Detailed Contents 12.5 How Does High-Thro Catalysts Lower the Free Energy ofActivation Allow Global Study of Millions of Genes o for a Reaction 443 Molecules at Once?420 Decreasing AG Increases Reaction Rate 444 High-Throughput Screening 42 13.3 What Equations Define the Kinetic DNA Laser Printing 421 of Enzyme-Catalyzed Reactions?444 The Substrate Binds at the Active Site of an Enzyme 445 2.6 an Enzymatic Reaction 445 stant During etic Deficiencies 423 Assume That Velocity Measurements Are Made Imm iately After Adding S446 onstant,K.Is Defined as 12.7 What Is the New Field of Synthetic Biology?425 Plots of Versus [S]llustrate the Relationships Between DNA as Code 425 V.K-.and Reaction Order 447 iGEM and BioBricks(Registry of Standard iological Parts)425 Ner Defines the Activity of One Ezyme Metabolic The Ratio.KDefines the Catalytic Efficienc) of an Enzyme 449 Genome Prokaryoti nBe eh- a Pr -Woolf Plots Are 428 A5 Synthetic Genomes 430 ongly Influenced by pH 451 SUMMARY 430 A DEEPER LOOK:An Ex e of the Effect of Amino Acid FOUNDATIONAL BIOCHEMISTRY 432 Substitutions onK. and Wild. ype and Mutant PROBLEMS 433 H FURTHER READING 434 Is Complex 453 34 What Can Be lear med from the Inhibition of Enzyme Activity?453 PART II PROTEIN DYNAMICS Enzymes May Be Inhibited Reversibly or Irreversibly 453 13 Enzymes-Kinetics and Specificity 437 Enzymes Are the Agents of Metabolic Function 438 13.1 What Characteristic Features Define Enzymes?438 The of Competitive ataly 13.5 What rof Enzymes Catalyzing UMAN BIOC EMISTRY.Vi Regulation of Enzyme Activity Ensures That the Rate s Appropriate to Cellua The Conversion of AEB to PEQ Is the Rate- clature Provides a Systematic Wa of Naming Metabolic Reactions439 the Leadin Substate Must Bind First 461 9 Coenzymes and Cofactors Are Nonprotein Components Essential to Enzyme Activity 440 oa 13.2 oAre One Way to Diagnose Be Def d in a Ma Multisubstrate Reactions Can Also Occur in Cells 465 13.6 How Can E mes Be S Reactant Molecules 442 s Are Reactions Involving Two Hypothesis Was the First Explanatio
Detailed Contents xiii 12.5 How Does High-Throughput Technology Allow Global Study of Millions of Genes or Molecules at Once? 420 High-Throughput Screening 421 DNA Laser Printing 421 High-Throughput RNAi Screening of Mammalian Genomes 422 High-Throughput Protein Screening 422 12.6 Is It Possible to Make Directed Changes in the Heredity of an Organism? 422 Human Gene Therapy Can Repair Genetic Deficiencies 423 Viruses as Vectors in Human Gene Therapy 423 Human Biochemistry: The Biochemical Defects in Cystic Fibrosis and ADA2 SCID 424 12.7 What Is the New Field of Synthetic Biology? 425 DNA as Code 425 iGEM and BioBricks (Registry of Standard Biological Parts) 425 Metabolic Engineering 426 Genome Engineering 427 Genome Editing with CRISPR/Cas9 427 CRITICAL DEVELOPMENTS IN BIOCHEMistry: CRISPR/Cas9—Exploiting the Biology of Prokaryotic Adaptive Immunity to Edit Genomes 428 Synthetic Genomes 430 SUMMARY 430 Foundational Biochemistry 432 PROBLEMS 433 Further Reading 434 Part II Protein Dynamics 13 Enzymes—Kinetics and Specificity 437 Enzymes Are the Agents of Metabolic Function 438 13.1 What Characteristic Features Define Enzymes? 438 Catalytic Power Is Defined as the Ratio of the EnzymeCatalyzed Rate of a Reaction to the Uncatalyzed Rate 438 Specificity Is the Term Used to Define the Selectivity of Enzymes for Their Substrates 439 Regulation of Enzyme Activity Ensures That the Rate of Metabolic Reactions Is Appropriate to Cellular Requirements 439 Enzyme Nomenclature Provides a Systematic Way of Naming Metabolic Reactions 439 Coenzymes and Cofactors Are Nonprotein Components Essential to Enzyme Activity 440 13.2 Can the Rate of an Enzyme-Catalyzed Reaction Be Defined in a Mathematical Way? 441 Chemical Kinetics Provides a Foundation for Exploring Enzyme Kinetics 441 Bimolecular Reactions Are Reactions Involving Two Reactant Molecules 442 Catalysts Lower the Free Energy of Activation for a Reaction 443 Decreasing DG‡ Increases Reaction Rate 444 13.3 What Equations Define the Kinetics of Enzyme-Catalyzed Reactions? 