Principles of Medical Biochemistry: With STUDENT CONSULT Online Access, 3e

601 Pages·2011·39.07 MB·English

by  Gerhard Meisenberg PhD

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PRINCIPLES OF
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PRINCIPLES OF
MEDICAL
BIOCHEMISTRY
G
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3rd EDITION
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n
Gerhard Meisenberg,
UPhD r
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Department of Biochemistry s
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Ross University School of Medicin e s
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Roseau, Commonwealth of Dominica, West Indies
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William H. Shimmons, s
PhD
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Department of Molecular Pharmacology and Therapeutics
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Loyola University School of Medicine
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Maywood, Illinois p
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1600JohnF.KennedyBlvd.
Ste1800
Philadelphia,PA19103-2899
PRINCIPLESOFMEDICALBIOCHEMISTRY,THIRDEDITION ISBN:978-0-323-07155-0
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PREFACE
It is rumored that among students embarking on a medical applications. However, it is intended for day-
course of study in the medical sciences, biochemistry to-day use by students. It is not a reference work for
is the most common cause of pretraumatic stress disor- students, professors, or physicians. It does not contain
der:thestateofmindintowhichpeoplefallinanticipa- “all a physician ever needs to know” about biochemis-
tionofunbearablestressandfrustration.Noother part try. This is impossible to acGhieve because the rapidly
oftheirpreclinicalcurriculumseemsasabstract,shape- expanding science requires new learning, and unlearn-
less, unintelligible, and littered with irrelevant detail as ing of received wisdomR, on a continuous basis.
is biochemistry. This prejudice is understandable. Bio- This book is evidently a compromise between the
chemistry is less intuitive than most other medical two conflicting dVemands of comprehensiveness and
sciences. Even worse, it is a vast field with an ever- brevity. This compromise was possible because medical
expanding frontier. From embryonic development to biochemistrydisnotarandomcross-sectionofthegeneral
carcinogenesis and drug action, biochemistry is becom- biochemistrythatistaughtinundergraduatecoursesand
e
ing the ultimate level of explanation. PhDprograms.Biochemistryforthemedicalprofessions
This third edition of Principles of Medical Biochem- is “pthysiological” chemistry: the chemistry needed to
i
istry is yet another attempt at imposing structure and unnderstand the structure and functions of the body
meaning on the blooming, buzzing confusion of this andtheirmalfunctionindisease.Therefore,wepaidlittle
U r
runaway science. This text is designed for first-year attention to topics of abstract theoretical interest, such
i
medicalstudentsaswellasveterinary,dental,andphar- as three-dimensional p.rotein structures and enzymatic

macy students and students in undergraduate premedi- reaction mechanismss, but we give thorough treatments
-
cal programs. Therefore, its aim goes bey ond the of medically imposrtant topics such as lipoprotein meta-
communication of basic biochemical facts9and con- bolism, mutagenesis and genetic diseases, the mole-
n
cepts. Of equal importance is the link between basic cular basis of cancer, nutritional disorders, and the
9
principles and medical applications. To achieve this hormonalaregulationofmetabolicpathways.
aim, we enhanced this edition withrnumerous clinical
i
examples that are embedded in thie chapters and illus- s
h
trate the importance of biochemistry for medicine. FACULTY RESOURCES
r
Althoughbiochemistryadavancesatafasterratethan
eAn image collection and test bank are available for
most other medical sciences, we did not match the
t your use when teaching via Evolve. Contact your local
increased volume of knowledge by an increased sizepof
salesrepresentativeformoreinformation,orgodirectly
the book. The day has only 24 hours, the cerebral cor-
. to the Evolve website to request access: http://evolve.
tex has only 30 billion neurons, and studentsphave to
elsevier.com.
learn many other subjects in addition to biochemistry.
i
Rather,we tried to be more selective andvmore concise.
