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Like most enzymes, these have names ending in ase--such asisomerase and dehydro genase-,lo indicate the type of reaction they catalyze.Although no molecular oxygen is used in glycolysis,oxidation occurs, in thatelectrons are removed by NAD+ (producing NADH) from some of the carbonsderived from the glucose molecule. The stepwise nature of the process releasesthe energy of oxidation in small packets,so that much of it can be stored in activated carrier molecules rather than all of it being released as heat (see Figure2-69). Thus, some of the energy releasedby oxidation drives the direct slmthesisof ATP molecules from ADP and Pi, and some remains with the electrons in thehigh-energy electron carrier NADH.TWomolecules of NADH are formed per molecule of glucosein the course ofglycolysis.
In aerobic organisms (those that require molecular oxygen to live),these NADH molecules donate their electrons to the electron-transport chaindescribed in Chapter 14, and the NAD+ formed from the NADH is used again forglycolysis (see step 6 in Panel 2-8, pp. 120-l2I).ProduceATPin the Absenceof OxygenFermentationsFor most animal and plant cells, glycolysis is only a prelude to the final stage of thebreakdo'ornof food molecules. In these cells, the p],'ruvateformed by glycolysis isFigure2-70 An outlineof glycolysis'Eachofthe 10 stepsshownis<GGGC>catalyzedby a differentenzyme.Notesugara six-carbonthat step4 cleavesso that thesugars,into two three-carbonat everystageafternumberof moleculesstep6 beginsthis doubles.As indicated,the energygenerationphaseofof ATPtwo moleculesglycolysis.Becausein the early,energYarehydrolyzedresultsin theinvestmentphase,glycolysisof 2 ATPand 2 NADHnet synthesismoleculesper moleculeof glucose(seealsoPanel2-B).90Chapter2: CellChemistryand Biosynthesisrapidly transported into the mitochondria, where it is converted into co2 plusacetyl CoA, which is then completely oxidized to CO2and H2O.In contrast, for many anaerobic organisms-which do not utilize morecularoxygen and can grow and divide without it-glycolysis is the principal source ofthe cell'sArP This is also true for certain animal tissues,such as skeletalmuscle,that can continue to function when molecular oxygen is limiting.
In these anaerobic conditions, the pyruvate and the NADH electrons stay in the cytosol. Thepyruvate is converted into products excreted from the cell-for example, intoethanol and co2 in the yeastsused in brewing and breadmaking, or into lactatein muscle. In this process,the NADH gives up its electrons and is converted backinto NAD+. This regeneration of NAD+ is required to maintain the reactions ofglycolysis (Figure 2--7l).Anaerobic energy-yielding pathways like these are called fermentations.process.The piecing together of the complete glycolltic pathway in the 1930swasa major triumph of biochemistry, and it was quickly followed by the recognition ofthe central role of ArP in cell processes.Thus, most of the fundamentalionceptsdiscussed in this chapter have been understood for manv vears.(A) FERMENTATIONLEADINGTO EXCRETIONOF LACTATEgrucose2 ADF-.r -2l|{4q:\ E/--E-E-;2 x pyruvateoo\,,o.o\./IIH- C-OHCCIIcH:rCH:2 x lactate( B ) F E R M E N T A T I OLNEADINGT O E X C R E T I OONFA L C O H O LANDCO.grucose-^-'........._.\'6t->I=-/.-'EDlr2 x pyruvateo.o\//CIHC:OICH:ICH:2 x acetaldehydeH-, Cl -OHCH:2xCOz2 x ethanolFigure2-71 Two pathwaysfor theanaerobicbreakdownof pyruvate.(A)Whenthereis inadequateoxygen,forexample,in a musclecellundergoingvigorouscontraction,the pyruvateproducedby glycolysisis convertedtolactateas shown.Thisreacttonregeneratesthe NADt consumedin step6 of glycolysis,but the whole pathwayyieldsmuch lessenergyoverallthancompleteoxidation.(B)In someorganismsthat can grow anaerobically,suchasyeasts,pyruvateis convertedviaacetaldehydeinto carbondioxideandethanol.Again,this pathwayregeneratesNAD+from NADH,as requiredto enableglycolysisto continue.Both(A)and (B)are exampfes of fermentations.HOWCELLSOBTAINENERGYFROMFOODGlycolysislllustratesHowEnzymesCoupleOxidationto EnergyStorageReturning to the paddle-wheel analogy that we used to introduce coupled reactions (see Figure 2-56), we can now equate enzymes with the paddle wheel.Enzymes act to harvest useful energy from the oxidation of organic moleculesby coupling an energetically unfavorable reaction with a favorable one.
