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In thisthat the total A5rn;u"rr"casethe reactionwill occurspontaneously,eventhough theseagivesup heat to the box during the reaction.An exampleofsucha reactionisthe dissolvingof sodiumchloridein a beakercontainingwater (the "box"), which is a spontaneousprocesseventhough the temperatureof the water dropsasthe saltgoesinto solution.Chemistshavefound it usefulto define a number of new"compositefunctions"that describecombinationsof physicalpropertiesof a system.The propertiesthat can be combinedincludethe temperature(f), pressure(P), volume (V), energy(E), and entropy (5). The enthalpy(H) is one suchcompositefunction.But by far the most usefulcompositefunction forbiologistsis the Gibbs free energy, G. lt servesas an accountingdevicethat allowsone to deducethe entropy changeof theuniverseresultingfrom a chemicalreactionin the box, whileavoidingany separateconsiderationof the entropychangeinthe sea.The definition of G isG=H-TSwhere, for a box of volume V, H is the enthalpydescribedabove(E + PV), r is the absolutetemperature,and 5 is the entropy.Eachof thesequantitiesappliesto the insideof the box only.
Thechangein free energyduring a reactionin the box (the G of theproductsminusthe G of the startingmaterials)is denoted asAGand, as we shallnow demonstrate,it is a direct measureof theamount of disorderthat is createdin the universewhen thereaction occurs.At constant temperature the change in free energy (AG)during a reactionequalsAH - IA5. Rememberingthat AH =-h, the heat absorbedfrom the sea,we haveBut h/f is equal to the entropy change of the sea (A5r""),andthe A5 in the above equation is A56o^.ThereforeWe concludethat the free-energychangeis a direct measureof the entropy changeof the universe.A reactionwill proceedin the directionthat causesthe changein the free energy(AG)to be lessthan zero, becausein this casethere will be a positiveentropy changein the universewhen the reactionoccurs.For a complexset of coupledreactionsinvolvingmanythe total free-energychangecan be comdifferent molecules,puted simplyby adding up the free energiesof all the differentmolecularspeciesafter the reactionand comparingthis valuewith the sum of free energiesbefore the reaction;for commonthe requiredfree-energyvaluescan be found fromsubstancespublishedtables.In this way one can predictthe directionofa reactionand thereby readilycheckthe feasibilityof anyproposedmechanism.Thus,for example,from the observedproton gradientvaluesfor the magnitudeof the electrochemicalacrossthe inner mitochondrialmembraneand the AG for ATPhydrolysisinsidethe mitochondrion,one can be certainthat ATPsynthaserequiresthe passageof more than one proton for eachmoleculeof ATPthat it synthesizes.The value of AG for a reactionis a direct measureof how farthe reactionis from equilibrium.The large negativevalueforATP hydrolysisin a cell merelyreflectsthe fact that cellskeepthe ATP hydrolysisreactionas much as 10 ordersof magnitudeaway from equilibrium.lf a reactionreachesequilibrium,AG = 0, the reactionthen proceedsat preciselyequal ratesin the forward and backward direction.
