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Regulationofglycolysis

1.WhenATPlevelsaresufficient,glycolysisactivitydecreasesHexokinaseinhibitedbyexcessglucose6-phosphatePFK-1isinhibitedbyATPandcitratePyruvate

kinaseisinhibitedbyATP2.WhenATPisneeded,glycolysisisactivatedAMP(theproductofATPconsumption)relievetheinhibitionofPFK-1byATPFructose2,6-bisphosphate(F2,6BP)relievetheinhibitionofPFK-1byATPPyruvate

kinaseisactivatedbyF1,6BPStep1Step3Step101

RegulationofHexokinaseHexokinasereactionismetabolicallyirreversibleG6P(product)levelsincreasewhen

glycolysisisinhibitedatsitesfurtheralonginthepathwayG6Pinhibitshexokinase

isozymesI,IIandIIIthatareactiveatnormalglucoseconcentrations(Kmvalues~10-6to10-4M)Glucokinase(hexokinaseIV,Km~10-2M)formsG6Pintheliver(forglycogensynthesis)whenglucoseisabundant(activityismodulatedbyfructosephosphatesandaregulatoryprotein)2RegulationofPFK-1ATPisasubstrateandanallosteric

inhibitorofPFK-1AMPallostericallyactivatesPFK-1byrelievingtheATPinhibition(ADPisalsoanactivatorinmammaliansystems)ChangesinAMPandADPconcentrationscancontrolthefluxthroughPFK-1Elevatedlevelsofcitrate(indicateamplesubstratesforcitricacidcycle)alsoinhibitPFK-13RegulationofPFK-1byFructose2,6-bisphosphate(F2,6BP)F2,6-BPisapotentactivatorofPFK-1F2,6-BPisformedfromF6Pbyphosphofructokinase-2(PFK-2),whichisabi-functionalenzymeb-D-Fructose2,6-bisphosphateFormationandhydrolysisofF2,6-BP

4HormoneglucagonisreleasedfromthepancreaswhenbloodglucoselevelsarelowPFK-2isbi-functionalGlucagonslowsglycolysisGlucagoninducesglucosesynthesisandconversiontoglucosefromglycogenEffectofglucagononliverglycolysis5RegulationofPyruvate

Kinase

FourPKisozymesexistinmammaliantissuesPKisallosterically

activatedbyF1,6BP,inhibitedbyATPGlucagonstimulatesproteinkinaseAwhichphosphorylatesPKconvertingittoaless

activeform(liverandintestinalcells)ActivatorF1,6BP(red)boundwithPK6ThePasteurEffectUnderanaerobic

conditionstheconversionofglucosetopyruvateismuch

higherthanunderaerobicconditions(yeastcellsproducemoreethanolandmusclecellsaccumulatelactate)ThePasteurEffectistheslowing

of

glycolysisinthepresenceofoxygenMore

ATPisproducedunderaerobicconditionsthanunderanaerobicconditions,thereforeless

glucoseisconsumedaerobically7RegulationofGluconeogenesis

8RegulationoftheTCAcycle9RegulationofGlycogenbreakdown10ConformationalchangesinglycogenphosphorylaseTstate:activesiteblockedbyloop;Arg569lessavailableforsubstratebindingRstate:rotationofsubunitstoachievemorefavorablep

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