Todemonstrate this coupling, we examine a step in glycolysis to see exactly howsuch coupled reactions occur.TWo central reactions in glycolysis (steps 6 and 7) convert the three-carbonsugar intermediate glyceraldehyde3-phosphate (an aldehyde) into 3-phosphoglycerate(a carboxylic acid; seePanel2-8, pp. 120-121).This entails the oxidationof an aldehyde group to a carboxylic acid group in a reaction that occurs in twosteps.The overall reaction releasesenough free energy to convert a molecule ofADP to AIP and to transfer two electrons from the aldehyde to NAD* to formNADH, while still releasing enough heat to the environment to make the overallreaction energeticallyfavorable (AG for the overall reaction is -3.0 kcal/mole).Figure 2-72 otttlines the means by which this remarkable feat of energy harvesting is accomplished.
The indicated chemical reactions are precisely guidedby two enzymes to which the sugar intermediates are tightly bound. In fact, asdetailed in Figure 2-72, the first enzyme (glyceraldehyde 3-phosphate dehydrogenase) forms a short-lived covalent bond to the aldehyde through a reactive -SH group on the enzyme, and catalyzes its oxidation by NAD+ in thisattached state. The reactive enzyme-substrate bond is then displaced by aninorganic phosphate ion to produce a high-energy phosphate intermediate,which is released from the enzyme.
This intermediate binds to the secondenzyme (phosphoglycerate kinase), which catalyzesthe energetically favorabletransfer of the high-energy phosphate just created to ADB forming AIP andcompleting the process of oxidizing an aldehyde to a carboxylic acid.We have shown this particular oxidation process in some detail because itprovides a clear example of enzyme-mediated energy storage through coupledreactions (Figure 2-73). Steps 6 and 7 are the onlyreactions in glycolysis thatcreate a high-energy phosphate linkage directly from inorganic phosphate. Assuch, they account for the net yield of two AIP molecules and two NADHmolecules per molecule of glucose (seePanel 2-8, pp.l20-I2l).As we have just seen,AIP can be formed readily from ADP when a reactionintermediate is formed with a phosphate bond of higher-energy than the phosphate bond in AIP Phosphatebonds can be ordered in energy by comparing thestandard free-energy change (AGl for the breakage of each bond by hydrolysis.Figure 2-74 compares the high-energy phosphoanhydride bonds in ATP withthe energy of some other phosphate bonds, several of which are generated during glycolysis.in SpecialReservoirsStoreFoodMoleculesOrganismsAll organisms need to maintain a high ATP/ADP ratio to maintain biologicalorder in their cells.
Yet animals have only periodic accessto food, and plantsneed to survive overnight without sunlight, when they are unable to producesugar from photosynthesis. For this reason, both plants and animals convertsugars and fats to special forms for storage (Figure 2-75).To compensate for long periods of fasting, animals store fatty acids as fatdroplets composed of water-insoluble triacylglycerols,largely in the cytoplasmof specialized fat cells, called adipocltes. For shorter-term storage, sugar isstored as glucose subunits in the large branched polysaccharide glycogen,which is present as small granules in the cltoplasm of many cells,including liverand muscle.
The synthesis and degradation of glycogen are rapidly regulatedaccording to need. \.A/hencells need more AIP than they can generate from thefood molecules taken in from the bloodstream, they break down glycogen in areaction that produces glucose 1-phosphate,which is rapidly converted to glucose 6-phosphate for glycolysis.9192Chapter2: CellChemistryand Biosynthesis(A)HO\ /(_/IH-C-OHglyceraldehyde3-phosphateSHA covalent bond is formed betweenglyceraldehyde3-phosphate(thesubstrate)and the -5H group of acysteineside chain of the enzymeglyceraldehyde3-phosphated e h y d r o g e n a s ew,h i c h a l s ob i n d snoncovalentlyto NAD+.t-? IH -C-OHIH_C_OHIOxidation of glyceraldehyde3-phosphateoccurs,as twoelectronsplus a proton (a hydrideion, see Figure2-60) aretransferredfrom glyceraldehyde3-phosphateto the bound NAD+,forming NADH.Part of the energyreleasedby the oxidation of thea l d e h y d ei s t h u s s t o r e di n N A D H ,and part goes into convertingthebond between the enzymeand itssubstrateglyceraldehyde3-phosphateinto a high-energythioester bondcH2oo(ocrFIH-C-OHHO-A m o l e c u l eo f i n o r g a n i cp h o s p h a t edisplacesthe high-energybond tothe enzymeto create 1,3-bisphosphoglycerate,which containsa high-energyacyl-anhydridebond.PIOtirU- iAL J1,3-bisphosphoglycerateC:OIH-C-OHl^cH2o(L)@@oF4Hr fr_A-r,CIH- C-OHl^cH2o(L)3 - p h o s p h olgy c e r a t eThe high-energybond to phosphateis transferredto ADP to form ATP.