For ATP hydrolysis,equilibriumis reachedwhen the vast majorityof the ATPhas been hydrolyzed,as occursin a dead cell'F o r e a c hs t e p ,t h e p a r t o f t h e m o l e c u l et h a t u n d e r g o e sa c h a n g ei s s h a d o w e di n b l u e ,a n d t h e n a m e o J t h e e n z y m et h a t c a t a l y z etsh e r e a c t i o ni s i n a y e l l o w b o x .S T E P1G l u c o s ei sphosphorylatedby ATPtof o r m a s u g a rp h o s p h a t e .T h e n e g a t i v ec h a r g eo f t h ephosphatepreventspassageof the sugarp h o s p h a t et h r o u g h t h ep r a s m am e m D r a n e ,t r a p p i n gg l u c o s ei n s i d ethe cell.o..H\,/'t-!Ir1CH?OHH-C.-OHl'f r o m c a r b o n1 t o H Oc a r o o nz , t o r m t n ga ketosefrom ana l d o s es u g a r ( S e ePanel2-4.)*'-i?+H.)-(--HlH-OHH-C-OH5|-CH,OqP(openchainform)H-C-OHl5.CH,OP( o p e nc h a i nf o r m )STEP3The new hydroxyl.lg r o u p o n c a r b o n1 ' ,phosphorylatedby ATP,inp r e p a r a t i o nf o r t h e f o r m a t i o no f t w o t h r e e - c a r b o ns u g a rphosphates.The entry of sugarsi n t o g l y c o l y s iiss c o n t r o l l e da t t h i ss t e p ,t h r o u g h r e g u l a t i o no f t h eenzyme p hosphof ru ctok i nase-P O H-) |C, " - \o(rLJ/lHr))(ringform)CH,O P|+tt''OHf ructose1,6-bisphosphateCH,O PSTEP4Thes i x - c a r b o sn u g a ri sc l e a v e dt o p r o d u c etwo three-carbonm o l e c u l e sO n l y t h eglyceraldehyde3-phosphatecanp r o c e e di m m e d i a t e l ythrough glycolysisIa-AIHOHO-C-HI+CH-C-OHIIcH2o PIH-C-OHIcH2oI( o p e nc h a i nf o r m )f r u c t o s e1 , 5 - b i s p h o s p h a t eCH,OH\//IH-C-OHcH2o PS T E P5Theotherproduct of step 4,ihyddroxyacetonep h o s p h a t ei,sisomerizedto formglyceraldehyde3-phosphate.ADPPglyceraldehyde?-nhncnh:teC,ro" IIH-C-OHcH2o Pg l y c e r a l d e h y d3e- p h o s p h a t etovo+EEEE+u*fH-C-OHlcH2o PF i g u r e2 - 7 3 )1,3-bisphosphoglycerateg l y c e r a l d e h y d3e- p h o s p h a t eS T E P7T h et r a n s f e rt o A D Po f t h eh i g h - e n e r g yp h o s p h a t egroupthat wasgenerated in step 6forms ATP.CII+H-C-OHcH2o P1,3-bisphosphoglycerateo.
.o\//o. .o\//'ClSTEP8Theremainingp h o s p h a t ee s t e rl i n k a g ei n3-phosphoglycerate,which hasa relativelylow free energy ofhydrolysis,is moved fromcarbon 3 to carbon 2 to form2-phosphoglycerate.CIH-C-Oi*PH-C-OH,l3-phosphoglycerateCCIH-C-OPIcH2oH2 - p h o s p h olgy c e r a t ePcHzp h o s ph o e n oIp y r u v a t eCCC-OIC-Oo.
.o\./o. .o\//I2-p hosphog lycerateo. .o\./o. .o\,/STEP9The removal ofwater from 2-phosphoglyceratec r e a t e sa h i g h - e n e r g ye n o lp h o s p h a t el i n k a g e .STEP10 The transfer toADP of the high-energyp h o s p h a t eg r o u p t h a t w a sgenerated in step 9 formsA T P ,c o m p l e t i n gg l y c o l y s i s .t-cH2oH- C H r O ' .P .PcHzp h o s p h o e n oply r u v a t eN E TR E S U LOT FG L Y C O L Y S I SIn addition to the pyruvate,the net productsaret w o m o l e c u l e so f A T Pa n d t w o m o l e c u l e so f N A D HIICH:HS-CoApyruvateThe completecitricacidcycle.The twocarbonsfrom acetylCoA that enter thisturn of the cycle(shadowedin) willbe convertedto CO, in subsequentturnsof the cycle:it is the two carbonsshadowed in blue that are convertedtoCO, in this cycle.(2c)acetyl CoAHS-CoAeoo*",tHO-C-COO-Step 1(+a^)in, \*'ioo\Po(6c)isocitratefn,HC COOtcitrate(6c)no-tHCoo-fumarate (4C)(x-ketoglutarate(5C)ffoo-€oo-2tfu't'CHs u c c i n a t e( 4 C ),rStep6GOO-HzoCozCH.succinylCoA (4C)t'Ioo-Icoo-2CH,il*p_:,t-C=OIS-CoAHS-CoAEE*tcozHS-CoADetailsof the eight stepsare shown below.
