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Analysis of the Glutathione S-Transferase (GST) Gene Family

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Analysis of the Glutathione S-Transferase (GST) Gene Family UPDATE ON GENOMECOMPLETION AND ANNOTATIONS Analysisofthe glutathione S -transferase ( GST )genefamily DanielW.Nebert1 *andVasilisVasiliou2 1 Department ofEnvironmentalHealthandCenterfor EnvironmentalGenetics(CEG),University ofCincinnatiMedicalCenter, Cincinnati, OH 45267–0056,USA 2 MolecularToxicologyandEnvironmentalHealthSciencesProgram,Department ofPharmaceuticalSciences,University ofColorado HealthSciencesCenter,Denver,CO80262,USA * Correspondence to:Tel: þ 1513 558 4347; Fax: þ 1513 558 3562; E-mail:[email protected] Datereceived (inrevised form):4thAugust2004 Abstract The glutathione S -transferase( GST)genefamily encodesgenesthatarecriticalfor certainlife processes,aswell asfor detoxication and toxification mechanisms,via conjugation ofreduced glutathione(GSH)withnumerous substratessuch aspharmaceuticals andenvironmental pollutants. The GST genesareupregulated inresponseto oxidativestress andareinexplicably overexpressed inmany tumours,leadingto problems duringcancerchemotherapy.Ananalysisofthe GST genefamily inthe HumanGenomeOrganization-sponsored HumanGene NomenclatureCommittee databaseshowed 21 putatively functionalgenes. Upon closerexamination,however,GST-kappa1(GSTK1 ), prostaglandinEsynthase( PTGES)andthree microsomalGSTs(MGST1 , MGST2 , MGST3 )weredetermined asencodingmembrane-bound enzymeshavingGST-likeactivity,but thesegenesarenot evolutionarily related to the GST genefamily.Itisconcluded thatthe complete GST genefamily comprises16genesinsixsubfamilies—alpha ( GSTA ),mu ( GSTM),omega ( GSTO ),pi( GSTP),theta( GSTT)andzeta( GSTZ). Keywords: humangenome, glutathione S -transferasegenefamily,microsomalglutathione S -transferases,prostaglandinEsynthase, MAPEG family, DsbA-likethioredoxindomain Introduction identification ofotherrelated members inbothdatabase searchesandthe literature. Onegoalofthis‘Updateon GenomeCompletion andAnno- Homologous regions of15–25percent ofnucleotidesor 1,2 tations’ series hasbeentoselectagene, or genefamily, amino acidscanbe detected bythe various alignment check for accuracyinthe databases,andthenhelp to suggest programs,denotingdivergence fromanancestralgene;asmall ways to correctany nomenclatureproblems thatmightexist. almost-invariant DNA motif or proteindomain—function- The glutathione S -transferases(GSTs) represent animportant ingasanenzymeactive-site, cofactor dockingsiteor ligand- group ofenzymeswhich detoxifybothendogenous com- bindingsite—isfurtherevidence ofdivergence froman poundsandforeignchemicals such aspharmaceuticals and ancestralgene.Oneofthe earliest examplesofthisnomen- environmentalpollutants. Although alarge numberofreviews clatureapproach for homologous geneswasthe cytochrome 3–11 about thisimportant enzymefamily haveappeared, there P450(CYP )genesuperfamily,inwhich itwasagreed that continuestobe considerableconfusion inthe fieldwithregard approximately 40percent or moreamino acid similarity to the namingandclassification ofthesegenesandgene allows twomembers to be placed inthe samefamily andabout products. 55 percent or greatersimilarity allows twomembers to be Homologous genes,havingacommon ancestralorigin assigned to the samesubfamily. 1 Thesecut-off valuesfollow 2billion years agoormore, canbe identifiedmorereadily, the originalrecommendations byMargaretDayhoff.At if theyaredesignated withastem(or root) symbol.Aroot present,morethan130 additionalgenesuperfamiliesand symbol isvery much encouraged bythe HumanGene large genefamilieshavesince followed thissameformat.1 NomenclatureCommittee (HGNC)asthe basisfor ahie- rarchicalseriesofgenes(eg for the ABC family,subfamily A , ABCA1 , ABCA2 , ABCA3 , ABCA4)thatareeitherthe Biochemistryofthe GST enzymes result ofevolutionary divergence ofanancient ancestralgene, or haveconserved functions—via pathways,interactions or The fundamentalbasisfor all GST catalytic activitiesisthe proteindomains. Such aroot symbol allowsthe easy capacity oftheseenzymestolowerthe pK a ofthe sulfhydryl 460 q HENRYSTEWART PUBLICATIONS 1473–9542. HUMANGENOMICS .VOL1. NO 6. 460–464NOVEMBER 2004 Nebert andVasiliou UPDATE ON GENOMECOMPLETION AND ReANNOTview ATIONS group ofreduced glutathione(GSH)from9.0 inaqueous examplesof convergent,ratherthandivergent,evolution;at solution to about6.5whenGSH isboundinthe activesite. 12 aparticularpoint intimeduringevolution,MotherNature GSH exists asthe thiolate(GS2 )anion atneutralpHwhen required anenzymeto carryout such amembrane-bound complexed withthe GST enzyme.CatalysisbyGSToccurs catalytic reaction andassigned thattaskto anenzymeclass through the combined capacity ofthe enzymeto promote different fromthatofthe cytosolic GSTs. GS2 formation andto bindhydrophobic electrophilic The realGSTshavethe twodomains GST_N 17 and compoundsataclosely adjacent site. 3 The GSH-bindingand GST_C. 18 Oneor the otherofthesedomains appears ina the hydrophobic substrate-bindingsiteshavebeencalled the numberofotherproteins.Thismightexplainwhysomeother G- andH-sites,respectively. 