Mammalian Alkaline Phosphatases: From Biology to Applications in Medicine and Biotechnology

339 Pages·2006·5.38 MB·English

by  José Luis Millan (Author)

Jos(cid:2)LuisMill(cid:3)n
MammalianAlkaline
Phosphatases
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Jos(cid:2) Luis Mill(cid:3)n
Mammalian Alkaline Phosphatases
From Biology to Applications in Medicine
and Biotechnology
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V
Contents
Preface IX
Abbreviations XI
Glossary XV
Introduction 1
PartI GeneandProteinStructure 3
1 GeneStructure 5
1.1 GenomicOrganizationandComplexity 5
1.2 RestrictionFragmentLengthPolymorphisms 11
2 DevelopmentalExpression 13
2.1 TheTNAPGene 13
2.2 TheTSAPGenes 15
3 GeneRegulation 19
3.1 TheTNAPGene 19
3.2 TheTSAPGenes 22
4 ProteinStructureandFunctionalDomains 25
4.1 TheThree-dimensionalStructureofPLAP 25
4.1.1 OverviewoftheStructure 25
4.1.2 TheActiveSite 28
4.1.3 TheCalciumSite 36
4.1.4 TheDisulfideBonds 38
4.1.5 TheN-terminalArm 38
4.1.6 TheCrownDomain 41
4.1.7 TheMonomer–MonomerInterface 46
4.1.8 TheNoncatalyticPeripheralBindingSite 46
4.2 GeneticPolymorphismandProteinVariability 49
VI Contents
4.3 Post-translationalModifications 54
4.3.1 GlycosylationSites 54
4.3.2 EctoplasmicLocalizationofAPsviaaGPIAnchor 56
4.3.3 NonenzymaticGlycationofAPs 61
4.3.4 QuaternaryStructureofAPs 62
4.3.5 SubcellularLocalizationofAPs 63
5 EnzymaticProperties 67
5.1 CatalyticInhibition 67
5.1.1 CompetitiveandNoncompetitiveInhibitorsofAPs 69
5.1.2 UncompetitiveInhibition 71
5.1.2.1 MechanismofInhibitioninPLAP/GCAP 71
5.1.2.2 InhibitorBindinginTNAP 76
5.2 AllostericBehavior 80
5.3 CatalyticEfficiencyofMammalianAPs 83
5.4 SubstrateSpecificities 85
5.5 APsasMembersofaSuperfamilyofEnzymes 88
6 EpitopeMaps 91
6.1 EpitopesinPLAPandGCAP 91
6.2 EpitopesinIAP 98
6.3 DiscriminationBetweenBoneandLiverTNAP 99
PartII InVivoFunctions 105
7 TheInVivoRoleofTNAP 107
7.1 FunctionofTNAPinBone 107
7.1.1 Hypophosphatasia 107
7.1.2 HypophosphatasiaMutations 109
7.1.3 VariablePenetranceandExpressivity 123
7.2 RoleofTNAPinNonskeletalTissues 124
7.3 ProposedBiologicalFunctionsofTSAPs 126
7.3.1 ProposedFunctionsofIAP 126
7.3.2 PutativeFunctionsofGCAPandPLAP 128
8 KnockoutMouseModels 131
8.1 PhenotypicAbnormalitiesinAkp2–/–mice 131
8.1.1 DevelopmentalandSkeletalDefects 131
8.1.2 DentalAbnormalitiesinAkp2–/–Mice 136
8.1.3 DeficientMineralizationbyAkp2–/–OsteoblastsInVitro 136
8.1.4 MetabolicPathwaysAffectedinAkp2–/–Mice 139
8.1.4.1 Neuro-physiologicalAbnormalities 139
8.1.4.2 TheFunctionofTNAPinBoneMineralization 141
8.1.4.3 Co-expressionofTNAPandFibrillarCollagensRestrictsCalcification
toSkeletalTissues 148
Contents VII
8.1.4.4 OtherOrgansAffectedinAkp2–/–Mice 152
8.2 PhenotypicAbnormalitiesinAkp3–/–Mice 154
8.3 PhenotypicAbnormalitiesinAkp5–/–Mice 160
PartIII APExpressioninHealthandDisease 165
9 APsasPhysiologicalandDiseaseMarkers 167
9.1 ClinicalUsefulnessofTNAP 167
9.1.1 TNAPasaMarkerofBoneFormation 167
9.1.2 TNAPandBoneCancerorBoneMetastasis 173
9.1.3 TNAPExpressioninCholestasis 175
9.1.4 TNAPinOtherConditions 178
9.2 ClinicalUsefulnessofPLAPinNormalandComplicated
Pregnancies 180
9.3 IAPExpressioninRelationtoABOStatus,FatFeedingandOther
Pathologies 182
9.4 ComplexesofAPsandImmunoglobulins 184
9.5 Hyperphosphatasia 185
10 NeoplasticExpressionofPLAP,GCAP,IAP(Regan,Nagao,Kasahara)
andTNAPIsozymes 187
10.1 SomeHistory 187
10.2 GCAPasMarkerforTesticularCancer 189
10.3 UsefulnessofPLAP/GCAPinOvarianCancer 194