444 The Substrate Binds at the Active Site of an Enzyme 445 The Michaelis–Menten Equation Is the Fundamental Equation of Enzyme Kinetics 445 Assume That [ES] Remains Constant During an Enzymatic Reaction 445 Assume That Velocity Measurements Are Made Immediately After Adding S 446 The Michaelis Constant, Km , Is Defined as (k21 1 k2)/k1 446 When [S] 5 Km , v 5 Vmax /2 447 Plots of v Versus [S] Illustrate the Relationships Between Vmax , Km , and Reaction Order 447 Turnover Number Defines the Activity of One Enzyme Molecule 448 The Ratio, kcat /Km , Defines the Catalytic Efficiency of an Enzyme 449 Linear Plots Can Be Derived from the Michaelis–Menten Equation 450 Nonlinear Lineweaver–Burk or Hanes–Woolf Plots Are a Property of Regulatory Enzymes 451 Enzymatic Activity Is Strongly Influenced by pH 451 A Deeper Look: An Example of the Effect of Amino Acid Substitutions on Km and kcat: Wild-Type and Mutant Forms of Human Sulfite Oxidase 452 The Response of Enzymatic Activity to Temperature Is Complex 453 13.4 What Can Be Learned from the Inhibition of Enzyme Activity? 453 Enzymes May Be Inhibited Reversibly or Irreversibly 453 Reversible Inhibitors May Bind at the Active Site or at Some Other Site 453 A Deeper Look: The Equations of Competitive Inhibition 455 Enzymes Also Can Be Inhibited in an Irreversible Manner 458 13.5 What Is the Kinetic Behavior of Enzymes Catalyzing Bimolecular Reactions? 459 Human Biochemistry: Viagra—An Unexpected Outcome in a Program of Drug Design 459 The Conversion of AEB to PEQ Is the Rate-Limiting Step in Random, Single-Displacement Reactions 460 In an Ordered, Single-Displacement Reaction, the Leading Substrate Must Bind First 461 Double-Displacement (Ping-Pong) Reactions Proceed Via Formation of a Covalently Modified Enzyme Intermediate 462 Exchange Reactions Are One Way to Diagnose Bisubstrate Mechanisms 464 Multisubstrate Reactions Can Also Occur in Cells 465 13.6 How Can Enzymes Be So Specific? 465 The “Lock and Key” Hypothesis Was the First Explanation for Specificity 465 Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it
xiv Detailed Contents The ind Hypothes Providesa More Accurate Transiti of the Transition State466 The Mechanism of Action of Asnartic Proteases 500 Specificity and Reactivity 466 The AIDS Virus HIV-1 Protease Is an Aspartic Protease 501 3.7 Are All E e)466 Chorismate Mutase:A Model for Understanding Are Catalytic Have Been Termed Catalytic Power and Efficiency 502 "Ribozymes"466 Antibody Molecules Can Have Catalytic Activity 469 tADCnggRrProeasenhbiosGnet 13.8 Is It Possible to Design an Enzyme to Catalyze Any Desired Reaction?470 FOUNDATIONAL BIOCHEMISTRY 507 SUMMARY 471 PROBLEMS 508 fOUNDATIONAL BIOCHEMISTRY 472 FURTHER READING 510 PROBIEMS 473 FURTHER READING 475 15 Enzyme Regulation 513 15.1 What Factors Influence Enzymatic Activity?513 14 Mechanisms of Enzyme Action 477 The Availability of Substrates and Cofactors 14.1 What Are the Magnitudes of Enzyme-Induced Rate Accelerations?477 14.2 arent Rat What Role Does Transition-State Stabilization Play in ease 514 Enzyme Catalysis?479 14.3 How Does Destabilization of ES Affect Enzyme Moment 514 Catalysis?480 Enzyme Activity Can Be Regulated Allosterically 514 14.4 How Tightly Do Transition-State Analogs Bind to the Active Site?481 yCan Be Regulated Through Covalen eActivity Also Can Be Accomplished 14.5 What Are the Mechanisms of Catalysis?485 Zymogens Are Inactive Precursors of Enzymes 515 of Near-Attack Isozymes Are Enzymes with Slightly Different Subunits 516 15.2 What Are the General Features of Allosteric Essential to En e Catalysis 485 Regulation?518 A DEEPER LOOK:Hov 486 Regulatory Enzymes Have Certain Exceptional Properties 518 Covalent