Thebookstilliscomprehensiveinthesenseofcovering Gerhard Meisenberg, PhD
most aspects of biochemistry that have significant William H. Simmons, PhD
v
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CONTENTS
PartONE FetalHemoglobinHasaHigherOxygen-BindingAffinitythan
PRINCIPLES OF MOLECULAR STRUCTURE AND DoesAdultHemoglobin 36
TheBohrEffectFacilitatesOxygenDelivery 36
FUNCTION 1
MostCarbonDioxideIsTransportedasBicarbonate 37
Summary 38
Chapter1
INTRODUCTION TO BIOMOLECULES 2 Chapter4
WaterIstheSolventofLife 2 ENZYMATIC REACTIONS 39
WaterContainsHydroniumIonsandHydroxylIons 3
TheEquilibriumConstantDescribestheEquilibriumofthe
IonizableGroupsAreCharacterizedbyTheirpKValues 4
Reaction 39
BondsAreFormedbyReactionsbetweenFunctionalGroups 4
TheFreeEnergyChangeIstheDrivingForceforChemical
IsomericFormsAreCommoninBiomolecules 5
Reactions 40
PropertiesofBiomoleculesAreDeterminedbyTheirNoncovalent
TheStandardFreeEnergyChangeDeterminestheEquilibrium 41
Interactions 7
EnzymesAreBothPowerfulandSelective 41
TriglyceridesConsistofFattyAcidsandGlycerol 8
TheSubstrateMustBindtoItsEnzymebeforetheReactionCan
MonosaccharidesArePolyalcoholswithaKetoGrouporan
Proceed 42
AldehydeGroup 9
RateConstantsAreUsefulforDescribingReactionRates 42
MonosaccharidesFormRingStructures 9
EnzymesDecreasetheFreeEnergyofActivation 43
ComplexCarbohydratesAreFormedbyGlycosidicBonds 11
ManyEnzymaticReactionsCanBeDescribedbyMichaelis-Menten
PolypeptidesAreFormedfromAminoAcids 11
Kinetics 44
NucleicAcidsAreFormedfromNucleotides 13 K andV CanBeDeterminedGraphically 45
MostBiomoleculesArePolymers 14 m max
SubstrateHalf-LifeCanBeDeterminedforFirst-OrderbutNot
Summary 14
Zero-OrderReactions 46
k /K PredictstheEnzymeActivityatLowSubstrate
cat m
Chapter2 Concentration 46
INTRODUCTION TO PROTEIN STRUCTURE 16 AllostericEnzymesDoNotConformtoMichaelis-Menten
AminoAcidsAreZwitterions 16 Kinetics 46
AminoAcidSideChainsFormManyNoncovalent EnzymeActivityDependsonTemperatureandpH 47
Interactions 16 DifferentTypesofReversibleEnzymeInhibitionCanBe
PeptideBondsandDisulfideBondsFormthePrimaryStructureof DistinguishedKinetically 47
Proteins 17 CovalentModificationCanInhibitEnzymesIrreversibly 49
ProteinsCanFoldThemselvesintoManyDifferentShapes 20 EnzymesAreClassifiedAccordingtoTheirReactionType 49
a-Helixandb-PleatedSheetAretheMostCommonSecondary EnzymesStabilizetheTransitionState 51
StructuresinProteins 20 ChymotrypsinFormsaTransientCovalentBondduring
GlobularProteinsHaveaHydrophobicCore 21 Catalysis 51
ProteinsLoseTheirBiologicalActivitiesWhenTheirHigher-Order Summary 53
StructureIsDestroyed 23
TheSolubilityofProteinsDependsonpHandSalt Chapter5
Concentration 23 COENZYMES 55
ProteinsAbsorbUltravioletRadiation 24 AdenosineTriphosphateHasTwoEnergy-RichBonds 55
ProteinsCanBeSeparatedbyTheirChargeorTheirMolecular ATPIsthePhosphateDonorinPhosphorylationReactions 57
Weight 24 ATPHydrolysisDrivesEndergonicReactions 57
AbnormalProteinAggregatesCanCauseDisease 26 CellsAlwaysTrytoMaintainaHighEnergyCharge 58
NeurodegenerativeDiseasesAreCausedbyProteinAggregates 27 DehydrogenaseReactionsRequireSpecializedCoenzymes 58
ProteinMisfoldingCanBeContagious 28 CoenzymeAActivatesOrganicAcids 58
Summary 29 S-AdenosylMethionineDonatesMethylGroups 59
ManyEnzymesRequireaMetalIon 59
Chapter3 Summary 62
OXYGEN TRANSPORTERS: HEMOGLOBIN AND
MYOGLOBIN 31
TheHemeGroupIstheOxygen-BindingSiteofHemoglobinand PartTWO
Myoglobin 31 GENETIC INFORMATION: DNA, RNA, AND
