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AcademicPressisanimprintofElsevier 225WymanStreet,Waltham,MA02451,USA 525BStreet,Suite1800,SanDiego,CA92101-4495,USA TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK 125LondonWall,London,EC2Y5AS,UK Firstedition2015 Copyright©2015ElsevierInc.Allrightsreserved. Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans, electronicormechanical,includingphotocopying,recording,oranyinformationstorageand retrievalsystem,withoutpermissioninwritingfromthepublisher.Detailsonhowtoseek permission,furtherinformationaboutthePublisher’spermissionspoliciesandour arrangementswithorganizationssuchastheCopyrightClearanceCenterandtheCopyright LicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions. Thisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightby thePublisher(otherthanasmaybenotedherein). Notices Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchand experiencebroadenourunderstanding,changesinresearchmethods,professionalpractices, ormedicaltreatmentmaybecomenecessary. Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgein evaluatingandusinganyinformation,methods,compounds,orexperimentsdescribed herein.Inusingsuchinformationormethodstheyshouldbemindfuloftheirownsafetyand thesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility. Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors, assumeanyliabilityforanyinjuryand/ordamagetopersonsorpropertyasamatterof productsliability,negligenceorotherwise,orfromanyuseoroperationofanymethods, products,instructions,orideascontainedinthematerialherein. ISBN:978-0-12-803908-3 ISSN:1874-6047 ForinformationonallAcademicPresspublications visitourwebsiteathttp://store.elsevier.com/ CONTRIBUTORS HiroyukiArai DepartmentofHealthChemistry,GraduateSchoolofPharmaceuticalSciences,the UniversityofTokyo,andAMED-CREST,JapanAgencyforMedicalResearchand Development,Tokyo,Japan BrianJ.Bahnson DepartmentofChemistryandBiochemistry,UniversityofDelaware,Newark,Delaware, USA GaryD.Clark DepartmentofPediatrics,NeurologyandNeuroscience,BaylorCollegeofMedicine,and TexasChildren’sHospital,Houston,Texas,USA TaraD.Gonzalez DepartmentofChemistryandBiochemistry,UniversityofDelaware,Newark,Delaware, USA MitsuharuHattori DepartmentofBiomedicalScience,GraduateSchoolofPharmaceuticalSciences,Nagoya CityUniversity,Nagoya,Aichi,Japan KeizoInoue FacultyofPharmaceuticalSciences,TeikyoUniversity,Tokyo,Japan SoniaKarabina SorbonneUniversite´s,UPMC,INSERMUMRS933,HoˆpitalArmand-Trousseau,Paris, France KenKarasawa FacultyofPharmaceuticalSciences,TeikyoUniversity,Tokyo,Japan MeghanM.Klems DepartmentofChemistryandBiochemistry,UniversityofDelaware,Newark,Delaware, USA NozomuKono DepartmentofHealthChemistry,GraduateSchoolofPharmaceuticalSciences,the UniversityofTokyo,Tokyo,Japan EwaNinio SorbonneUniversite´s,UPMC,INSERMUMRS1166,ICAN,Genomicsand PathophysiologyofCardiovascularDiseasesTeam,Paris,France DianaM.Stafforini HuntsmanCancerInstituteandDivisionofCardiovascularMedicine,Departmentof InternalMedicine,UniversityofUtah,SaltLakeCity,Utah,USA ix PREFACE Platelet-activating factor (PAF) is a lipid mediator involved in a variety of physiologicalfunctions.Oneofthekeyenzymesthatappeartobeinvolved in the regulation of PAF levels is a phospholipase A2 that catalyzes the hydrolysisoftheacetylgrouppresentinPAF.Thediscoveryofthisenzyme, calledplatelet-activatingfactoracetylhydrolase(PAF-AH),inthe1980sled tosubsequentstudiesthatidentifiedadditionalacetylhydrolaseswithsimilar properties. This work from multiple laboratories across the world defined “PAF-AH”asafamilyofenzymes,characterizedthestructureandproper- ties of individual members, identified substrates recognized by each of the proteins, and elucidated the mechanisms involved in substrate hydrolysis. Inaddition,thesignificanceofPAF-AHinphysiologyanddiseasehasbeen investigated in a large number of studies that used biochemical, molecular, genetic, and pharmacologic approaches. Therearethreetypesofenzymesthatcatalyzethehydrolysisoftheacetyl esterofPAF.Oneisanextracellularenzyme(plasmaPAF-AH)andtwoare intracellularenzymes(PAF-AHIandII).InChapter1,weprovideanover- view of this enzyme family. Chapters 2–5 deal with the two intracellular forms and Chapters 6–10 discuss thesecreted form of theenzyme. Diverse functions of PAF-AH are discussed throughout the volume. Theideaofcompilingourknowledgeonthisimportantenzymefamily wasconceivedinlate2014.Withextraordinaryeffortfromallthecontrib- utors,wehavebeenabletoassemblethisvolumeinarelativelyshortperiod oftime.Weareverygratefultotheauthorswhosubmittedtheirchaptersina timely fashion. There are, however, a number of topics that we could not cover suffi- cientlyinthisvolume,primarilyduetospaceconstraints.Forexample, we could only briefly discuss the topic regarding small-molecule inhibitors of PAF-AH.This,aswellasothertopics,willbethefocusofafuturevolume focused on PAF-AH. We would like to thank Mary Ann Zimmerman and Helene Kabes of Elsevier for their guidance and encouragement. KEIZO INOUE DIANA STAFFORINI FUYUHIKO TAMANOI October 2015 xi CHAPTER ONE Overview of PAF-Degrading Enzymes Ken Karasawa, Keizo Inoue1 FacultyofPharmaceuticalSciences,TeikyoUniversity,Tokyo,Japan 1Correspondingauthor:e-mailaddress:[email protected] Contents 1. Introduction 2 2. IntracellularPAF-AHI 5 2.1 Characteristics 5 2.2 BrainDevelopment 6 2.3 Spermatogenesis 7 2.4 AβGenerationandSecretion 7 2.5 CancerPathogenicity 8 2.6 ProteinTraffickingandSorting 9 2.7 AspirinMetabolism 9 3. IntracellularPAF-AHII 10 3.1 Characteristics 10 3.2 ProtectiveRoleAgainstOxidativeStress 10 3.3 EpidermalMorphogenesis 11 3.4 TransacetylationfromPAFtoOtherLipidMediators 12 4. PlasmaPAF-AH 13 4.1 Characteristics 13 4.2 InvolvementofAtherosclerosis 13 4.3 InvolvementinAsthma 14 5. Conclusion 15 References 16 Abstract Because the acetyl group of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (PAF) is essentialforitsbiologicalactivity,thedegradationofPAFisthemostimportantmech- anismthatregulatesthelevelofPAF.Theenzymethatcatalyzesthehydrolysisofacetyl group at the sn-2 position of PAF was termed PAF-acetylhydrolase (PAF-AH). Subse- quent research revealed that the PAF-AH family includes intracellular forms called PAF-AH I and PAF-AH II as well as an extracellular isoform, plasma PAF-AH. PAF-AH I forms a complex consisting of catalytic subunits α , α , and β regulatory subunits. 1 2 PAF-AH I was identified from the brain, and previous studies focused on the role of PAF-AHIinbraindevelopment.However,subsequentstudiesfoundthatPAF-AHIis TheEnzymes,Volume38 #2015ElsevierInc. 1 ISSN1874-6047 Allrightsreserved. http://dx.doi.org/10.1016/bs.enz.2015.09.006 2 KenKarasawaandKeizoInoue involved in diverse functions such as spermatogenesis, amyloid-β generation, cancer pathogenesis,andproteintrafficking.Anotherintracellularenzyme,PAF-AHII,hasno homologywithPAF-AHI,althoughthisenzymesharessequencesimilaritytoplasma PAF-AH.BecausePAF-AHpreferentiallyhydrolyzesoxidativelymodulatedortruncated phospholipids,itisconsideredtoplayaprotectiveroleagainstoxidativestress.Homo- logsofthisenzymearewidelydistributedamongevolutionarilydiverseorganisms.For example, studies of Caenorhabditis elegans PAF-AH II demonstrate itscontribution to epidermalmorphogenesis.ExtracellularplasmaPAF-AHassociatesstronglywithplasma lipoproteins.BecausePAF-AHismainlyassociatedwithLDLparticles,itisconsideredto playananti-inflammatoryrolebyremovingoxidizedphospholipidsgeneratedinLDLs exposedtooxidativestress.Inthisoverview,wedescribethecrucialrolesofthesethree PAF-degradingenzymesincellfunctionandcellpathology. 