Catalysis 488 15.3 Can Allosteric Regulation Be Explained eral Acid-Ba Low-Barrier Hvd by Conformational Changes in Proteins?519 Quantum Mechanical Tunneling in Electron and Proton Transfers 491 on Ligand-Induced Conformationa Changes 520 Is Based Do Active-Site Residues Interact 154 to Support catalysis?492 What Kinds of Covalent Modification Regulate the Activity of Enzymes?521 Through Reversible 4.6 What Can Be Control 521 The Digestive Serine Proteases 494 The Chy otrypsin Mechanism in Detail:Kinetics 495 a10 The Serine Protease Mechanism in Detail:Events 15.5 at the Active Site 497 The Aspartic Proteases 497 Modification?525
xiv Detailed Contents The “Induced Fit” Hypothesis Provides a More Accurate Description of Specificity 465 “Induced Fit” Favors Formation of the Transition State 466 Specificity and Reactivity 466 13.7 Are All Enzymes Proteins? 466 RNA Molecules That Are Catalytic Have Been Termed “Ribozymes” 466 Antibody Molecules Can Have Catalytic Activity 469 13.8 Is It Possible to Design an Enzyme to Catalyze Any Desired Reaction? 470 SUMMARY 471 Foundational Biochemistry 472 PROBLEMS 473 Further Reading 475 14 Mechanisms of Enzyme Action 477 14.1 What Are the Magnitudes of Enzyme-Induced Rate Accelerations? 477 14.2 What Role Does Transition-State Stabilization Play in Enzyme Catalysis? 479 14.3 How Does Destabilization of ES Affect Enzyme Catalysis? 480 14.4 How Tightly Do Transition-State Analogs Bind to the Active Site? 481 A Deeper Look: Transition-State Analogs Make Our World Better 482 14.5 What Are the Mechanisms of Catalysis? 485 Enzymes Facilitate Formation of Near-Attack Conformations 485 Protein Motions Are Essential to Enzyme Catalysis 485 A Deeper Look: How to Read and Write Mechanisms 486 Covalent Catalysis 488 General Acid–Base Catalysis 489 Low-Barrier Hydrogen Bonds 490 Quantum Mechanical Tunneling in Electron and Proton Transfers 491 HUMAN BIOCHEMISTRY: Antibiotic Resistance by Superbugs 491 Metal Ion Catalysis 492 A Deeper Look: How Do Active-Site Residues Interact to Support Catalysis? 492 CRITICAL DEVELOPMENTS IN BIOCHEMistry: Measuring the Electric Fields That Accelerate an Enzyme Reaction 493 14.6 What Can Be Learned from Typical Enzyme Mechanisms? 494 Serine Proteases 494 The Digestive Serine Proteases 494 The Chymotrypsin Mechanism in Detail: Kinetics 495 The Serine Protease Mechanism in Detail: Events at the Active Site 497 The Aspartic Proteases 497 A Deeper Look: Transition-State Stabilization in the Serine Proteases 499 The Mechanism of Action of Aspartic Proteases 500 The AIDS Virus HIV-1 Protease Is an Aspartic Protease 501 Chorismate Mutase: A Model for Understanding Catalytic Power and Efficiency 502 Human Biochemistry: Protease Inhibitors Give Life to AIDS Patients 504 SUMMARY 507 Foundational Biochemistry 507 PROBLEMS 508 Further Reading 510 15 Enzyme Regulation 513 15.1 What Factors Influence Enzymatic Activity? 513 The Availability of Substrates and Cofactors Usually Determines How Fast the Reaction Goes 514 As Product Accumulates, the Apparent Rate of the Enzymatic Reaction Will Decrease 514 Genetic Regulation of Enzyme Synthesis and Decay Determines the Amount of Enzyme Present at Any Moment 514 Enzyme Activity Can Be Regulated Allosterically 514 Enzyme Activity Can Be Regulated Through Covalent Modification 514 Regulation of Enzyme Activity Also Can Be Accomplished in Other Ways 515 Zymogens Are Inactive Precursors of Enzymes 515 Isozymes Are Enzymes with Slightly Different Subunits 516 15.2 What Are the General Features of Allosteric Regulation? 518 Regulatory Enzymes Have Certain Exceptional Properties 518 15.3 Can Allosteric Regulation Be Explained by Conformational Changes in Proteins? 519 The Symmetry Model for Allosteric Regulation Is Based on Two Conformational States for a Protein 519 The Sequential Model for Allosteric Regulation Is Based on Ligand-Induced Conformational Changes 520 Changes in the Oligomeric State of a Protein Can Also Give Allosteric Behavior 521 15.4 What Kinds of Covalent Modification Regulate the Activity of Enzymes? 