Platelet-Activating Factor Acetylhydrolases (PAF-AH)

208 Pages·2015·14.77 MB·English

by  Fuyuhiko Tamanoi

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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