PREFACEXI·The chapter on plasma proteins, immunoglobulins, and blood coagulation in the previous edition has been splitintotwo new chapters on plasma proteins and immunoglobulinsand on hemostasis and thrombosis..New information has been added in appropriate chapters on lipid rafts and caveolae, aquaporins, connexins, dis-orders due to mutations in genes encoding proteins involved in intracellular membrane transport, absorption ofiron,andconformationaldiseasesandpharmacogenomics.:A new and final chapter on“The Human Genome Project" (HGP) has been added, which builds on the materialcovered inChapters35through40.Becauseof the impactoftheresultsoftheHGPonthefutureofbiologyandmedicine,it appeared appropriate to conclude thetext with a summary of its major findings and their implica-tionsforfuture work· As initiated in the previous edition, references to useful Web sites have been included in a brief Appendix at theend of the text.ORGANIZATIONOFTHEBOOKThe text is divided into two introductory chapters ("Biochemistry & Medicine"and "Water & pH")followed by sixmainsectionsSectionI deals with the structures and functions of proteins and enzymes,the workhorses of the body.Becausealmost all of the reactions in cells are catalyzed by enzymes, it is vital to understand the properties of enzymes beforeconsidering other topics.SectionIIexplains how various cellularreactions either utilize or release energy,and ittraces the pathways bywhich carbohydrates and lipids are synthesized and degraded. It also describes the many functions of these twoclasses of molecules.Section Ill deals with the amino acids and their many fates and also describes certain key features of protein ca-tabolism.Section IV describes the structures and functions of the nucleotides and nucleic acids, and covers many majortopics such as DNAreplication and repair,RNA synthesis andmodification,and protein synthesis.Italso discussesnew findings on how genes are regulated and presents the principles of recombinant DNA technology.SectionVdeals with aspects of extracellular and intracellular communication.Topics covered include membranestructure and function,the molecular bases of the actions of hormones, and thekeyfield of signal transduction.Section VI consists of discussions of eleven special topics: nutrition,digestion, and absorption; vitamins andminerals; intracellular traffic and sorting of proteins; glycoproteins; the extracellular matrix; muscle and the cy-toskeleton; plasma proteins and immunoglobulins; hemostasis and thrombosis; red and white blood cells; the me-tabolism ofxenobiotics; andtheHuman GenomeProject.ACKNOWLEDGMENTSThe authors thank Janet Foltin for her thoroughly professional approach. Her constant interest and input have had asignificant impact on the final structure of this text.We are again immensely grateful to Jim Ransom for his excel-lent editorial work; it has been a pleasure to work with an individual who constantly offered wise and informed alter-natives to the sometimes primitive text transmitted by the authors.The superb editorial skills of Janene MatragranoOransky and Harriet Lebowitz are warmly acknowledged,as is the excellent artwork of Charissa Baker and her col-leagues.The authors are very grateful to Kathy Pitcoff for her thoughtful and meticulous work in preparing theIndex.Suggestionsfrom students and colleagues around theworld have been mosthelpful in theformulation of thisedition.Welook forward to receiving similar input in the future.Robert K.Murray, MD, PhDDaryl K. Granner, MDPeter A. Mayes, PhD, DScVictor W. Rodwell, PhDToronto,OntarioNashville, TennesseeLondonWest Lafayette, IndianaMarch 2003
• The chapter on plasma proteins, immunoglobulins, and blood coagulation in the previous edition has been split into two new chapters on plasma proteins and immunoglobulins and on hemostasis and thrombosis. • New information has been added in appropriate chapters on lipid rafts and caveolae, aquaporins, connexins, disorders due to mutations in genes encoding proteins involved in intracellular membrane transport, absorption of iron, and conformational diseases and pharmacogenomics. • A new and final chapter on “The Human Genome Project” (HGP) has been added, which builds on the material covered in Chapters 35 through 40. Because of the impact of the results of the HGP on the future of biology and medicine, it appeared appropriate to conclude the text with a summary of its major findings and their implications for future work. • As initiated in the previous edition, references to useful Web sites have been included in a brief Appendix at the end of the text. ORGANIZATION OF