MyoglobinIsaTightlyPackedGlobularProtein 32 PROTEIN SYNTHESIS 63
TheRedBloodCellsAreSpecializedforOxygenTransport 32
TheHemoglobinsAreTetramericProteins 32
OxygenatedandDeoxygenatedHemoglobinHaveDifferent Chapter6
QuaternaryStructures 33 DNA, RNA, AND PROTEIN SYNTHESIS 64
OxygenBindingtoHemoglobinIsCooperative 34 AllLivingOrganismsUseDNAasTheirGeneticDatabank 64
2,3-BisphosphoglycerateIsaNegativeAllostericEffectorof DNAContainsFourBases 64
OxygenBindingtoHemoglobin 35 DNAFormsaDoubleHelix 66
vii
viii Contents
DNACanBeDenatured 68 Chapter8
DNAIsSupercoiled 68
DNAReplicationIsSemiconservative 69 PROTEIN TARGETING 118
DNAIsSynthesizedbyDNAPolymerases 69 ASignalSequenceDirectsPolypeptidestotheEndoplasmic
BacterialDNAPolymerasesHaveExonucleaseActivities 70 Reticulum 118
UnwindingProteinsPresentaSingle-StrandedTemplatetothe GlycoproteinsAreProcessedintheSecretoryPathway 118
DNAPolymerases 72 TheEndocyticPathwayBringsProteinsintotheCell 120
OneoftheNewDNAStrandsIsSynthesizedDiscontinuously 73 LysosomesAreOrganellesofIntracellularDigestion 123
RNAPlaysKeyRolesinGeneExpression 73 CellularProteinsandOrganellesAreRecycledbyAutophagy 124
ThesSubunitRecognizesPromoters 75 PoorlyFoldedProteinsAreEitherRepairedorDestroyed 125
DNAIsFaithfullyCopiedintoRNA 75 TheProteasomeDegradesUbiquitinatedProteins 126
SomeRNAsAreChemicallyModifiedafterTranscription 78 Summary 126
TheGeneticCodeDefinestheRelationshipbetweenBaseSequence
ofmRNAandAminoAcidSequenceof Chapter9
Polypeptide 78 INTRODUCTION TO GENETIC DISEASES 128
TransferRNAIstheAdapterMoleculeinProteinSynthesis 81 MutationsAreanImportantCauseofPoorHealth 128
AminoAcidsAreActivatedbyanEsterBondwiththe30 Terminus FourTypesofGeneticDisease 128
ofthetRNA 81 SmallMutationsLeadtoAbnormalProteins 129
ManyTransferRNAsRecognizeMorethanOneCodon 82 TheBasalMutationRateIsCausedMainlybyReplication
RibosomesAretheWorkbenchesforProteinSynthesis 83 Errors 130
TheInitiationComplexBringsTogetherRibosome,Messenger MutationsCanBeInducedbyRadiationandChemicals 130
RNA,andInitiatortRNA 83 MismatchRepairCorrectsReplicationErrors 132
PolypeptidesGrowStepwisefromtheAminoTerminustothe MissingBasesandAbnormalBasesNeedtoBeReplaced 133
CarboxylTerminus 84 NucleotideExcisionRepairRemovesBulkyLesions 134
ProteinSynthesisIsEnergeticallyExpensive 86 RepairofDNADouble-StrandBreaksIsDifficult 135
GeneExpressionIsTightlyRegulated 87 HemoglobinGenesFormTwoGeneClusters 137
ARepressorProteinRegulatesTranscriptionofthelacOperon ManyPointMutationsinHemoglobinGenesAreKnown 138
inE.coli 87 SickleCellDiseaseIsCausedbyaPointMutationintheb-Chain
AnabolicOperonsAreRepressedbytheEndProductofthe Gene 138
Pathway 88 SAHeterozygotesAreProtectedfromTropicalMalaria 140
GlucoseRegulatestheTranscriptionofManyCatabolic a-ThalassemiaIsMostOftenCausedbyLargeDeletions 140
Operons 89 ManyDifferentMutationsCanCauseb-Thalassemia 141
TranscriptionalRegulationDependsonDNA-Binding FetalHemoglobinProtectsfromtheEffectsofb-Thalassemiaand
Proteins 90 SickleCellDisease 142
Summary 91 Summary 143
Chapter7 Chapter10
THE HUMAN GENOME 93 VIRUSES 145
ChromatinConsistsofDNAandHistones 93 VirusesCanReplicateOnlyinaHostCell 145
TheNucleosomeIstheStructuralUnitofChromatin 93 BacteriophageT4DestroysItsHostCell 145
CovalentHistoneModificationsRegulateDNAReplicationand DNAVirusesSubstituteTheirOwnDNAfortheHostCell
Transcription 93 DNA 146
DNAMethylationSilencesGenes 94 lPhageCanIntegrateItsDNAintotheHostCell