For eachstep,the part of the moleculethat undergoesa changeis shadowedin hlueand the name of the enzymethat catalyzesthe reactionis in a yellow box.O:C -S-CoASTEP1After the enzymeremovesa proton from theCH, group on acetyl CoA,t h e n e g a t i v e l yc h a r g e dC H r - f o r m sa b o n d t o acarbonylcarbon ofoxaloacetate.Thes u b s e q u e nlto s sb yh y d r o l y s ios f t h e c o e n z y m eA (CoA)drivesthe reactionstrongly forward.S T E P2An isomerizationreaction,in which water isf i r s t r e m o v e da n d t h e nadded back, movesthehydroxyl group from onec a r b o na t o m t o i t s n e i g h b o rICH,cooICHrt-HO-C-COOI9H,lcoo-t-HO-C-COO+ HS-CoA + H*ICH,t-coocitratecoo-HzoH-citratecooIC-HIc-cootlC-HIcoo-cls-aconitateintermediateH-CcooI-HIH-C -COO-IHO-C -HIcooisocitrateSTEP3ln the first off o u r o x i d a t i o ns t e p si n t h ecycle,the carbon carryingthe hydroxyl group isconvertedto a carbonylg r o u p .T h e i m m e d i a t ep r o d u c ti s u n s t a b l e l,o s i n gC O ,w h i l e s t i l l b o u n d t othe enzyme.cooIH-C -HIH-C -HIa-iIcoocooI-HH-CH_CIHO-c-HIcoo-(x-ketogIutarateisocitrateSTEP4The o-ketog/utaratedehyd ro gen asecomplex closelyr e s e m b l etsh e l a r g ee n z y m ecomplexthat convertspyruvateto acetyl co{(pyruvatedehydrogenase).lt likewisecatalyzesan oxidation thatproducesNADH,CO2,and ah i g h - e n e r g yt h i o e s t e rb o n d t ocoenzymeA (CoA).STEP5A phosphatem o l e c u l ef r o m s o l u t i o nd i s p l a c etsh e C o A ,f o r m i n g ah i g h - e n e r g yp h o s p h a t el i n k a g et o s u c c i n a t eT.
h i sp h o s p h a t ei s t h e n p a s s e dt oG D Pt o f o r m G T P .( l n b a c t e r i aand plants,ATP is formedinstead.)cooIH-C-HI-HcooIH-C -HIH-C-HIc:oIcoo-H-CSsuccinyl-CoA(x-ketoglutaratecooH-C-HH-CIS-CoAs u c c ln a r eH-CcooI-HIH-C-Hs u c cni a t ecooIC-HH-CIcoof u marateS T E P8l n t h e l a s to f J o u ro x i d a t i o ns t e p si n t h e c y c l et,h ec a r b o nc a r r y i n gt h e h y d r o x y lgroup is convertedt o a c a r b o n y lg r o u p ,regeneratingthe oxaloacetaten e e d e df o r s t e p 1 .,,Icoo-IcooS T E P7T h e a d d i t i o no fwater to fumarate placesahydroxyl group next to ac a r b o n y lc a r b o n .cooI-HI,,)n-L-rIH-C-HIsuccinyl-CoAS T E P6ln the thirdoxidation step in the cycle,FADremovestwo hydrogen atomsfrom succinate.cooIHO-C -HIH-C-HIcoomalateII-CoAsuccinatedehydrogenase-cooIC-H/\rlH-CIcoof umaratecooIHO-C -HIH-C-HIcoomalatecooIc:oICH,Icoooxa loacetate+ HS-CoA124Chapter2: CellChemistryand BiosynthesisREFERENCESGeneralBerg,JM,Tymoczko,JL& StryerL (2006)Biochemistry,6th ed NewYork:WH FreemanGarrettRH& GrishamCM (2005)Biochemistry,3rded philadelphia:ThomsonBrooks/ColeHortonl-1R,MoranLA,Scrimgeouret a (2005)PrincipesofBioch-.mistry4th ed UpperSaddleRiver,NJ:prenticeHallNelsonDL& CoxMM (2004)LehnlngerPrinciplesof Biochemistry,4th ed NewYork:WorthNichollsDG& FergusonS_l(2002)Bioenergerics,3rded Newyork:AcademicPressMathewsCK,van Ho de KE& AhernK G (2000)Biochemistry,3rded5 a ql r a r c , s c oB: e n j a rr C u m m i n g sMooreJA(1993)SclenceAsa Wayof