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Just as the energy stored in the raised bucket of water in Figure 2-568 can drive a wide variety of hydraulic machines, ATP is a convenientand versatile store, or currency, of energy used to drive a variety of chemicalreactions in cells.ATP is synthesizedin an energeticallyunfavorable phosphorylation reaction in which a phosphate group is added to ADP (adenosine diphosphate).
\.Vhenrequired, ATP gives up its energy packet through its energeticallyfavorable hydrolysis to ADP and inorganic phosphate (Figure Z-SZ). The regenerated ADP is then available to be used for another round of the phosphorylation reaction that forms AIPThe energetically favorable reaction of AIP hydrolysis is coupled to manyotherwise unfavorable reactions through which other molecules are slnthesized.We shall encounter severalof these reactions later in this chapter. Many ofthem involve the transfer of the terminal phosphate in ATP to another molecule,as illustrated by the phosphorylation reaction in Figure 2-58.hydroxylg r o u po n| |HO-C-C-P H O S P H A TTERANSFERo-- O - Pl ;l lO - C - C llrllOiphosphoesterbondoo+ -O-P-O-P-O-CH,lriloolt-Figure2-58 An exampleof a phosphatetransferreaction.Becausean energy-richphosphoanhydridebond in ATPisconvertedto a phosphoesterbond,thisreactionis energeticallyfavorable,havinga largenegativeAG.Reactionsof thistype areinvolvedin the synthesisofphospholipidsand in the initialstepsofreactionsthat catabolizesuoars.CATALYSISANDTHEUSEOFENERGYBYCELLS(A)81(B)_.,J,,.'z\'IAtP nvorotvsrsA-BFigure2-59 An example of an energeticallyunfavorablebiosyntheticreactiondriven by ATPhydrolysis.(A)Schematicillustrationof the formationof A-B in the condensationreactiondescribedin the text.(B)The biosynthesisof the commonaminoacidglutamine.Glutamicacidis firstconvertedto a high-energy(correspondingphosphorylatedintermediateto the compoundB-O-PO3describedin the text),whichthen reactswith ammonta(correspondingto A-H) to form glutamine.In this examplebothstepsoccuron the surfaceof the sameenzyme,glutaminehigh energybonds are shadedred.synthetase.TheooH\/zCI1",CH,t-H3N* -CH-COOg l u t a m i ca c i dATP is the most abundant activated carrier in cells.
As one example, it supplies energy for many of the pumps that transport substances into and out ofthe cell (discussedin Chapter 1l). It also powers the molecular motors thatenable muscle cells to contract and nerve cells to transport materials from oneend of their long axons to another (discussedin Chapter 16).EnergyStoredin ATPls Often Harnessedto JoinTwo MoleculesTogetherWe have previously discussedone way in which an energetically favorable reaction can be coupled to an energetically unfavorable reaction, X -+ Y so as toenable it to occur. In that scheme a second enzyme catalyzesthe energeticallyfavorable reactionY -+ Z, pulling all of the X toY in the process (seeFigure 2-54).But when the required product is Y and not Z, this mechanism is not useful.A typical biosynthetic reaction is one in which two molecules, A and B, arejoined together to produce A-B in the energetically unfavorable condensationreactionA-H + B-OH -+ A-B + HzOThere is an indirect pathway that allows A-H and B-OH to form A-8, in which acoupling to ATP hydrolysis makes the reaction go.
Here energy from ATP hydrolysis is first used to convert B-OH to a higher-energy intermediate compound,which then reacts directly with A-H to give A-B. The simplest possible mechanism involves the transfer of a phosphate from AIP to B-OH to make B-OPOa,in which casethe reaction pathway contains only two steps:Net result:aCH,t_IH3N'-CH-COOintermediatehigh-energyACTIVATIONSTEP1.2./|'oB -OHItr\B-OH + AIP -+ B-O-POg + ADPA-H + B-O-POg -+ A-B + PlB-OH + AIP + A-H -+ A-B + ADP + P1The condensation reaction, which by itself is energeticallyunfavorable, is forcedto occur by being directly coupled to ATP hydrolysis in an enzyme-catalyzedreaction pathway (Figure 2-59A).A biosynthetic reaction of exactly this tlpe synthesizes the amino acid glutamine (Figure 2-598).
