Flux Balance Analysis of Mycolic Acid Pathway Targets for Anti-Tubercular Drugs 英文参考文献.docVIP

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Flux Balance Analysis of Mycolic Acid Pathway Targets for Anti-Tubercular Drugs 英文参考文献.doc

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Flux Balance Analysis of Mycolic Acid Pathway Targets for Anti-Tubercular Drugs 英文参考文献

FluxBalanceAnalysisofMycolicAcid Pathway:TargetsforAnti-TubercularDrugs Karthik Raman, Preethi Rajagopalan, Nagasuma Chandra* BioinformaticsCentre,SupercomputerEducationandResearchCentre,IndianInstituteofScience,Bangalore,India Mycobacteriumtuberculosisisthefocusofseveralinvestigationsfordesignofnewerdrugs,astuberculosisremainsa major epidemic despite the availability of several drugs and a vaccine. Mycobacteria owe many of their unique qualitiestomycolicacids,whichareknowntobeimportantfortheirgrowth,survival,andpathogenicity.Mycolicacid biosynthesishasthereforebeenthefocusofanumberofbiochemicalandgeneticstudies.Italsoturnsouttobethe pathwayinhibitedbyfront-lineanti-tuberculardrugssuchasisoniazidandethionamide.Recentyearshaveseenthe emergenceofsystems-basedmethodologiesthatcanbeusedtostudymicrobialmetabolism.Here,weseektoapply insightsfromflux balanceanalysesofthemycolic acid pathway(MAP)for theidentification ofanti-tuberculardrug targets.WepresentacomprehensivemodelofmycolicacidsynthesisinthepathogenM.tuberculosisinvolving197 metabolitesparticipatingin219reactionscatalysedby28proteins.Fluxbalanceanalysis(FBA)hasbeenperformedon theMAPmodel,whichhasprovidedinsightsintothemetaboliccapabilitiesofthepathway.Insilicosystematicgene deletionsandinhibitionofInhAbyisoniazid,studiedhere,providecluesaboutproteinsessentialforthepathwayand henceleadtoarationalidentificationofpossibledrugtargets.FeasibilitystudiesusingsequenceanalysisoftheM. tuberculosis H37Rv and human proteomes indicate that, apart from the known InhA, potential targets for anti- tubercular drug design are AccD3, Fas, FabH, Pks13, DesA1/2, and DesA3. Proteins identified as essential by FBA correlatewellwiththosepreviouslyidentifiedexperimentallythroughtransposonsitehybridisationmutagenesis.This studydemonstratestheapplicationofFBAforrationalidentificationofpotentialanti-tuberculardrugtargets,which canindeedbeageneralstrategyindrugdesign.Thetargets,chosenbasedonthecriticalpointsinthepathway,forma readyshort