THE BOOK The text is divided into two introductory chapters (“Biochemistry & Medicine” and “Water & pH”) followed by six main sections. Section I deals with the structures and functions of proteins and enzymes, the workhorses of the body. Because almost all of the reactions in cells are catalyzed by enzymes, it is vital to understand the properties of enzymes before considering other topics. Section II explains how various cellular reactions either utilize or release energy, and it traces the pathways by which carbohydrates and lipids are synthesized and degraded. It also describes the many functions of these two classes of molecules. Section III deals with the amino acids and their many fates and also describes certain key features of protein catabolism. Section IV describes the structures and functions of the nucleotides and nucleic acids, and covers many major topics such as DNA replication and repair, RNA synthesis and modification, and protein synthesis. It also discusses new findings on how genes are regulated and presents the principles of recombinant DNA technology. Section V deals with aspects of extracellular and intracellular communication. Topics covered include membrane structure and function, the molecular bases of the actions of hormones, and the key field of signal transduction. Section VI consists of discussions of eleven special topics: nutrition, digestion, and absorption; vitamins and minerals; intracellular traffic and sorting of proteins; glycoproteins; the extracellular matrix; muscle and the cytoskeleton; plasma proteins and immunoglobulins; hemostasis and thrombosis; red and white blood cells; the metabolism of xenobiotics; and the Human Genome Project. ACKNOWLEDGMENTS The authors thank Janet Foltin for her thoroughly professional approach. Her constant interest and input have had a significant impact on the final structure of this text. We are again immensely grateful to Jim Ransom for his excellent editorial work; it has been a pleasure to work with an individual who constantly offered wise and informed alternatives to the sometimes primitive text transmitted by the authors. The superb editorial skills of Janene Matragrano Oransky and Harriet Lebowitz are warmly acknowledged, as is the excellent artwork of Charissa Baker and her colleagues. The authors are very grateful to Kathy Pitcoff for her thoughtful and meticulous work in preparing the Index. Suggestions from students and colleagues around the world have been most helpful in the formulation of this edition. We look forward to receiving similar input in the future. Robert K. Murray, MD, PhD Daryl K. Granner, MD Peter A. Mayes, PhD, DSc Victor W. Rodwell, PhD Toronto, Ontario Nashville, Tennessee London West Lafayette, Indiana March 2003 x / PREFACE fm01.qxd 3/16/04 11:10 AM Page x
ContentsPrefa1.Biochemistry&MedicineRobertKMurray,MD,PhD2.Water&pHVictorW.Rodwell,PhD,Peter J.Kennelly,PhDSECTIONLSTRUCTURES&FUNCTIONSOFPROTEINS&ENZYMES3.AminoAcids&PeptidesVictorW.Rodwell, PhD,PeterJ.Kennelly,PhD144.Proteins:Determination ofPrimary StructureVictorW.Rodwell, PhD,Peter J.Kennelly,PhD215.Proteins: HigherOrders of StructureVictorW.Rodwell,PhD,Peter J.Kennelly,PhD306.Proteins:Myoglobin&Hemoglobin40VictorW.Rodwell,PhD,PeterJ.Kennelly,PhD.7.Enzymes:MechanismofActionVictorW.Rodwell,PhD,Peter .Kennelly,PhD.498.Enzymes:KineticsVictorW.Rodwell,PhD,Peter J.Kennelly,PhD609.Enzymes:Regulation of ActivitiesVictorW.Rodwell,PhD,PeterJ.Kennelly,PhD.72SECTIONII.BIOENERGETICS&THEMETABOLISMOFCARBOHYDRATES80&LIPIDS10.Bioenergetics:The Role ofATP80PeterA.Mayes,PhD,DSc,Kathleen M.Botham,PhD,DSc11.BiologicOxidation86PeterA.Mayes,PhD,DSc,KathleenM.Botham,PhD,DS12.TheRespiratoryChain&OxidativePhosphorylation92Peter A.Mayes,PhD, DSc, Kathleen M.Botham, PhD,DS13.Carbohydrates of Physiologic Significance102PeterA.Mayes,PhD,DSc, David A.Bender,PhDili
Contents iii Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1. Biochemistry & Medicine Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Water & pH Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 SECTION I. STRUCTURES & FUNCTIONS OF PROTEINS & ENZYMES . . . . . . . . . . . . . . . . . . . 