We will see shortly that similar (but more complex)mechanisms are also used to produce nearly all of the large molecules of the cell.i#"f;rPrprod*ts ofATPhydrolysisO\NH"cI,,,CH,t'ICHtl-H3N'-CH-COOglutamine82Chapter2: CellChemistryand BiosynthesisNADHand NADPHAre lmportantElectronCarriersOther important activated carrier molecules participate in oxidation-reductionreactions and are commonly part of coupled reactions in cells. These activatedcarriers are specialized to carry high-energy electrons and hydrogen atoms.The most important of these electron carriers are NAD+ (nicotinamide adenine dinucleotide) and the closely related molecule NADP+ (nicotinamideadenine dinucleotide phosphate). Later, we examine some of the reactions inwhich they participate.
NAD+ and NADP+ each pick up a "packet of energy" corresponding to two high-energy electrons plus a proton (H+)-being converted toNADH (reduced nicotinamide adenine dinucleotide) and NADPH (reducednicotinamide adenine dinucleotide phosphate), respectively.These moleculescan therefore also be regarded as carriers of hydride ions (the H+ plus two electrons, or H-).Like ATP, NADPH is an activated carrier that participates in many importantbiosyrrthetic reactions that would otherwise be energetically unfavorable. TheNADPH is produced according to the general scheme shov,rrin Figure 2-60A.
During a special set of energy-yielding catabolic reactions, a hydrogen atom plus twoelectrons are removed from the substrate molecule and added to the nicotinamidering of NADP+ to form NADPH, with a proton (H+) being released into solution.This is a typical oxidation-reduction reaction; the substrate is oxidized and NADP*is reduced. The structures of NADP+ and NADPH are shor,rmin Figure 2-608.NADPH readily gives up the hydride ion it carries in a subsequent oxidation-reduction reaction, becausethe nicotinamide ring can achieve a more stable arrangement of electrons without it. In this subsequent reaction, whichregeneratesNADP*, it is the NADPH that is oxidized and the substrate that isreduced.
The NADPH is an effective donor of its hvdride ion to other molecules(A)- c -IIIH-C-OIH-C-IIIICC-Io x i d a t i o no fm o l e c u l e1(B)r e d u c t i o no fm o l e c u l e2o x i d i z e df o r mCnicotinamidenn9//oNHzOoreducedformFigure2-60 NADPH,an importantcarrierof electrons.(A) NADPHisproducedin reactionsof the generaltypeshownon the left,in whichrwohydrogenatomsare removedfrom asubstrate.Theoxidizedform of the carriermolecule,NADP+,receivesone hydrogenatom plusan electron(a hydrideion);theproton(H+)from the other H atom isreleasedinto solution.BecauseNADPHholdsits hydrideion in a high-energylinkage,the addedhydrideion can easilybe transferredto other molecules,asshownon the right.(B)ThestructuresofNADP+and NADPH.The part of theNADP+moleculeknownasthenicotinamidering acceptstwo electronstogetherwith a proton(theequivalentofa hydrideion,H-),formingNADPH.ThemoleculesNAD+and NADHareidenticalin structureto NADP+and NADPH,respectively,exceptthat the indicatedphosphategroupis absentfrom both.C83LYSISANDTHEUSEOF ENERGYBYCELLSfor the same reason that ATP readily transfers a phosphate: in both casesthetransfer is accompanied by a large negative free-energychange.
One example ofthe use of NADPH in biosynthesis is shown in Figure 2-61.The extra phosphate group on NADPH has no effect on the electron-transfer properties of NADPH compared with NADH, being far away from the regioninvolved in electron transfer (see Figure 2-608). It does, however, give amolecule of NADPH a slightly different shape from that of NADH, making it possible for NADPH and NADH to bind as substratesto completely different sets ofenzymes.Thus the two types of carriers are used to transfer electrons (or hydrideions) between two different sets of molecules.\Mhy should there be this division of labor? The answer lies in the need toregulate two sets of electron-transfer reactions independently.
NADPH operateschiefly with enzyrnes that catalyze anabolic reactions, supplying the high-energyelectrons needed to synthesizeenergy-rich biological molecules. NADH, by contrast, has a special role as an intermediate in the catabolic system of reactionsthat generate ATP through the oxidation of food molecules, as we will discussshortly. The genesisof NADH from NAD+ and that of NADPH from NADP+occurby different pathways and are independently regulated, so that the cell canadjust the supply of electrons for these two contrasting purposes. Inside the cellthe ratio of NAD+ to NADH is kept high, whereas the ratio of NADP+ to NADPHis kept low. This provides plenty of NAD+ to act as an oxidizing agent and plentyof NADPH to act as a reducing agent-as required for their special roles incatabolism and anabolism, respectively.ThereAreManyOtherActivatedCarrierMoleculesin CellsOther activated carriers also pick up and carry a chemical group in an easilytransferred, high-energy linkage.
