Honours Project 2004- “Metabolic Pathways” Literat

HonoursProject2004-\MetabolicPathwaysLiteratureReviewTimConradCSSEMonashUniversity,[e-mail]misthesumofallanorganism'schemicalreactions.Almosteverymetabolic(orbiochemical)reactionconvertsamoleculecalled`Substrate'toamoleculecalled`Product'(Figure1-left).Thearrowindicatesthe`direction'ofthereaction.Ametabolicpathwaysisasequenceofmetabolicreactions(Figure1-right).Metabolicpathwaysarecomplexnetworkscombiningalargevolumeofdi-versebiological,chemical,andphysicaldata.Becausetheunderlyingbiologicaldataisoftenincompleteandbiasedthedevelopmentofcorrectmodelsisachal-lengetotheoreticalbiology.Computationalmethodsareneededtomodelthecomplexbiologicalprocessesinordertoanalyzeandunderstandthem.Duringthelastdecadesremarkableprogresshasbeenachievedinthe¯eldofmolecularbiology,progressthathasledtoabetterunderstandingofbiologicalsystemsatacellularandmolecularlevel.Newhigh-throughputtechniqueshaveenabledsequencingofwholegenomes,whichleadtotheuncoveringofnewrelationshipsinmetabolicpathways.Other`low-throughput'studiesthatfocusedonspeci¯cphenomenainthecellhavealsoaidawealthofinformation.Thankstothis,wenowhaveageneralideaoftheinteractioninsidethecell,plusdetailedinformationaboutmanypiecesofthebigpicture.Onofthe¯rstwellstudiedmetabolicpathwaymodelsisshowninFigure2.Backin1991,AlbertGoldbeter[Goldbeter,1991]proposedatheorywhichFigure1:Left:Metabolicreaction;Right:Metabolicpathway1Figure2:ExampleofaMetabolicPathway.(See[Goldbeter,1991]formoreinformation.)wascapabletodescribethemolecularmechanismsunderlyingtheoscillatorycellcycle.Studieswithyeastandembryoniccellssuggestthatthecellcycleistriggeredbytheperiodicactivationofasubstancewhichwerefertoas`M'forthesakeofsimplicity.Usingthisexperimentaldata,Goldbeterdevelopedamin-imalmathematicalmodelwhichdescribesanoscillationprocessbetweenthreesubstances(`cyclin',`M',and`X').*representsthefractionoftheparticularin-activesubstance.E1andE2areenzymesandnegligibleinthisexample.Solidarrowsindicateabiochemicalreaction,whiledashedonesstandforactivationorampli¯cationofaprocess.CyclinisproducedinthecellindependentlyofMandX.Inthe¯rstcycleofthebicyclicmodel,cyclinpromotestheactivationofM.Inthesecondcycle,MactivatesX,whichdegradescyclin.SincecyclinactivatesM,andinturn,Mindirectlytriggersthedegradationofcyclin,cyclinoscillationslikeshowninFigure3mayoriginatefromanegativefeedbackloop.Althoughthismodelisbasedoncertainassumptionsanditisasimpli¯cationofthebiologicalcellcycle,ithassu±cientdetailtodescribethedynamicsofthemolecularmechanismsunderlyingthecellcycleoscillations.Simulationsofthecombinedmodelshowthatthefrequencyofthecellcycleoscillationscanbealteredbyregulatingthe`speed'ofthesinglereactions,andsomenewinsightsaboutthecellcycleprocesshavebeenderivedbythesesimulations.Asonecanseefromthissimpleexample,mathematicalmodeling,theirabstractions,andcomputersimulationtechniquescanbemorethenahandy2Figure3:TimeseriesofGoldbetermodel.Takenfrom:T.Conrad,2002,\Gold-beter'sModelofthecell-cycleandextensions,seminartalkatFreeUniversityBerlintool.Especiallywhenthenetworksgetbiggerandmorecomplicated,theycanbeveryusefulforvisualizingandhelpingtounderstandthetopologyanddynamicsofsuchmetabolicnetworks.Asaresultofthisconclusion,newapproachesintheareaoftheoreticalbiologyhaveemergedwhichapplythesecomputationaltechniquestocellularsystemsandmetabolicpathways.Theseinsilicosimulationshavesomead-vantagesovertraditionalinvivo1andinvitro2approaches,intermsofease,speed,costandvariability.Additionally,experimentswhicharenotfeasibleinlivingsystemscan(usually)besimulated,andcansuggestnovelexperimentsfortestinghypothesis,basedonthemodelingexperiences.Ofcourse,therearealsosomedrawbacks:Themainoneisprobablythatmodelingcan(almost)neverbeexact,itwilleverbeanapproximation,becausetheparametersarederivedfrom(°awed)experiments,ornonveri¯ableorprovablepresumptions.Thisreviewgivesanoverviewoftheevolutionoftheareasofmodeling,checking,visualizingandsimulatingofMetabolicPathways.Inthelastfewyearsthenumberofpapersdealingwiththesetopicsseemstohavegrowninanexponentialfashion.Moreover,inthelast12monthsseveralresearchgroupsfromallovertheworldhaveproposedexcellentnewapproachestotackleopenproblems.1Latinfor(with)intheliving-meanswithinalivingorganism(acell)2Latinfor(with)inglass-meanswithinatesttube,orjustoutsidealivingorganism(acell)3ModelingItwasclearfrom¯rstsimulationexperiencesthatmodelingabiologicalsystemismorethanjustwritingdowntheformulaesandgluingthemtogether.Asaresult,specializedsoftwarewasdevelopedtohelptheuserenterthesemodelsinamorebiologyorientedfashion.Thisleadtothe¯rstgenerallyacceptedapproachinde¯ningbiochemicalnetworksandpathways:assimplelistsofreactionsandkineticlawsbetweenthem.Anotherapproach,whichhasbecomequitepopularinrecentyears,istheuseofformalmodelingtechniques.Thus,severaldescriptionlanguageshavebeenproposedtomodeltheconcurrenttransitionsoccurringbetweenstatesinthesemodels.Thesemodelsarebasedonthetheoryofformallanguages,automata,objects,rules,expertsystems,hybridconcurrentconstraintlanguage