521 Covalent Modification Through Reversible Phosphorylation 521 Protein Kinases: Target Recognition and Intrasteric Control 521 Phosphorylation Is Not the Only Form of Covalent Modification That Regulates Protein Function 523 Acetylation Is a Prominent Modification for the Regulation of Metabolic Enzymes 524 15.5 Is the Activity of Some Enzymes Controlled by Both Allosteric Regulation and Covalent Modification? 525 Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it
Detailed Contents The glcogen phosphorylase reaction con 16 Molecular Motors 547 16.1 What Is a Molecular Motor?547 Glycogen ses a Homodi 16.2 What Is the Molecular Mechanism of Muscle Contraction?548 Covalent Modification of Glycogen Phosphorylase Trumps Allosteric Regulation 528 Glycogen Phosphorylase The molecular structure of skeletal muscle is Based ature Tha on Actin and Myosin 549 Structure and the fmergence of allosteric pro hedct2nimoMstecoatacionlsBased ties? Hemoglobin and Myoglobin Paradigms of Proteir The P.Loop NTPases-Energy to Run Structure and Function 529 the Motors 552 HUMAN BIOCHEMISTRY:The Molecular Defect tery 530 in D hy Involves Binds to the Mb Heme Group 531 O,Binding Alters Mb Conformation 531 ce557 A DEEPER LOOK:The Oxy 16.3 What Are the Molecular Motors That Or chestrate the Mechanochemistry of Microtubules?55 Cooperative ofOxygen by H Cytoskeleton Are Highways That Move ure 533 of Motr Proteins Move Cargo 560 n by Less Than 0.04 nm on as mational nHemoglobin 53 Cytoskeletal Motors Are Highly Processive 563 gn8medcgDmehndoeand RY:D overing the"Tubuln Code56 neins Movemen Hem 16.4 How Do Molecular Mot eDissociation of ,eintheHeme lon A DEERERI0OK.Cha Papillomavirus El Helicase Moves along DNA on a Spiral Staircase 570 Zci6phSpteoeb5ge57nmportantAlosieic 16.5 How Do Bacterial Flagella Use a Proton Gradient to Drive Rotation?573 BPC Binding to Hb Has Important Physiological Significance 538 The Flagellar Rotor Is a Complex Structure 574 radients of H+and Na'Drive Flagellar Rotors 574 BPG 53 SefAssembles ina Spontaneous Her nts Are Composed of Protofilaments of Flagellin 575 Sickle-Cell Anemia is a molecular Disease 540 ment Proteins 5. SUMMARY 541 FOUNDATIONAL BIOCHEMISTRY 542 SUMMARY 578 PROBLEMS FOUNDATIONAL BIOCHEMISTRY 579 543 PROBLEMS 579 FURTHER READING 544 FURTHER READING 580
Detailed Contents xv The Glycogen Phosphorylase Reaction Converts Glycogen into Readily Usable Fuel in the Form of Glucose-1-Phosphate 525 Glycogen Phosphorylase Is a Homodimer 525 Glycogen Phosphorylase Activity Is Regulated Allosterically 526 Covalent Modification of Glycogen Phosphorylase Trumps Allosteric Regulation 528 Enzyme Cascades Regulate Glycogen Phosphorylase Covalent Modification 528 Special Focus: Is There an Example in Nature That Exemplifies the Relationship Between Quaternary Structure and the Emergence of Allosteric Properties? Hemoglobin and Myoglobin—Paradigms of Protein Structure and Function 529 The Comparative Biochemistry of Myoglobin and Hemoglobin Reveals Insights into Allostery 530 Myoglobin Is an Oxygen-Storage Protein 531 O2 Binds to the Mb Heme Group 531 O2 Binding Alters Mb Conformation 531 A Deeper Look: The Oxygen-Binding Curves of Myoglobin and Hemoglobin 532 Cooperative Binding of Oxygen by Hemoglobin Has Important Physiological Significance 533 Hemoglobin Has an a2b2 Tetrameric Structure 533 Oxygenation Markedly Alters the Quaternary Structure of Hb 534 Movement of the Heme Iron by Less Than 0.04 nm Induces the Conformational Change in Hemoglobin 534 A Deeper Look: The Physiological Significance of the Hb∶O2 Interaction 535 The Oxy and Deoxy Forms of Hemoglobin Represent Two Different Conformational States 535 The Allosteric Behavior of Hemoglobin Has Both Symmetry (MWC) Model and Sequential (KNF) Model Components 535 H1 Promotes the Dissociation of Oxygen from Hemoglobin 536 CO2 Also Promotes the Dissociation of O2 from Hemoglobin 536 A Deeper Look: Changes in the Heme Iron upon O2 Binding 537 2,3-Bisphosphoglycerate Is an Important Allosteric Effector for Hemoglobin 537 BPG Binding to Hb Has Important Physiological Significance 538 Fetal Hemoglobin Has a Higher Affinity for O2 Because It Has a Lower Affinity for BPG 538 Human Biochemistry: Hemoglobin and Nitric Oxide 539 Sickle-Cell Anemia Is Characterized by Abnormal Red Blood Cells 540 Sickle-Cell Anemia Is a Molecular Disease 540 SUMMARY 541 Foundational Biochemistry 542 PROBLEMS 543 Further Reading 544 16 Molecular Motors 547 16.1 What Is a Molecular Motor? 547 16.2 What Is the Molecular Mechanism of Muscle Contraction? 548 Muscle Contraction Is Triggered by Ca21 Release from Intracellular Stores 548 Human Biochemistry: Smooth Muscle Effectors Are Useful Drugs 549 The Molecular Structure of Skeletal Muscle Is Based on Actin and Myosin 549 The Mechanism of Muscle Contraction Is Based on Sliding Filaments 552 A Deeper Look: The P-Loop NTPases—Energy to Run the Motors 552 Human Biochemistry: The Molecular Defect in Duchenne Muscular Dystrophy Involves an Actin-Anchoring Protein 553 Critical Developments in Biochemistry: Molecular “Tweezers” of Light Take the Measure of a Muscle Fiber’s Force 557 16.3 What Are the Molecular Motors That Orchestrate the Mechanochemistry of Microtubules? 558 Filaments of the Cytoskeleton Are Highways That Move Cellular Cargo 558 Three Classes of Motor Proteins Move Intracellular Cargo 560 Human Biochemistry: Effectors of Microtubule Polymerization as Therapeutic Agents 561 Dyneins Move Organelles in a Plus-to-Minus Direction; Kinesins, in a Minus-to-Plus Direction—Mostly 563 Cytoskeletal Motors Are Highly Processive 563 ATP Binding and Hydrolysis Drive Hand-over-Hand Movement of Kinesin 564 Human Biochemistry: Discovering the “Tubulin Code” 566 The Conformation Change That Leads to Movement Is Different in Myosins and Dyneins 567 16.4 How Do Molecular Motors Unwind DNA? 568 Negative Cooperativity Facilitates Hand-over-Hand Movement 569 Papillomavirus E1 Helicase Moves along DNA on a Spiral Staircase 570 16.5 How Do Bacterial Flagella Use a Proton Gradient to Drive Rotation? 573 The Flagellar Rotor Is a Complex Structure 574 Gradients of H1 and Na1 Drive Flagellar Rotors 574 The Flagellar Rotor Self-Assembles in a Spontaneous Process 575 Flagellar Filaments Are Composed of Protofilaments of Flagellin 575 Motor Reversal Involves Conformation Switching of Motor and Filament Proteins 576 SUMMARY 578 Foundational Biochemistry 579 PROBLEMS 579 Further Reading 580 Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it
xvi Detailed Contents PART II METABOLISM AND ITS REGULATION 18 Glycolysis 611 181 What Are the Essential Features of Glycolysis?611 17 Metabolism:An Overview 583 Why Are Coupled 18.3 s Exhibit Metab en Is Essential to Life for Aerobes 584 The he Carbor A DEEPER LOOK:Glucokin -An Enzy ewith Differen e58goeakumGbonaABoogtalsnt Roles in Different Cells 617 17.2 What Can Be Learned from Metabolic Maps?585 Rtom2phopb92co0pe TeMetaboi Map Can Be Viewedsa Set of Dots A DEEPER LOOK:Phosphoglucoisomerase- A Moonlighting Protein 620 Multienzyme Systems May Take Different Forms 589 phate Aldolas 17.3 How Do Anabolic and Catabolic Processes Form the 62 Core of Metabolic Pathways?590 Anabolism Is Biosynthesis 590 gGaomeMu 18.4 What Are the Chemical Principles and Features of the Second Phase of Glycolysis?622 Reaction 6:Glyceraldehyde-3-Phosphate Dehydrogenase reates a H n-Energy Inter mediate 62 Anabolic Pathways Diverge,Synthesizing an Astounding sthe Break-Even Reaction 8:Phosphoglycerate mutase catalyzes Amphibolic Intermediates play Dual Roles 593 a Phosphoryl Transfer 625 fCatabolism and Anabolism Reaction9:Dehydration