For example, coenzyme A carries an acetylgroup in a readily transferable linkage, and in this activated form is known asacetyl CoA (acetyl coenzymeA). Acetyl CoA (Figure 2-62) is used to add two carbon units in the biosynthesis of larger molecules.In acetyl CoA as in other carrier molecules, the transferable group makes uponly a small part of the molecule.
The rest consists of a large organic portion thatT.DEHYDROCHOLESTEROLHOHOffHCHOLESTEROLFigure2-61 The final stagein one of thebiosyntheticroutes leading toAs in manyothercholesterol.the reductionofreactions,biosyntheticthe C=Cbond is achievedby the transferof a hydrideion from the carriermoleculeNADPH,plusa proton(H+)from thesolution.nu c l e o t i d eH HO H HO H CH.HOoH-. C .| |il | |il | l-lC S _ C _ C - N - C - C - C - N - C _ C - C - C - O - P-o- PlllIlllln//lllH H Hhigh-energyoonoH H HOHCH3HOo-- O - P I: OIoacetylgroupCoenzymeA (CoA)Figure2-62 The structure of theimportantactivatedcarriermoleculemodelisacetylCoA.A space-fillingThesulfurshownabovethe structure.atom (yellow)formsa thioesterbond tothis is a high-energyacetate.Becausea largeamountof freelinkage,releasingenergywhen it is hydrolyzed,the acetatetomoleculecan be readilytransferredother molecules.84Chapter2: CellChemistryand BiosynthesisTable2-5 SomeActivatedCarrierMoleculesWidelyUsedin MetabolismATPNADH,NADPH,FADH2AcetylCoACarboxylatedbiotinS-AdenosylmethionineglucoseUridinediphosphatephosphateelectronsandhydrogensacetylgroupgroupcarboxylmethylgroup9rucoseserves as a convenient "handle," facilitating the recognition of the carriermolecule by specific enzymes.As with acetyl CoA, this handle portion very oftencontains a nucleotide (usually adenosine),a curious fact that may be a relic froman early stage of evolution.
It is currently thought that the main catalysts forearly life-forms-before DNA or proteins-were RNA molecules (or their closerelatives),as described in Chapter 6. It is tempting to speculate that many of thecarrier molecules that we find today originated in this earlier RNA world, wheretheir nucleotide portions could have been useful for binding them to RNAenzyrnes.Figures 2-58 and 2-61 have presented examples of the type of transfer reactions powered by the activated carrier molecules AIP (transfer of phosphate)and NADPH (transfer of electrons and hydrogen). The reactions of other activated carrier molecules involve the transfer of a methyl, carboxyl, or glucosegroup for the purpose of biosynthesis (Table 2-5). These activated carriers aregenerated in reactions that are coupled to ATP hydrolysis, as in the example inFigure 2-63.
Therefore, the energy that enables their groups to be used forbiosynthesis ultimately comes from the catabolic reactions that generate ATPSimilar processesoccur in the synthesis of the very large molecules of the cellthe nucleic acids, proteins, and polysaccharides-that we discuss next.TheSynthesisof BiologicalPolymersls Drivenby ATPHydrolysisAs discussed previously, the macromolecules of the cell constitute most of itsdry mass-that is, of the mass not due to water (see Figure 2-29). TheseFigure2-63 A carboxylgroup transferreactionusingan activatedcarriermolecule.Carboxylatedbiotinis usedbythe enzyme pyruvatecarboxylasetotransfera carboxylgroup in theproductionof oxaloacetate,a moleculeneededfor the citricacidcycle.Theacceptormoleculefor this grouptransferreactionis pyruvate.Otherenzymesusebiotinto transfercarboxylgroupstootheracceptormolecules.Notethatsynthesisof carboxylatedbiotinrequiresenergythat is derivedfromATP-a generalfeatureof manyactivatedcarriers.CARBOXYLGROUPACTIVATION\ENZYMEP P PC)-CH,fl(.()(() ()pyruvalebiotinno.\ / oCItl( .
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