The Citric Acid Cycle

TheKrebscycle,alsocalledthecitricacidcycle,isafundamentalmetabolicpathwayinvolvingeightenzymesessentialforenergyproductionthroughaerobicrespiration,and,likeglycolysis,aroseearlyinevolution.Thispathwayisalsoanimportantsourceofbiosyntheticbuildingblocksusedingluconeogenesis,aminoacidbiosynthesis,andfattyacidbiosynthesis.TheKrebscycletakesplaceinmitochondriawhereitoxidizesacetyl-CoA,releasingcarbondioxideandextractingenergyprimarilyasthereducedhigh-energyelectroncarriersNADHandFADH2.NADHandFADH2transferchemicalenergyfrommetabolicintermediatestotheelectrontransportchaintocreateadifferentformofenergy,agradientofprotonsacrosstheinnermitochondrialmembrane.Theenergyoftheprotongradientinturndrivessynthesisofthehigh-energyphosphatebondsinATP,thecommonenergycurrencyofthecellusedtodriveahugevarietyofreactionsandprocesses.Anacetyl-CoAmolecule(2carbons)entersthecyclewhencitratesynthasecondensesitwithoxaloacetate(4carbons)tocreatecitrate(6carbons).Onesourceoftheacetyl-CoAthatenterstheKrebscycleistheconversionofpyruvatefromglycolysistoacetyl-CoAbypyruvatedehydrogenase.Acetyl-CoAisakeymetabolicjunction,derivednotonlyfromglycolysisbutalsofromtheoxidationoffattyacids.Asthecycleproceeds,theKrebscycleintermediatesareoxidized,transferringtheirenergytocreatereducedNADHandFADH2.Theoxidationofthemetabolicintermediatesofthepathwayalsoreleasestwocarbondioxidemoleculesforeachacetyl-CoAthatentersthecycle,leavingthenetcarbonsthesamewitheachturnofthecycle.Thiscarbondioxide,alongwithmorereleasedbypyruvatedehydrogenase,isthesourceofCO2releasedintotheatmospherewhenyoubreathe.TheKrebscycle,likeothermetabolicpathways,istightlyregulatedtoefficientlymeettheneedsofthecellandtheorganis.Theirreversiblesynthesisofacetyl-CoAfrompyruvatebypyruvatedehydrogenaseisoneimportantregulatorystep,andisinhibitedbyhighconcentrationsofATPthatindicateabundantenergy.Citratesynthase,alpha-ketoglutaratedehydrogenaseandisocitratedehydrogenaseareallkeyregulatorystepsinthecycleandareeachinhibitedbyabundantenergyinthecell,indicatedthroughhighconcentrationsofATPorNADH.TheactivityoftheKrebscycleiscloselylinkedtotheavailabilityofoxygen,althoughnoneofthestepsinthepathwaydirectlyuseoxygen.Oxygenisrequiredfortheelectrontransportchaintofunction,whichrecyclesNADHbacktoNAD+andFADH2backtoFADH,providingNAD+andADHrequiredbyenzymesintheKrebscycle.Iftheoxygensupplytoamusclecellorayeastcellislow,NAD+andFADHlevelsfall,theKrebscyclecannotproceedforward,andthecellmustresorttofermentationtocontinuemakingATP.SomeKrebscycleenzymesrequirenon-proteincofactorsforactivity,suchasthiamine,vitaminB1.Insufficientquantitiesofthisvitamininthedietleadstodecreasedactivityofpyruvatedehydrogenaseandalpha-ketoglutaratedehydrogenase,andadecreaseintheabilityoftheKrebscycletomeetmetabolicdemands,causingthediseaseberiberi.AlthoughtheelucidationoftheKrebscycleremainsoneofthelandmarksofbiochemistry,aspectsoftheKrebscycleanditsenzymesarestillactivelyresearchedinthemodernproteomicera.

Contributor:GlennCroston,PhD

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