AllEukaryoticChromosomesHaveaCentromere,Telomeres,and Chromosome 147
ReplicationOrigins 96 RNAVirusesRequireanRNA-DependentRNAPolymerase 149
TelomeraseIsRequired(butNotSufficient)forImmortality 96 RetrovirusesReplicateThroughaDNAIntermediate 150
EukaryoticDNAReplicationRequiresThreeDNA PlasmidsAreSmall“AccessoryChromosomes”or“Symbiotic
Polymerases 98 Viruses”ofBacteria 152
MostHumanDNADoesNotCodeforProteins 99 BacteriaCanExchangeGenesbyTransformationand
GeneFamiliesOriginatebyGeneDuplication 99 Transduction 153
TheGenomeContainsManyTandemRepeats 99 JumpingGenesCanChangeTheirPositionintheGenome 155
SomeDNASequencesAreCopiesofFunctionalRNAs 100 Summary 157
ManyRepetitiveDNASequencesAre(orWere)Mobile 100
L1ElementsEncodeaReverseTranscriptase 102 Chapter11
AluSequencesSpreadwiththeHelpofL1Reverse DNA TECHNOLOGY 158
Transcriptase 102 RestrictionEndonucleasesCutLargeDNAMoleculesintoSmaller
MobileElementsAreDangerous 104 Fragments 158
HumansHaveApproximately25,000Genes 104 ComplementaryDNAProbesAreUsedforInSitu
TranscriptionalInitiationRequiresGeneralTranscription Hybridization 158
Factors 104 DotBlottingIsUsedforGeneticScreening 158
GenesAreSurroundedbyRegulatorySites 105 SouthernBlottingDeterminestheSizeofRestriction
GeneExpressionIsRegulatedbyDNA-BindingProteins 106 Fragments 160
EukaryoticMessengerRNAIsExtensivelyProcessedinthe DNACanBeAmplifiedwiththePolymeraseChainReaction 161
Nucleus 107 PCRIsUsedforPreimplantationGeneticDiagnosis 161
mRNAProcessingStartsduringTranscription 108 AllelicHeterogeneityIstheGreatestChallengeforMolecular
TranslationalInitiationRequiresManyInitiationFactors 109 GeneticDiagnosis 161
mRNAProcessingandTranslationAreOftenRegulated 109 NormalPolymorphismsAreUsedasGeneticMarkers 164
SmallRNAMoleculesInhibitGeneExpression 113 TandemRepeatsAreUsedforDNAFingerprinting 164
MitochondriaHaveTheirOwnDNA 114 DNAMicroarraysCanBeUsedforGeneticScreening 165
HumanGenomesAreVeryDiverse 115 DNAMicroarraysAreUsedfortheStudyofGeneExpression 168
HumanGenomesHaveManyLow-FrequencyCopyNumber DNAIsSequencedbyControlledChainTermination 168
Variations 116 MassivelyParallelSequencingPermitsCost-Efficient
Summary 116 Whole-GenomeGeneticDiagnosis 168
Contents ix
PathogenicDNAVariantsAreLocatedbyGenome-Wide SulfatedGlycosaminoglycansAreCovalentlyBoundtoCore
AssociationStudies 169 Proteins 220
GenomicDNAFragmentsCanBePropagatedinBacterial CartilageContainsLargeProteoglycanAggregates 220
Plasmids 171 ProteoglycansAreSynthesizedintheERandDegradedin
ExpressionVectorsAreUsedtoManufactureUsefulProteins 172 Lysosomes 221
GeneTherapyTargetsSomaticCells 172 MucopolysaccharidosesAreCausedbyDeficiencyof
VirusesAreUsedasVectorsforGeneTherapy 173 Glycosaminoglycan-DegradingEnzymes 223
RetrovirusesCanSpliceaTransgeneintotheCell’sGenome 174 BoneConsistsofCalciumPhosphatesinaCollagenous
AntisenseOligonucleotidesCanBlocktheExpressionofRogue Matrix 225
Genes 174 BasementMembranesContainTypeIVCollagen,Laminin,
GenesCanBeAlteredinAnimals 175 andHeparanSulfateProteoglycans 225
Tissue-SpecificGeneExpressionCanBeEngineeredinto FibronectinGluesCellsandCollagenFibersTogether 227
Animals 177 Summary 228
ProductionofTransgenicHumansIsTechnicallyPossible 178
Summary 178
PartFOUR
MOLECULAR PHYSIOLOGY 231
PartTHREE
CELL AND TISSUE STRUCTURE 181 Chapter15
PLASMA PROTEINS 232
Chapter12 TheBloodpHIsTightlyRegulated 232
BIOLOGICAL MEMBRANES 182 AcidosisandAlkalosisAreCommoninClinicalPractice 232