10.4 OtherTumors 196
10.5 ImmunolocalizationandImmunotherapyofTumors
UsingPLAP/GCAPasTargets 197
10.6 TumoralExpressionofIAP 204
PartIV UsesofAPsinIndustryandBiotechnology 207
11 ApplicationsofRecombinantAPs 209
11.1 ExpressionofRecombinantAPs 209
11.2 APsasInVitroandInVivoReporters 213
11.3 APsasMolecularBiologyandDiagnosticReagents 218
12 UseofAPsinProdrugConvertingStrategies 223
13 APsasTherapeuticAgents 227
13.1 IntheTreatmentofHypophosphatasia 227
13.2 IntheTreatmentofCPPDDisease 231
13.3 EndotoxinTreatment 231
13.4 TNAPasTherapeuticTargetfortheManagementof
EctopicCalcification 234
VIII Contents
14 APsintheFoodIndustry 237
15 VeterinaryUsesofAPDeterminations 239
16 Methodologies 241
16.1 Amperometric,SpectrophotometricandPotentiometricAssays 241
16.2 UsingInhibitorsandHeatInactivation 244
16.3 ElectrophoreticMethods 245
16.4 Lectin-basedAssays 245
16.5 High-performanceLiquidChromatographicMethods 247
16.6 SpecificImmunoassayswithPolyclonalandMAbs 249
16.7 mRNA-basedAssays 253
16.8 HistochemicalandImmunohistochemicalDetection 254
References 257
Index 315
IX
Preface
Determinationsofserumlevelsofalkalinephosphatase(AP)isozymesareperhaps
the most widely used biochemical measurements in the clinical laboratory but,
despitetheirwidespreadclinicalutility,thestructureandbiologicalfunctionsofthese
widelyknownenzymeshaveremainedelusivefordecades.However,greatprogress
isnowbeingmadeinthisareaofresearchthatjustifiesthewritingofthismonograph
summarizingmajorrecentadvances.Thisbookisnotintendedtobeanexhaustive
treatiseonthesubject.AsuperbcompilationonAPs,summarizingknowledgeinthis
fielduptothelate70s,waspublishedbyDrsRobertMcComb,GeorgeBowersand
SolomonPosen(McCombetal.,1979)forreferencespublishedbefore1979,butafew
paperspublishedinthe1960sand1970sarespecificallycitedherebecauseoftheir
uniquerelevancetosomeofourdiscussions.Twosubsequentreports,muchsmaller
inscoperelativetoMcCombetal.’simpressivebook,havealsobeenpublished:the
first(HumanAlkalinePhosphatases,inProgressinClinicalandBiologicalResearch,
Vol.166,EditorsTorgnyStigbrandandWilliamH.Fishman,AlanR.Liss,NewYork,
1984),reportedtheProceedingsoftheFirstSymposiumonAlkalinePhosphatases
heldinUme(cid:2),Sweden,September16–17,1983.Thesecond,publishedasaspe-
cial issue of Clinica Chimica Acta [Vol 186 (2), pp. 125–320, 1990; Guest Editor
Jos(cid:3)LuisMill(cid:4)n],presentedselectedpapersfromtheThirdAlkalinePhosphatase
SymposiumthattookplaceattheLaJollaCancerResearchFoundationonFebru-
ary1–3,1989,ontheoccasionofDrWilliamH.Fishman’sretirement.Iwillrefer
toindividualpapersinthesetwosmallvolumeswhenneeded.
The present work is intended to highlight and discuss key new information
obtainedinthelast25years(1980–2005),withspecialemphasisonthestructure
oftheproteinsandgenes,thefunctionoftheisozymesasrevealedfromthestudy
ofthe individual mouseknockoutstrainsandnewuses ofthese isozymesinthe
clinical setting and in biotechnology. In this period, approximately 5000 papers
havebeenpublishedcontainingalkalinephosphataseinthetitle.Ifonesearches
forpapersusingalkalinephosphataseasakeyword,thenumberclimbsto36000.
Hence it would have been impossible to cite each of these references in a small
treatisesuchasthisandIapologizetothoseresearcherswhoseworkiseithernot
cited or not presented in as much detail as I would have liked. Owing to space
considerations, I have chosen to cite those references that, in my opinion, best
illustrate new findings, a novel property or a function that advances the field.