14 3. Amino Acids & Peptides Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 4. Proteins: Determination of Primary Structure Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 5. Proteins: Higher Orders of Structure Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 6. Proteins: Myoglobin & Hemoglobin Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 7. Enzymes: Mechanism of Action Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 8. Enzymes: Kinetics Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 9. Enzymes: Regulation of Activities Victor W. Rodwell, PhD, & Peter J. Kennelly, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 72 SECTION II. BIOENERGETICS & THE METABOLISM OF CARBOHYDRATES & LIPIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 10. Bioenergetics: The Role of ATP Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 11. Biologic Oxidation Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86 12. The Respiratory Chain & Oxidative Phosphorylation Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 13. Carbohydrates of Physiologic Significance Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 fm01.qxd 3/16/04 11:10 AM Page iii
iv1CONTENTS14.Lipids ofPhysiologic SignificancePeterA.Mayes,PhD,DSc,KathleenM.Botham,PhD,DSc11115.Overviewof MetabolismPeter A.Mayes, PhD, DSc, David A.Bender, PhD12216.The Citric Acid Cycle:The Catabolism of Acetyl-CoA130Peter A.Mayes, PhD,DSc, David ABender,PhD17.Glycolysis&theOxidation of PyruvatePeterAMayes,PhD,DSc,DavidA.Bender,PhD13618.MetabolismofGlycogenPeterA.Mayes,PhD,DSc,DavidA.Bender,PhD14519.Gluconeogenesis&Control of the Blood GlucosePeterA.Mayes,PhD,DSc, David A.Bender,PhD15320.ThePentosePhosphatePathway&OtherPathwaysof Hexose Metabolism163PeterAMayes,PhD,DSc,DavidA.Bender,PhD21.Biosynthesis of Fatty AcidsPeterA.Mayes,PhD,DSc,KathleenM.Botham,PhD,DS17322.Oxidation of FattyAcids:KetogenesisPeterA.Mayes, PhD,DSc, Kathleen M.Botham,PhD,DSc18023.MetabolismofUnsaturatedFattyAcids&Eicosanoids190PeterA.Mayes,PhD,DSc,Kathleen M.Botham,PhD,DS24.Metabolism of Acylglycerols & Sphingolipids197PeterA.Mayes,PhD,DSc, KathleenM.Botham,PhD,DSc25.Lipid Transport & StoragePeterA.Mayes,PhD,DSc,KathleenM.Botham,PhD,DSc20526.Cholesterol Synthesis,Transport,&Excretion219PeterA.Mayes,PhD,DSc,KathleenM.Botham,PhD,DSe27.IntegrationofMetabolism-theProvisionofMetabolicFuels231DavidABender,PhD,PeterA.Mayes,PhD,DScSECTIONIIIL.METABOLISMOFPROTEINS&AMINOACIDS23728.Biosynthesis of theNutritionallyNonessential AminoAcidsVictorW.Rodwell, PhD.23729.Catabolismof Proteins&of AminoAcidNitrogen242VictorW.Rodwell,PhD
14. Lipids of Physiologic Significance Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 15. Overview of Metabolism Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 16. The Citric Acid Cycle: The Catabolism of Acetyl-CoA Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130 17. Glycolysis & the Oxidation of Pyruvate Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 18. Metabolism of Glycogen Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145 19. Gluconeogenesis & Control of the Blood Glucose Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153 20. The Pentose Phosphate Pathway & Other Pathways of Hexose Metabolism Peter A. Mayes, PhD, DSc, & David A. Bender, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 163 21. Biosynthesis of Fatty Acids Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 22. Oxidation of Fatty Acids: Ketogenesis Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 23. Metabolism of Unsaturated Fatty Acids & Eicosanoids Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 190 24. Metabolism of Acylglycerols & Sphingolipids Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 25. Lipid Transport & Storage Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 26. Cholesterol Synthesis, Transport, & Excretion Peter A. Mayes, PhD, DSc, & Kathleen M. Botham, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 27. Integration of Metabolism—the Provision of Metabolic Fuels David A. Bender, PhD, & Peter A. Mayes, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 SECTION III. METABOLISM OF PROTEINS & AMINO ACIDS . . . . . . . . . . . . . . . . . . . . . . . . . 237 28. Biosynthesis of the Nutritionally Nonessential Amino Acids Victor W. Rodwell, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 237 29. Catabolism of Proteins & of Amino Acid Nitrogen Victor W. Rodwell, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 iv / CONTENTS fm01.qxd 3/16/04 11:10 AM Page iv
CONTENTS30.CatabolismoftheCarbonSkeletonsofAminoAcids249VictorW.Rodwell,PhD.31.Conversionof AminoAcidstoSpecializedProducts264VictorW.RodwellPhD32.Porphyrins & Bile Pigments270RobertKMurray,MD,PhDSECTIONIV.STRUCTURE,FUNCTION,&REPLICATION286OFINFORMATIONALMACROMOLECULES33.Nucleotides286VictorW.Rodwell,PhD34.Metabolism of Purine&PyrimidineNucleotides293VictorW.Rodwell,PhD.35.NucleicAcid Structure&Function.303DarylKGranner,MD36.DNAOrganization,Replication,&Repair314DarylKGranner,MD,P.AnthonyWeil, PhD37.RNASynthesis,Processing,&Modification341DarylKGranner,MD,P.AnthonyWeil,PhD38.Protein Synthesis& the Genetic Code358DarylKGranner,MD39.RegulationofGeneExpression374Daryl KGranner,MD,P.AnthonyWeil, PhD40.Molecular Genetics, Recombinant DNA,&Genomic Technology396Daryl KGranner,MD,P.AnthonyWeil,PhDSECTIONV.BIOCHEMISTRYOFEXTRACELLULAR415&INTRACELLULARCOMMUNICATION41.Membranes:Structure&FunctionRobertKMurray,MD,PhD,DarylKGranner,MD41542.TheDiversity of theEndocrine System434DarylKGranner,MD43.HormoneAction&Signal Transduction456DarylKGranner,MD