(B)SUMMARYOF STEPS6 AND 7Much of the energy of oxidationhas been stored in the activateocarriersATPand NADH.Figure2-72 Energystoragein steps6and 7 of glycolysis.In thesestepstheoxidationof an aldehydeto a carboxylicacidis coupledto the formationof ATPand NADH.(A)Step6 beginswith theformationof a covalentbond betweenthe substrate(glyceraldehyde3-phosphate)and an -5H groupexposedon the surfaceof the enzyme(glyceraldehyde3-phosphatedehydrogenase).Theenzymethencatalyzestransferof hydrogen(asahydrideion-a protonplustwoelectrons)from the boundglyceraldehyde3-phosphateto amoleculeof NAD+.Partof the energyreleasedin this oxidationis usedto forma moleculeof NADHand part is usedtoconvertthe originallinkagebetweentheenzymeand its substrateto a highenergythioesterbond (shownin red.).A moleculeof inorganicphosphatethendisplacesthis high-energybond on theenzyme,creatinga high-energysugarphosphatebond instead(red).At thispoint the enzymehas not only storedenergyin NADH,but alsocoupledtheenergeticallyfavorableoxidationof analdehydeto the energeticallyunfavorableformationof a high-energyphosphatebond.Thesecondreactionhasbeendrivenby the first,therebyactinglikethe"paddle-wheel"couplerin Figure2-56.In reactionstep7, the high-energyjust made,sugar-phosphateintermediate1,3-bisphosphoglycerate,bindsto asecondenzyme,phosphoglyceratekinase.Thereactivephosphateistransferredto ADP,forming a moleculeofATPand leavinga freecarboxylicacidgroupon the oxidizedsugar.(B)Summaryof the overallchemicalchangeproducedby reactions6 and 7.93HOWCELLSOBTAINENERGYFROMFOODoMEocoaooFigure 2-73 Schematicview of thecoupledreactionsthat form NADHandATPin steps 6 and 7 of glycolysis.TheC-H bond oxidationenergydrivestheformationof both NADHand a highenergyphosphatebond.The breakageofbond then drivesATPthe high-energyformation.\,/CI\,,CIC-H bondoxidationenergy+STEP67STEPt o t a l e n e r g yc h a n g ef o r s t e p6 f o l l o w e d b y s t e p 7 i s a f a v o r a b l e- 3 k c a l / m o l eo-o\//COenol phosphatebondrllH'' C : C - O - .
PHro-O-/ ,/lo-p h o s p h o e n oply r u v a t eisee ianel Z-8,'pp. 120-121)- 14'6(-61 e)ootltlc-c-o y'P o-anhydridebondto carbonoHro/phosphatebond increaTtnephosphateanhydridebondtophosphate(phosphoanhydridebond)a._a)-oooililtli-"-i-o7i-"o-o-for example,1,3-bisphosphoglycerate(seePanel2-8)c r e a t i n eo h o s p h a t e( a c t i v a t e dc a r r i e rt h a tstoresenergy in muscle)(-43.0)for example,ATPwhen hydrolyzedtOADP-7.3(-306)-10.3/o-HzoHOphosphoesterbondlll, -i-"vP-o-for example,g l u c o s e6 - p h o s p h a t e(seePanel2-8)",/o-Hzotype of phosphatebondspecificexamplesshowing thestandardfree-energychange (AG')for hydrolysisof phosphatebondFigwe 2-74 Phosphatebonds have different energies.Examplesof differenttypes of phosphatebondswith their sitesof hydrolysisareshown in the moleculesdepictedon the left.Thoseitarting with a gray catbonatom show only part of a molecule.Examplesof molecules(kilojoulestransferin parentheses)'Thein kilocalorieschangefor hydrolysiscontainingsuchbondsaregivenon the right,with the free-energy(AG')theofforhydrolysischangefree-energyifthestandardphosfhategroupfavorableof afrom one moleculeto anotheris energeticallyThus,a phosphategroupof the phosphatebond in the second.phosphatebond of the firstmoleculeis more negativethan that for hydrolysisto ADPto form ATPThe hydrolysisreactioncan be viewedas the transferof the phosphateis readilytransferredfrom 1,3-bisphosphoglycerategroup to water.94Chapter2: CellChemistyand Biosynthesis9rycogeng r a n u l e isnthe cytoplasmo f a l i v e rc e l lb r a n c hp o i n tg l u c o s es u b u n i t s1pmqla 1,4-glycosidicbond in backbone,,-Figure2-75 The storageof sugarsandfats in animaland plant cells.(A)Thestructuresof starchand glycogen,thestorageform of sugarsin plantsandanimals,respectively.Botharestoragepolymersof the sugarglucoseand differonly in the frequencyof branchpoints(theregioninyellowisshownenlargedbelow).Therearemanymore branchesinglycogenthan in starch.(B)An electronmicrographshowsglycogengranulesinthe cytoplasmof a livercell.(C)A thinsectionof a singlechloroplastfrom aplantcell,showingthe starchgranulesand lipid(fatdroplets)that haveaccumulatedasa resultof thebiosynthesesoccurringthere.(D)Fatdroplets(stainedred)beginningtoaccumulatein developingfat cellsof ananimal.(8,courtesyof RobertFletterickand DanielS.Friend;C,courtesyofK.Plaskitt;D,courtesyof RonaldM.
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