1. INTRODUCTION Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3- phosphocholine)isaphospholipidthatisapotentmediatorofdiversephys- iological events. The sn-2 acetyl group is essential for the activity of PAF via a specific receptor because lysoPAF (1-O-alkyl-sn-glycero-3- phosphocholine), which is produced by removal of the sn-2 acetyl group, lacksthebiologicalandpharmacologicalactivitiesofPAF(Fig.1).Farretal. [1] first detected enzyme activities in human sera that inactivate PAF through the degradation of the acetyl ester at the sn-2 position [2]. Blank etal.detectedPAF-degradingactivitiesinthecytosolicfractionofavariety of rat tissues [3]. Extracellular and intracellular enzymes are Ca2+ indepen- dent and are distinguished from phospholipase A that hydrolyzes a long- 2 chainacylresiduelocatedatthesn-2positionofphospholipids.Researchers termedtheseenzymesPAF-degradingenzymes,namelyPAF-acetylhydrolase (PAF-AH). Studies on enzymes that degrade the acetyl ester moiety of PAF revealed one extracellular and two intracellular enzymes (Table 1). CH−O−(CH)CH CH−O−(CH) CH O 2 2n 3, n=15,17 2 2n 3, n=15,17 HO CHCOOH 2 3 CH−C−O−C−H HO−C−H 3 O O + PAF-AH + CH−O−P−O−(CH)−N(CH) CH−O−P−O−(CH)−N(CH) 2 22 33 2 22 33 O O PAF LysoPAF Figure1 DegradationofPAFbyPAF-acetylhydrolase(PAF-AH). Table1 IntracellularandExtracellularEnzymesThatDegradePAF Localization Intracellular Extracellular Group of Group VIII Group VIIB Group VIIA phospholipase A 2 Conventional PAF-AH I PAF-AH II Plasma PAF-AH name (Lp-PLA ) Ia Ib 2 Structural features Catalytic Complexconsistingofcatalyticdimmer, (cid:129) Monomer (cid:129) Monomer dimmer, α α and/orα withregulatorydimmer,β (cid:129) Myristoylated at the (cid:129) Association with 1 1 2 and/or α N-terminus lipoproteins 2 Source Intracellular Intracellular proteins inmammal Intracellular proteins in Secreted proteins from proteins in mammal to C.elegans liver, platelet, mammal macrophage Subunits α α β 1 2 Gene symbol PAFAH1B3 PAFAH1B2 PAFAH1B1 PAFAH2 PLA2G7 approved by HGNC Subunit name Ib3 Ib2 Ib1 based on gene symbol Molecular mass 29 30 45 40 44 (kDa) Amino acids 231 229 411 392 441 Continued Table1 IntracellularandExtracellularEnzymesThatDegradePAF—cont'd Localization Intracellular Extracellular Gene identity (%) 62.4%! 43.0%! Cytogenetic 19q13.2 11q23.3 17p13.3 1p36.11 6p21.1 location Enzyme reaction (cid:129) Hydrolysis of acetyl residue of (cid:129) Hydrolysis of acyl residue of oxidized phospholipids and other lipids phospholipids (cid:129) Hydrolysis ofacetyl residue ofaspirin (cid:129) Transacetylation from PAFto other acceptor lipids OverviewofPAF-DegradingEnzymes 5 They were conventionally named PAF-AH I, PAF-AH II, and plasma PAF-AH (Lp-PLA ). 