by Enolase Creates PEP625 Reaction 10:Pyruvate Kinase Yields More ATP 626 ATP Serves in a Cellular Energy Cycle593 NADCollects Electrons Released in Catabolism 594 18.5 Are the s of NA 2629 olism of Py t or Ethanol 629 to Lactate 17.4 What Expe Lactate Accumulates Under Anaerobic Conditions Tissues 62 Mutations create Snecific Metabolic Blocks 597 Isotopic Tracers Can Be Used as Metabolic Probes 598 NMR Spectroscopy is a noninvasive metabolic Probe 599 The Old Shell Game- -How Turtles Survive the Vinter 632 18.6 How Do Cells Regulate Glycolysis?632 17.5 What Can the Metabolome Tell Us about a Biological Are Substrates Other Than Glucose Used System?602 in Glycolysis?632 17.6 行om hm Harm nnose En a ohydrates Provide Metabolc tose Ente via the Leloir Pathway 633 An Enzyme Deficiency Causes Lactose Intolerance 636 FOUNDATIONAL BIOCHEMISTRY 607 Glycerol Can Also Enter Glycolysis 636 PROBLEMS 608 HUMAN BIOCHEMISTRY:Lact om Mother's Milk FURTHER READING 609 to Yogurt-and Lactose Intolerance 636
xvi Detailed Contents Part III Metabolism and Its Regulation 17 Metabolism: An Overview 583 17.1 Is Metabolism Similar in Different Organisms? 583 Living Things Exhibit Metabolic Diversity 584 Oxygen Is Essential to Life for Aerobes 584 The Flow of Energy in the Biosphere and the Carbon and Oxygen Cycles Are Intimately Related 584 A Deeper Look: Calcium Carbonate—A Biological Sink for CO2 585 17.2 What Can Be Learned from Metabolic Maps? 585 The Metabolic Map Can Be Viewed as a Set of Dots and Lines 585 Alternative Models Can Provide New Insights into Pathways 588 Multienzyme Systems May Take Different Forms 589 17.3 How Do Anabolic and Catabolic Processes Form the Core of Metabolic Pathways? 590 Anabolism Is Biosynthesis 590 Anabolism and Catabolism Are Not Mutually Exclusive 591 The Pathways of Catabolism Converge to a Few End Products 591 Anabolic Pathways Diverge, Synthesizing an Astounding Variety of Biomolecules from a Limited Set of Building Blocks 591 Amphibolic Intermediates Play Dual Roles 593 Corresponding Pathways of Catabolism and Anabolism Differ in Important Ways 593 ATP Serves in a Cellular Energy Cycle 593 NAD1 Collects Electrons Released in Catabolism 594 NADPH Provides the Reducing Power for Anabolic Processes 595 Coenzymes and Vitamins Provide Unique Chemistry and Essential Nutrients to Pathways 595 17.4 What Experiments Can Be Used to Elucidate Metabolic Pathways? 597 Mutations Create Specific Metabolic Blocks 597 Isotopic Tracers Can Be Used as Metabolic Probes 598 NMR Spectroscopy Is a Noninvasive Metabolic Probe 599 Metabolic Pathways Are Compartmentalized Within Cells 600 17.5 What Can the Metabolome Tell Us about a Biological System? 602 17.6 What Food Substances Form the Basis of Human Nutrition? 605 Humans Require Protein 605 Carbohydrates Provide Metabolic Energy 606 Lipids Are Essential, but in Moderation 606 SUMMARY 606 Foundational Biochemistry 607 PROBLEMS 608 Further Reading 609 18 Glycolysis 611 18.1 What Are the Essential Features of Glycolysis? 611 18.2 Why Are Coupled Reactions Important in Glycolysis? 613 18.3 What Are the Chemical Principles and Features of the First Phase of Glycolysis? 614 Reaction 1: Glucose Is Phosphorylated by Hexokinase or Glucokinase—The First Priming Reaction 614 A Deeper Look: Glucokinase—An Enzyme with Different Roles in Different Cells 617 Reaction 2: Phosphoglucoisomerase Catalyzes the Isomerization of Glucose-6-Phosphate 618 Reaction 3: ATP Drives a Second Phosphorylation by Phosphofructokinase—The Second Priming Reaction 619 A Deeper Look: Phosphoglucoisomerase— A Moonlighting Protein 620 Reaction 4: Cleavage by Fructose Bisphosphate Aldolase Creates Two 3-Carbon Intermediates 620 Reaction 5: Triose Phosphate Isomerase Completes the First Phase of Glycolysis 621 18.4 What Are the Chemical Principles and Features of the Second Phase of Glycolysis? 