30. Catabolism of the Carbon Skeletons of Amino Acids Victor W. Rodwell, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 31. Conversion of Amino Acids to Specialized Products Victor W. Rodwell, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 264 32. Porphyrins & Bile Pigments Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270 SECTION IV. STRUCTURE, FUNCTION, & REPLICATION OF INFORMATIONAL MACROMOLECULES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 33. Nucleotides Victor W. Rodwell, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 286 34. Metabolism of Purine & Pyrimidine Nucleotides Victor W. Rodwell, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 35. Nucleic Acid Structure & Function Daryl K. Granner, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 303 36. DNA Organization, Replication, & Repair Daryl K. Granner, MD, & P. Anthony Weil, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 314 37. RNA Synthesis, Processing, & Modification Daryl K. Granner, MD, & P. Anthony Weil, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 38. Protein Synthesis & the Genetic Code Daryl K. Granner, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 358 39. Regulation of Gene Expression Daryl K. Granner, MD, & P. Anthony Weil, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 374 40. Molecular Genetics, Recombinant DNA, & Genomic Technology Daryl K. Granner, MD, & P. Anthony Weil, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 396 SECTION V. BIOCHEMISTRY OF EXTRACELLULAR & INTRACELLULAR COMMUNICATION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 41. Membranes: Structure & Function Robert K. Murray, MD, PhD, & Daryl K. Granner, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 415 42. The Diversity of the Endocrine System Daryl K. Granner, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 434 43. Hormone Action & Signal Transduction Daryl K. Granner, MD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 456 CONTENTS / v fm01.qxd 3/16/04 11:10 AM Page v
vi1CONTENTSSECTIONVI.SPECIALTOPICS47444.Nutrition,Digestion,&Absorption474David A.Bender,PhD,PeterA.Mayes,PhD,DSc45.Vitamins&Minerals481David ABender, PhD,Peter A.Mayes,PhD, DSc46.IntracellularTraffic&Sortingof Proteins498Robert K. Murray, MD, PhD47.Glycoproteins514RobertK.Murray,MD,PhD48.The Extracellular MatrixRobertKMurray,MD,PhD,FrederickW.Keeley,PhD53549.Muscle& the Cytoskeleton556RobertK.Murray,MD,PhD50.PlasmaProteins&Immunoglobulins580RobertK.Murray,MD,PhD51.Hemostasis&Thrombosis598MargaretL.RandPhD,RobertK.Murray,MD,PhD52.Red&WhiteBlood CellsRobertK.Murray,MD,PhD60953.MetabolismofXenobiotics626RobertKMurray,MD,PhD54.TheHumanGenomeProject633Robert K.Murray, MD, PhD.Appendix.639.643Index
SECTION VI. SPECIAL TOPICS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474 44. Nutrition, Digestion, & Absorption David A. Bender, PhD, & Peter A. Mayes, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 474 45. Vitamins & Minerals David A. Bender, PhD, & Peter A. Mayes, PhD, DSc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 481 46. Intracellular Traffic & Sorting of Proteins Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 498 47. Glycoproteins Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 514 48. The Extracellular Matrix Robert K. Murray, MD, PhD, & Frederick W. Keeley, PhD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 535 49. Muscle & the Cytoskeleton Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 556 50. Plasma Proteins & Immunoglobulins Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 580 51. Hemostasis & Thrombosis Margaret L. Rand, PhD, & Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 598 52. Red & White Blood Cells Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 609 53. Metabolism of Xenobiotics Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 626 54. The Human Genome Project Robert K. Murray, MD, PhD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 633 Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 639 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 643 vi / CONTENTS fm01.qxd 3/16/04 11:10 AM Page vi