemical signals thatregulate gene expression in other cells

Biofilms are complex comm unities of prokaryotes

31.4 Gene Expression Can Be Controlled atPosttranscriptional LevelsAttenuation is a prokaryot ic mechanism for regulatingtranscription through the modulation of nascentRNA secondary structure

cbepter sz The Control of Gene Expressionin Eukaryotes

32.1 Eukaryotic DNA Is Organized intoChromatinN ucleosomes are com plexes of DNA and histones

D N A wraps around histone octamers to formnucleosomes

32.2 Transcription Factors Bind DNA andRegulate Transcription InitiationA range of D NA-bindin g structures are employedby eukaryotic D NA-bindin g proteins

Activation domains interact with other proteins

Multiple transcription factors interact with eukaryoticregulatory regions

Enhancers can stimulate transcription in spec ificcell types

Induced pluripotent stem cells can be generated byintroducing four transcription factors intodifferent iated cells

32.3 The Control of Gene Expression CanRequire Chromatin RemodelingThe methylation of DN A can alter patterns ofgeneexpression

Steroids and related hydrophobic molecules passthrough membran es and bind to DNA -binding receptors

N uclear hormone receptors regulate transcription byrecruiting coactivators to the transcription complex

Steroid-hormone receptors are targets for drugs

Chromatin structure is modul ated through covalentmodifications of histone tails

Histone deacetylases contribute to transcriptionalrepresston

32.4 Eukaryotic Gene Expression Can BeControlled at Posttranscriptional LevelsGenes associated with iron metabolism aretranslationally regulated in animals

Small RN As regulate the express ion of manyeukaryotic genes

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Part IV RESPONDING TO 34.1 Antibodies Possess Distinct

ENVIRONMENTAL CHANGES Antigen-Binding and Effector Units 1021

34.2 Antibodies Bind Specific MoleculesChapter 33 Sensory System s 995 Through Hypervariable Loops 1023

33.1 A Wide Variety of Organic CompoundsThe immunoglobulin fold cons ists of a beta-s andwichframework with hypervariable loops 1024

Are Detected by Olfaction 996Xcray analyses have revealed how ant ibodies

Olfaction is mediated by an enormous family of bind antigens 1024seven. transmembrane-helix receptors 996

Large antigens bind antibodies with numerousOdoran ts are decoded by a combinatorial mechanism 998 interactions 1026

33.2 Taste Is a Combination of Senses That 34.3 Diversity Is Generated by GeneFunction by Different Mechanisms 1000 Rearrangements 1027Sequencing of the human genome led to the

1001J (joining) genes and D (diversity) genes increase

discovery of a large fami ly of7TM bitter receptors antibody diversity 1027A heterodimeric 7TM receptor responds to sweet More than 108 antibodies can be formed bycompounds 1002 combinatorial association and somatic mutation 1028Umami, the taste of glutamate and aspartate, is The oligomerization ofantibodies expressed on themediated by a heterodimeric receptor related to surfaces ofimmature B cells triggers antibody secretion 1029the sweet receptor 1003

Different classes of antibodies are formed bySalty tas tes are detected primarily by the passage of the hopping of VH genes 1030sodium ions th rough channels 1003

34.4 Major-Histocompatibility-ComplexSour tastes arise from the effects of hydrogen

Proteins Present Peptide Antigens on Cellions (acids) on channels 1003Surfaces for Recognition by T-Cell Receptors 1031

33.3 Photoreceptor Molecules in the EyePeptides presented by MHC proteins occupy a deep

Detect Visible Light 1004groove flanked by alpha helices 1032

Rhodopsin, a specialized 7TM receptor, absorbs T -cell receptors are antibody-like proteinsvisible light 1004 containing variable and constant regions 1034Ligh t absorption induces a spec ific isomerization of

CDS on cytotoxic T cells acts in concert withbound ll -cis-retinal 1005

T -cell receptors 1034Light -induced lowering of the calciu m level Helper T cells st imulate cells that display fore igncoordinates recovery 1006

peptides bound to class 11 MHC proteins 1036Color vision is me diated by three cone receptors Helper T cells rely on the T-cell receptor and CD4 tothat are homologs of rhodopsin 1007

recognize foreign peptides on an tigen-presenting cells 1036Rearrangements in the genes for the green and

MHC proteins are highly diverse 1038red pigments lead to "co lor blindness 1008

H uman immunodeficiency viruses subvert the33.4 Hearing Depends on the Speedy immune system by destroying helper T cells 1039Detection of Mechanical Stimuli 1009 34.5 The Immune System Contributes to theHair cells use a connected bundle of stereocilia to Prevention and the Development of Humandetect tiny motions 1009

Diseases 1040Mechanosensory channels have been identified in

T cells are subjected to positive and negativeDrosophilaand vertebrates 1010selection in the thymus 1040

33.5 Touch Includes the Sensing of Pressure, Autoimmune diseases result from the generationTemperature, and Other Factors 1011 of immune responses against self-antigens 1041Studies of capsaicin reveal a receptor for sensing T he immune system plays a role in cancer prevention 1041high temperatures and other painful stimuli 1011 Vaccines are a powerful means to prevent andMore sensory systems remain to be studied 1012 eradicate disease 1042

Chapter 34 The Imm une System 1017 Chapter 35 Mo lecular Motors 1049

Innate immunity is an evolutionarily ancient 35.1 Most Molecular-Motor Proteins Aredefense system 1018 Members of the P-Loop NTPase Superfamily 1050The adaptive immune system responds by using Molecular mo tors are generally oligomeric proteinsthe principles of evolution 1019 with an ATPase core and an extended structure 1050

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ATP binding and hydrolysis induce changes in theconformation and binding affinity ofmotor proteins

15.2 Myosins Move Along Actin FilamentsActin is a polar, self-assembling, dynamic polymer

Myosin head domains bind to actin filaments

Motions of single motor proteins can be directlyobserved

Phosphate release triggers the myosin power stroke

Muscle is a complex of myosin and actin

The length of the lever arm determ ines motorvelocity

15.1 Kinesin and Dynein Move AlongMicrotubulesMicrotubules are hollow cylindrical polymers

Kinesin motion is highly processive

15.4 A Rotary Motor Drives Bacterial MotionBacteria swim by rotating their flagella

Proton flow drives bacterial flagellar rotat ion

Bacterial chemotaxis depends on reversal of thedirection of flagellar rotation

Chapter 16 Drug Development

16.1 The Development of Drugs PresentsHuge ChallengesDrug candidates must be potent modulators oftheir targets

Drugs must have suitable properties to reach theirtargets

Toxicity can limit drug effectiveness

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105410541056

105610571057

1060

106010601062

106410641064

1066

1073

1074

1074

10751080

16.2 Drug Candidates Can Be Discoveredby Serendipity, Screening, or DesignSerendipitous observations can drive drugdevelopment

Screening libraries of compounds can yield drugsor drug leads

Drugs can be designed on the basis ofthree-dimensional structural informationabout their targets

16.1 Analyses of Genomes Hold GreatPromise for Drug DiscoveryPotential targets can be identified in the humanproteome

Animal models can be developed to test thevalidity of potential drug targets

Potential targets can be identified in the genomesof pathogens

Genetic differences influence individual responsesto drugs

16.4 The Development of Drugs ProceedsThrough Several StagesClinical trials are time consuming and expensive

The evolution of drug resistance can limitthe utility of drugs for infectious agentsand cancer

Answers to Problems

Index

10E

101

10l

10,

108

108

109

109

109

109:109:

109'

Ai

B1