OptForce An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions 英文参考文献.docVIP

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OptForce An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions 英文参考文献.doc

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OptForce An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions 英文参考文献

OptForce:AnOptimizationProcedureforIdentifyingAll GeneticManipulationsLeadingtoTargeted Overproductions SridharRanganathan1,PatrickF.Suthers2,CostasD.Maranas2* 1HuckInstitutesofLifeSciences,ThePennsylvaniaStateUniversity,UniversityPark,Pennsylvania,UnitedStatesofAmerica,2DepartmentofChemicalEngineering,The PennsylvaniaStateUniversity,UniversityPark,Pennsylvania,UnitedStatesofAmerica Abstract Computational procedures for predicting metabolic interventions leading to the overproduction of biochemicals in microbialstrainsarewidelyinuse.However,thesemethodsrelyonsurrogatebiologicalobjectives(e.g.,maximizegrowth rateorminimizemetabolicadjustments)anddonotmakeuseoffluxmeasurementsoftenavailableforthewild-typestrain. In this work, we introduce the OptForce procedure that identifies all possible engineering interventions by classifying reactionsinthemetabolicmodeldependinguponwhethertheirfluxvaluesmustincrease,decreaseorbecomeequalto zero to meet a pre-specified overproduction target. We hierarchically apply this classification rule for pairs, triples, quadruples,etc.ofreactions.Thisleadstotheidentificationofasufficientandnon-redundantsetoffluxesthatmustchange (i.e.,MUSTset)tomeetapre-specifiedoverproductiontarget.Startingwiththissetwesubsequentlyextractaminimalsetof fluxesthatmustactivelybeforcedthroughgeneticmanipulations(i.e.,FORCEset)toensurethatallfluxesinthenetwork are consistent with the overproduction objective. We demonstrate our OptForce framework for succinate production in EscherichiacoliusingthemostrecentinsilicoE.colimodel,iAF1260.Themethodnotonlyrecapitulatesexistingengineering strategies but also reveals non-intuitive ones that boost succinate production by performing coordinated changes on pathwaysdistantfromthelaststepsofsuccinatesynthesis. Citation:RanganathanS,SuthersPF,MaranasCD(2010)OptForce:AnOptimizationProcedureforIdentifyingAllGeneticManipulationsLeadingtoTargeted Overproductions.PLoSComputBiol6(4):e1000744.doi:10.1371/journal.pcbi.1000744 Editor