2 Schaloske and Dennis classified these phospholipase A isoforms as 2 groups VIII, IIB, and IIA, respectively [4]. Although PAF is the primary endogenous substrate for these enzymes, the structural requirements for the substrate are varied. For example, Gelb et al. reported that plasma PAF-AH and PAF-AH II hydrolyze short-chain diacylglycerols, triacylglycerols, and acetylated alkanols [5], suggesting that the minimal structuralrequirementforasubstrateisthepositionofaglyceridederivative thatincludesan sn-2ester andareasonablyhydrophobicchainin theposi- tionoccupiedbythesn-1chain.Inaddition,aspirinisdegradedbyPAF-AH I in erythrocytes [6]. PAF-AH I was reported to be involved in various events such as brain development and spermatogenesis. As described later, PAF-AHIImayfunctionasaprotectoragainstoxidativestress-inducedcell injuryanddysfunctionbyhydrolyzinganoxidizedacylresidueinphospho- lipids [7–12]. Various interesting observations, which suggest that the enzyme may playaroleinregulationofcellularfunctionsindependentofitsdegradation of PAF, have recently been reported [13,14]. In this chapter, we focus on canonical PAF-AH, although it is unknown whether certain physiological roles of these enzymes are mediated through the degradation of PAF. 2. INTRACELLULAR PAF-AH I 2.1 Characteristics Hattorietal.detectedintracellularPAF-AHactivitiesinbovinebraincyto- sol[15].Thetwopeaksofenzymeactivityresolvedusingion-exchangecol- umn chromatography are designated as PAF-AH I and PAF-AH II. HydroxyapatitecolumnchromatographyseparatesPAF-AHIintotwofrac- tionsdesignatedIaandIb.PurifiedPAF-AHIbformsacomplexcomprising noncatalytic45-kDaandcatalytic30and29-kDasubunits.PAF-AHIalacks the 45-kDa polypeptide. These subunits were first named α, β, and γ, respectively,butwererenamedβ,α ,andα ,respectively,becausetheter- 2 1 tiary folding of the catalytic subunits is reminiscent of the GTP-binding domainoftheαsubunitoftrimericG-proteins[16].Certainresearchgroups use the designations Ib1 (β), Ib2 (α ), and Ib3 (α ) according to the gene 2 1 symbols approved by the Human Gene Nomenclature Committee (Table 1). 6 KenKarasawaandKeizoInoue TheaminoacidsequenceofhumanPAF-AHIbα is62.4%identicalto 1 that of the α subunit [17,18]. The cDNAs of three subunits were cloned 2 from bovine [19–21], human [17,18], mouse [22], and rat [23] tissues, and their predicted amino acid sequences are highly similar. Moreover, thesequencesoftheα subunitsaremorethan95%identical.Althoughboth 1 catalytic subunits do not contain the conserved serine residue within the esterase consensus sequence (Gly-X-Ser-X-Gly), an active serine residue was identified on the basis of incorporation of [3H]DFP in the enzyme and the presence of the chymotrypsin-like Ser-Asp-His triad [20]. PAF-AHIb was first detected in bovine brainas a complex comprising α andα heterodimersandtheβsubunit.However,α ismuchmoreabun- 1 2 2 dantthanα intheanimaltissues[18,21,24].Comparedwiththeα subunit, 1 2 theexpressionoftheα subunitisrelativelyrestrictedtotissuessuchasfetal 1 brain [24], spermatogonia [25], and red blood cells [26]. The α-dimer subunit was detected as a discrete species or in a complex withtheβsubunit.Thus,sixisoformsformedbytheα /α ,α /α ,andα / 1 2 1 1 2 α homodimersandtheircomplexeswiththeβsubunitmayexistinnature. 2 Studiesofeachsubunitexpressedusingthebaculovirussystemshowthatthe substratespecificitiesofthethreeαdimersdifferandaremodulatedbybind- ing to the β subunit in a manner dependent on dimer composition [27]. 