622 Reaction 6: Glyceraldehyde-3-Phosphate Dehydrogenase Creates a High-Energy Intermediate 622 Reaction 7: Phosphoglycerate Kinase Is the Break-Even Reaction 624 Reaction 8: Phosphoglycerate Mutase Catalyzes a Phosphoryl Transfer 625 Reaction 9: Dehydration by Enolase Creates PEP 625 Reaction 10: Pyruvate Kinase Yields More ATP 626 HUMAN BIOCHEMISTRY: Pyruvate Kinase M2— A Moonlighting Protein Kinase in Cancer 628 18.5 What Are the Metabolic Fates of NADH and Pyruvate Produced in Glycolysis? 629 Anaerobic Metabolism of Pyruvate Leads to Lactate or Ethanol 629 Lactate Accumulates Under Anaerobic Conditions in Animal Tissues 629 Critical Developments in Biochemistry: The Warburg Effect and Cancer 631 The Old Shell Game—How Turtles Survive the Winter 632 18.6 How Do Cells Regulate Glycolysis? 632 18.7 Are Substrates Other Than Glucose Used in Glycolysis? 632 Fructose Catabolism in Liver is Unregulated—and Potentially Harmful 632 Mannose Enters Glycolysis in Two Steps 633 Galactose Enters Glycolysis via the Leloir Pathway 633 Human Biochemistry: Tumor Diagnosis Using Positron Emission Tomography (PET) 634 An Enzyme Deficiency Causes Lactose Intolerance 636 Glycerol Can Also Enter Glycolysis 636 Human Biochemistry: Lactose—From Mother’s Milk to Yogurt—and Lactose Intolerance 636 Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it
Detailed Contents 18.8 How Do Cells Respond to Hypoxic Stress?637 HUMAN BIOCHEMISTRY:TCA Metabolites play roles in SUMMARY 638 Many Pathways Via Post-Translational Modifications 669 FOUNDATIONAL BIOCHEMISTRY 639 The TCA Cycle Operates as a Metabolon 669 PROBLEMS 639 19.9 Can Any Organisms Use Acetate as Their Sole Carbon FURTHER READING 64 Source?670 The Glyoxylate Cycle Operates in Spe 19 The Tricarboxylic Acid Cycle 643 19.1 What Is the Chemical Logic of the TCA Cycle?644 The TCA Cycle Provides a Che The Glyoxylate Cycle Helps Plants Grow in the Dark 672 Muret Ror 19.2 How Is Pyruvate Oxidatively Decarboxylated SUMMARY 673 to Acetyl-CoA)645 FOUNDATIONAL BIOCHEMISTRY 674 PROBLEMS 674 193 FURTHER READING 675 20 Electron Transport and Oxidative The Citrate Synthase Reaction the TCA Phosphorylation 679 Citrate Is so rized by Aco 20.1 ron I 679 19.4 How Is Oxaloacetate Regenerated to Complete Disease the TCA Cycle?656 Matrix Contains the Enzymes Succinate Dehydrogenase Is FAD-De ndent 657 20.2 How s the Electron-ar ChainOr anized?682 Th EL on of Fu to Form Malate65 in Four Complexes68 Complex l Oxidizes NAdH and Reduces coenzyme o 683 Completes the Cycle 19.5 Our Treatment ase 685 What Are the Energetic Consequences of the TCA eSuccinate and Reduces lexl Mediates Electron Transport from CoenzymeQ The Carbon Atoms of Acetyl-CoA Have Different Fates to Cytochromec688 in the TCA Cycle 660 Complex IV Transters Elect ons from Cytochrome c 19.6 Can the TCA Cycle Provide Intermediates xygen on th for Biosynthesis?662 Is Coupled to Oxygen Reduction 694 Mithondrial Diseae as Superco 79.7 20.3 A DEEPER LOOK:Fool's Gold and the Reductive Citric Acid 20.4 Cycle-The First Metabolic Pathway?665 19.8 How Is the TCA Cycle Regulated?665 ATD Cu dF,andF。698 Pyruvate Dehydrogenase Is Regulated The Catalytic Sites of ATP Synthase Adopt Three Different Conformations 699 Dehydr Regulated 668 Boyer's Exchange Experin nent Identified Regu cle Enzymes ations Regulate E.ocitrate
Detailed Contents xvii 18.8 How Do Cells Respond to Hypoxic Stress? 637 SUMMARY 638 Foundational Biochemistry 639 PROBLEMS 639 Further Reading 641 19 The Tricarboxylic Acid Cycle 643 19.1 What Is the Chemical Logic of the TCA Cycle? 644 The TCA Cycle Provides a Chemically Feasible Way of Cleaving a Two-Carbon Compound 645 19.2 How Is Pyruvate Oxidatively Decarboxylated to Acetyl-CoA? 645 A Deeper Look: The Coenzymes of the Pyruvate Dehydrogenase Complex 647 19.3 How Are Two CO2 Molecules Produced from Acetyl-CoA? 652 The Citrate Synthase Reaction Initiates the TCA Cycle 652 Citrate Is Isomerized by Aconitase to Form Isocitrate 653 Isocitrate Dehydrogenase Catalyzes the First Oxidative Decarboxylation in the Cycle 655 a-Ketoglutarate Dehydrogenase Catalyzes the Second Oxidative Decarboxylation of the TCA Cycle 656 19.4 How Is Oxaloacetate Regenerated to Complete the TCA Cycle? 