MembranesConsistofLipidandProtein 182 PlasmaProteinsAreBothSynthesizedandDestroyedinthe
PhosphoglyceridesAretheMostAbundantMembraneLipids 182 Liver 234
MostSphingolipidsAreGlycolipids 184 AlbuminPreventsEdema 234
CholesterolIstheMostHydrophobicMembraneLipid 185 AlbuminBindsManySmallMolecules 235
MembraneLipidsFormaBilayer 186 SomePlasmaProteinsAreSpecializedCarriersofSmall
TheLipidBilayerIsaTwo-DimensionalFluid 186 Molecules 235
TheLipidBilayerIsaDiffusionBarrier 187 Deficiencyofa1-AntiproteaseCausesLungEmphysema 236
MembranesContainIntegralandPeripheralMembrane LevelsofPlasmaProteinsAreAffectedbyManyDiseases 237
Proteins 188 BloodComponentsAreUsedforTransfusions 238
MembranesAreAsymmetrical 188 ImmunoglobulinsBindAntigensVerySelectively 239
MembranesAreFragile 190 AntibodiesConsistofTwoLightChainsandTwoHeavy
MembraneProteinsCarrySolutesacrosstheLipidBilayer 191 Chains 240
TransportagainstanElectrochemicalGradientRequiresMetabolic DifferentImmunoglobulinClassesHaveDifferentProperties 242
Energy 191 AdaptiveImmuneResponsesAreBasedonClonalSelection 244
ActiveTransportConsumesATP 193 ImmunoglobulinGenesAreRearrangedduringB-Cell
SodiumCotransportBringsMoleculesintotheCell 195 Development 245
Summary 196 MonoclonalGammopathiesAreNeoplasticDiseasesofPlasma
Cells 246
Chapter13 BloodClottingMustBeTightlyControlled 248
THE CYTOSKELETON 198 PlateletsAdheretoExposedSubendothelialTissue 248
InsolubleFibrinIsFormedfromSolubleFibrinogen 248
TheErythrocyteMembraneIsReinforcedbyaSpectrin
ThrombinIsDerivedfromProthrombin 248
Network 198
FactorXCanBeActivatedbytheExtrinsicandIntrinsic
KeratinsAretheMostImportantStructuralProteinsofEpithelial
Pathways 250
Tissues 199
NegativeControlsAreNecessarytoPreventThrombosis 251
ActinFilamentsAreFormedfromGlobularSubunits 201
PlasminDegradestheFibrinClot 253
StriatedMuscleContainsThickandThinFilaments 202
HeparinandtheVitaminKAntagonistsAreImportant
MyosinIsaTwo-HeadedMoleculewithATPaseActivity 202
Anticoagulants 253
MuscleContractionRequiresCalciumandATP 205
ClottingFactorDeficienciesCauseAbnormalBleeding 255
TheCytoskeletonofSkeletalMuscleIsLinkedtotheExtracellular
TissueDamageCausesReleaseofCellularEnzymesinto
Matrix 206
Blood 255
MicrotubulesConsistofTubulin 207
EukaryoticCiliaandFlagellaContaina9þ2Arrayof SerumEnzymesAreUsedfortheDiagnosisofManyDiseases 256
Microtubules 208 Summary 259
CellsFormSpecializedJunctionswithOtherCellsandwiththe
ExtracellularMatrix 209 Chapter16
Summary 210 EXTRACELLULAR MESSENGERS 261
SteroidHormonesAreMadefromCholesterol 261
Chapter14 ProgestinsAretheBiosyntheticPrecursorsofAllOtherSteroid
THE EXTRACELLULAR MATRIX 212 Hormones 261
CollagenIstheMostAbundantProteinintheHumanBody 212 ThyroidHormonesAreSynthesizedfromProtein-Bound
TropocollagenMoleculeFormsaLongTripleHelix 213 Tyrosine 266
CollagenFibrilsAreStaggeredArraysofTropocollagen BothHypothyroidismandHyperthyroidismAreCommon
Molecules 214 Disorders 268
CollagenIsSubjecttoExtensivePosttranslationalProcessing 215 InsulinIsReleasedTogetherwiththeC-Peptide 269
CollagenMetabolismIsAlteredinAgingandDisease 215 ProopiomelanocortinFormsSeveralActiveProducts 271
ManyGeneticDefectsofCollagenStructureandBiosynthesisAre AngiotensinIsFormedfromCirculatingAngiotensinogen 271
Known 216 ImmunoassaysAretheMostVersatileMethodsforDetermination
ElasticFibersContainElastinandFibrillin 217 ofHormoneLevels 272
HyaluronicAcidIsaComponentoftheAmorphousGround ArachidonicAcidIsConvertedtoBiologicallyActive
Substance 219 Products 273