2.2 Brain Development The β subunit of the human PAF-AH Ib complex, which is encoded by LIS1 that when deleted or mutated causes Miller–Dieker lissencephaly, interacts with the microtubule motor cytoplasmic dynein, in contrast to the α subunits, and may stimulate dynein functions related to neuronal migrationandaxonalgrowth[19].Becauseswitchingcatalyticsubunitsfrom theα /α heterodimertotheα /α homodimerinratneuronalcellsoccurs 1 2 2 2 duringpostnatalstages,thissuggeststhateithertheα /α heterodimerorits 1 2 complexwiththeβsubunitplaysavitalroleinneuronaldevelopment[24]. Because the β subunit of PAF-AH Ib is the product of LIS1, researchers’ interestfocusedontheroleofthePAF-AHαsubunitsinneuronalmigration during brain development. For example, LIS1 mutations detected in a patient with lissencephaly alter or abolish the binding with the α and α 1 2 catalytic subunits [28]. Overexpression of the α subunits, particularly α , 2 in Chinese hamster ovary (CHO) cells induces changes in nuclear shape, centrosomal amplification, and microtubule disorganization [29]. The cat- alytic activity and binding of α to LIS1/β are necessary for this effect, 2 because a catalytically inactive α mutant abolishes LIS1/β binding. At 2 OverviewofPAF-DegradingEnzymes 7 present,itisbelievedthatLIS1/βprimarilyregulatesthelocationofdynein on microtubules through the combined activities of accessory proteins. In addition to the PAF-AH I catalytic subunits, LIS1/β binds proteins such as tubulin, CLIP-170, Nde1 (formerly NUDE), and Ndel1 (formerly NUDEL). For example, Kitagawa et al. found that Nde1, the mammalian homolog of fungal nuclear distribution gene (rNUDE), and the catalytic subunits of PAF-AH I competitively interact with LIS1/β [30]. Tarricone etal.foundthataLIS1/βhomodimerbindstoeitheraPAF-AHα homo- 2 dimerorNdel1toformatetramer[31].Ndel1andNde1bindcompetitively to PAF-AH I α subunits. Thus, LIS1/β function may be differentially reg- ulatedduringneuronalmigrationbytheinteractionofLIS1/βwithmultiple protein partners such as PAF-AH I α subunits. Theimportanceof PAF-AHIbin braindevelopmentisemphasizedby the findings of a chromosomal genomics approach [32]. Nothwang et al. analyzed the reciprocal chromosomal translocation t(1;19)(q21.3;q13.2) in afemalewithmentalretardation,ataxia,andatrophyofthebrainandfound thatthegeneencodingPAF-AHIα isdisruptedbetweenexons4and5by 1 thetranslocationofchromosome19q13.2[32].Thistranslocationtruncates the allele that encodes a protein with only first 136 of 232 amino acid res- idues.Because 47-Sercannot form acatalytictriad with 192-Aspand 195- His, this truncated protein is catalytically inactive. The functional hemizygosity of the α subunit of this patient suggested that PAF-AH Ib 1 plays an important role in normal brain development and function. 2.3 Spermatogenesis Koizumietal.[25]andYanetal.[33]independentlyreportedthatthecat- alytic subunits of PAF-AH I are involved in spermatogenesis. Adult mice abundantly expressed the α , α , and β subunits of PAF-AH I in the brain 1 2 andtestis,andKoizumietal.[25]foundthatα isspecificallylocalizedinthe 1 cytoplasm of spermatogonia and that the α and β subunits are widely 2 expressed in the cytoplasm of all types of spermatogenic cells and Sertoli cells. Both research groups generated knockout mice that lack the α and 1 α genes and found that deficiency of these catalytic subunits affects sper- 2 matogenesis [25,33]. 2.4 Aβ Generation and Secretion Evidenceindicatesthattheamyloid-β(Aβ)peptideplaysanimportantrole in the pathogenesis of Alzheimer disease. Using RNA interference- mediated knockdown to screen a Drosophila genomic library, Page

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This volume of The Enzymes summarizes the most important discoveries associated with a group of enzymes that play an important role in normal biological processes as presented and discussed by leaders authorities in the field.Contributions from leading authoritiesInforms and updates on all the lates
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