656 Succinyl-CoA Synthetase Catalyzes Substrate-Level Phosphorylation 656 Succinate Dehydrogenase Is FAD-Dependent 657 Fumarase Catalyzes the Trans-Hydration of Fumarate to Form l-Malate 658 Malate Dehydrogenase Completes the Cycle by Oxidizing Malate to Oxaloacetate 659 19.5 What Are the Energetic Consequences of the TCA Cycle? 659 A Deeper Look: Steric Preferences in NAD1-Dependent Dehydrogenases 660 The Carbon Atoms of Acetyl-CoA Have Different Fates in the TCA Cycle 660 19.6 Can the TCA Cycle Provide Intermediates for Biosynthesis? 662 Human Biochemistry: Mitochondrial Diseases Are Rare 663 19.7 What Are the Anaplerotic, or “Filling Up,” Reactions? 663 A Deeper Look: Anaplerosis Plays a Critical Role in Insulin Secretion 664 A Deeper Look: Fool’s Gold and the Reductive Citric Acid Cycle—The First Metabolic Pathway? 665 19.8 How Is the TCA Cycle Regulated? 665 Pyruvate Dehydrogenase Is Regulated by Phosphorylation/Dephosphorylation 667 Isocitrate Dehydrogenase Is Strongly Regulated 668 Regulation of TCA Cycle Enzymes by Acetylation 668 Two Covalent Modifications Regulate E. coli Isocitrate Dehydrogenase 668 Human Biochemistry: TCA Metabolites Play Roles in Many Pathways Via Post-Translational Modifications 669 The TCA Cycle Operates as a Metabolon 669 19.9 Can Any Organisms Use Acetate as Their Sole Carbon Source? 670 The Glyoxylate Cycle Operates in Specialized Organelles 671 Isocitrate Lyase Short-Circuits the TCA Cycle by Producing Glyoxylate and Succinate 671 The Glyoxylate Cycle Helps Plants Grow in the Dark 672 Glyoxysomes Must Borrow Three Reactions from Mitochondria 672 SUMMARY 673 Foundational Biochemistry 674 PROBLEMS 674 Further Reading 675 20 Electron Transport and Oxidative Phosphorylation 679 20.1 Where in the Cell Do Electron Transport and Oxidative Phosphorylation Occur? 679 Mitochondrial Functions Are Localized in Specific Compartments 680 Human Biochemistry: Mitochondrial Dynamics in Human Diseases 681 The Mitochondrial Matrix Contains the Enzymes of the TCA Cycle 682 20.2 How Is the Electron-Transport Chain Organized? 682 The Electron-Transport Chain Can Be Isolated in Four Complexes 682 Complex I Oxidizes NADH and Reduces Coenzyme Q 683 Human Biochemistry: Solving a Medical Mystery Revolutionized Our Treatment of Parkinson’s Disease 685 Complex II Oxidizes Succinate and Reduces Coenzyme Q 687 Complex III Mediates Electron Transport from Coenzyme Q to Cytochrome c 688 Complex IV Transfers Electrons from Cytochrome c to Reduce Oxygen on the Matrix Side 692 Proton Transport Across Cytochrome c Oxidase Is Coupled to Oxygen Reduction 694 The Complexes of Electron Transport May Function as Supercomplexes 695 Electron Transfer Energy Stored in a Proton Gradient: The Mitchell Hypothesis 696 20.3 What Are the Thermodynamic Implications of Chemiosmotic Coupling? 697 20.4 How Does a Proton Gradient Drive the Synthesis of ATP? 698 ATP Synthase Is Composed of F1 and F0 698 The Catalytic Sites of ATP Synthase Adopt Three Different Conformations 699 Boyer’s 18O Exchange Experiment Identified the Energy-Requiring Step 700 Boyer’s Binding Change Mechanism Describes the Events of Rotational Catalysis 701 Copyright 2017 Cengage Learning. All Rights Reserved. May not be copied, scanned, or duplicated, in whole or in part. Due to electronic rights, some third party content may be suppressed from the eBook and/or eChapter(s). Editorial review has deemed that any suppressed content does not materially affect the overall learning experience. Cengage Learning reserves the right to remove additional content at any time if subsequent rights restrictions require it