13 Inthe caseofcertainsubstrates proteins exhibitGST-likeactivity. (eg benzyl andphenethyl isothiocyanates,alkyl dihalides), GST cancatalyseboththe forwardandreversereactions, leadingto increased toxicity ratherthandetoxication. 3 HGNC search for GST genes The activecytosolic enzymeexistsasadimeroftwo subunits.3,4 Aquick search ofthe GST genedatabase(Table1) showed 22 putatively functionalgenesandfivepseudogenes. Upon closerinspection, 19 itwasdetermined that GSTM1L isa Evolution ofthe GST genes pseudogene—which changesthe numberto21functional genesandsixpseudogenes. Thereisaclusteroffive GSTA GSTsarewidely distributed innature—frombacteria and geneslocated atChr6p12; aclusteroffive GSTM genesat yeast to plants andanimals. Plant GSTsinclude the phi, 1p13;two GST-omegagenesat10q25.1; GSTP1 at11q13- tau,theta, zetaandlambda classes; the thetaandzetahave qter; two GST-thetagenesat22q11.2; andasinglegene counterpartsinanimals.4,5 The sigmaandthetaclassesare GSTZ1 at14q24.3. Pseudogenesareoftenfoundatdifferent abundant innon-vertebrateanimals.3 Thereissignificant chromosomallocationsfromthe clusteroffunctionalgenes homologybetweenaclass thetaGST andadichloromethane fromwhich the pseudogenesoriginated.Interestingly, dehalogenaseenzymefromthe prokaryote Methylobacterium, 14 GSTZ1isidenticaltomaleylacetoacetateisomerase, akey suggestingthatthe ancestralprogenitor for mammalian enzymeintyrosinecatabolism,catalysingthe GSH- GSTsprobably arosefromthe thetaclass. dependent isomerisation ofmaleylacetoacetateto fumarylace- The analysisinthisreviewwill focus only on human GST toacetate. 20 genes. Numerous polymorphisms exist inthe human GST Itwill be shownthatthe remainingfivegenes— GSTK1 , genes, 10,11 includingthe completeabsence ofthe GSTM1 or PTGES andthe three microsomal GSTs—arenot evolu- the GST theta1gene—atfrequenciesashigh as20percent tionarily part ofthe GST genefamily.Phylogenetic analysis to 50percent insomepopulations. Giventhe absence in (Figure1) placesthesefivegenesatoneedge ofthe putative certainGST activities,onecansee how thismightlead to evolutionary tree,atalmost the samedistance asthe GSTW, decreased detoxication ofenvironmentalcarcinogens or GSTZ1 and GSTQ genesatthe otheredge.The tree-making chemotherapeutic agents andthus to clinicalproblems in algorithm,however,scoressequence similarity betweeneach patientslackingthesegenes. Evidence isalso emergingthat pairofproteinsequences. Whatthe tree showsisthatthe GST genesfromsomepathogens mightexert immunomo- omega, zetaandthetaGSTsarealmost asdissimilartothe dulatory functions towardsthe immunesystem,involving othermoretypicalGSTsasarethe GSTK1,PTGES andthree separateprofilesofcytokinegenetranscription anddifferent microsomalGST proteins. patternsofcell growth. 6 Antioxidants,aswell asoxidative Bymeans ofCLUSTAL alignment, 21 consensus GST_N stress,induce transcription ofmany ofthe GST genes, 8,9 andGST_Cdomains werefound, plus significant stretchesof leadingto increased protection ofthe cell againstinsult by sequence alignment,for the above-mentioned 16 GST genes environmentalchemicals anddrugs. (Figure2),but noneofthesewerefoundinthe otherfive genes(datanot illustrated). Upon furtheranalysis,itwasdis- covered thatthe microsomal GSTs,aswell asprostaglandinE Cytosolic versus membrane-bound synthase, belongto the m embrane-a ssociated p roteins in GSTs e icosanoid and g lutathionemetabolism (MAPEG)genefamily (pfam01124). Dueto structuralsimilaritiesinthe activesitesof Many ofthe GST reviews include membrane-boundaswell as 5-lipoxygenase-activatingprotein(FLAP),leukotrieneC4 4,7 15 cytosolic enzymes. MicrosomalGST andleukotrieneC4 synthaseandprostaglandinEsynthase, substratesfor synthase 16 havebeendescribed asmembers ofthe GSTfamily, each enzymecancompetewithoneanotherandmodulate although ithasbeennoted3 thatneithersharessequence synthetic activity. 22 Bycontrast,GSTK1hasabacterial identity withthe cytosolic GSTs. Itwouldthereforeappear disulphide-bond-A (DsbA)-likethioredoxindomain likely thatthesemembrane-boundGST enzymesrepresent (pfam01323)andisamemberofadiversesetofproteins q HENRYSTEWART PUBLICATIONS 1473–9542. HUMANGENOMICS .VOL1. NO 6. 460–464NOVEMBER 2004 461 UPDATEReONvieGENOMw ECOMPLETION AND ANNOTATIONS Nebert andVasiliou Ta ble1. List ofhuman GST putatively functionalgenes. Approved genesymbol Approved genenameChromosomallocation GSTA1 Glutathione S -transferase(alpha)A16p12 GSTA2 Glutathione S -transferaseA26p12.2 GSTA3 Glutathione S -transferaseA36p12 GSTA4 Glutathione S -transferaseA46p12 GSTA5 Glutathione S -transferaseA56p12.1 GSTAP1 Glutathione S -transferaseApseudogene1Reserved GSTAP2
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