KnowingCambridge,MA:HarvardUniversityPressVoetD,Voet.lG& PrattCIV(2004)Fundamentalsof Biochemistry,2nd ed NewYork:WileyThe ChemicalComponentsof a CellAbelesRH,FreyPA& JencksWP(1992)BiochemistryBoston:Jones&BartlettAtkinsPW('l996)Mo ecues NewYork:WH FreemanBrandenC & ToozeJ (l 999) ntroductionto ProteinStructure,2nd edNewYork:GarlandScenceBretscherMS(,l985)Themoleculesof the cel membrane5clAm2 5 3 :01O I O 9Burey 5K& PetskoGA(t 9BB)Weaklypolarinteractionsin proteins,4dyPrateinChem39.125-189De DuveC (2005)Singulanties:Landmarkson the pathwaysof Lif-.Cambridge:CambridgeUniversityPressDowhanW (1997)Molecularphospholipidbasisfor membranediversity:Whyarethereso many ipids?AnnuRevBiochem66:j99-232EsenbergD & KauzmanW (l 969)TheStructureand propertiesofWaterOxford:OxfordUniversty PressFershtAR(198/)Ihe hydrogenbond in molecularrecognitionIrendjBiochemSci123A1-304FranksF ('l993)WaterCambridge:RoyalSocietyof ChemistryHendersonll (1927)TheFitnessof the Envronment,1958ed Boston:BeaconNeidhardtFC,Ingraham_lL& SchaechterM (t 990)physioiogyof theBacterialCel: A Mo ecularApproachSunderland,MA:SinauerPaulingL (1960)Ihe Natureof the ChemicalBond,3rded thaca,Ny:CornellUniversityPressSaengerW (l 984)Princrplesof NucleicAcidStructure,New yorx:S p rni g e rSharonN (1980)Carbohydrates5ci,4,m243.90116StillingerFH(1980)WarerrevisitedScience2a9.45j-457TanfordC ('1978)Thehydrophobtceffectandthe organizationof livingm a t t e rS c l e n c2e0 0 : , l 0 1l2O l 8TanfordC (1980)ThelydrophobicEffectFormationof MicelesandBioogicalMembranes,2nd ed Newyork.JohnWi eyCatalysisand the Use of Energy by CellsAtkinsPW(1994)Ihe SecondLaw:Energy,Chaosand Form Newyork:Scientifc AmericanBooksAtkinsPW& De PaulaiD (2006)PhysicalChemistryfor the LifepressSciencesOxford:OxfordUniversityBaldwinJE& KrebsH (1981)TheEvolurionof MetabolicCyclesNciure291:381-382BergHC(1983)RandomWalksin B ology Princeton,NJ:princetonUniversityPressDickersonRE(,1969)MolecularThermodynamicsMenlopark,CA:B e n j a m iCn u m m i n g sDillKA& BrombergS (2003)MolecularDrivingForces:StatisticalThermodynamicsin Chemistryand Bioogy Newyork:GarlandScienceDresslerD & PotterH (1991)DiscovelngEnzymesNewyork:SclentificAmericanL braryEinsteinA (1956)lnvestigationson the Theoryof BrownianMovementNewYork:DoverFrutonJS(1999)Proteins,Enzymes,Genes:The nterplayof Chemistryand Bioogy NewHaven:YaleUniversityPress,GoodseI DS(1991)nsidea livingcell TrendsBiochemSci16:203-206KarplusM & McCammonJA (1986)Thedynamicsof protens SclAm254:42-51) o l e c u l adry n a m i cssi m u l a t i o ni nsK a r p l uMs & P e t s kGo A( 1 9 9 0Mbiology Nature347:631639KauzmannW (1967)ThermodynamicsandStatistics:withApplicationstoGasesIn ThermalPropertiesof MatterVol2 NewYork:WA Benjamin,IncKornbergA (1989)Forthe Loveof EnzymesCambridge,MA:HarvardUniversityPressLavendaBH(,1985)BrownianMotion5ci,4m252:7085LawlorDW (2001)Photosynthesis,3rded Oxford:BIOSL e h n i n g eArL ( 1 9 1 1T) h eM o l e c u l aBra s iosf B i o l o g i cEanl ergyTransformations,2nd ed MenloPark,CA:BenjaminCummingsLipmannF (1941)Metabolicgenerationand uti izationof phosphatebondenergyAdvEnzymol1:99-162LipmannF (1971)Wanderingsof a BiochemistNewYork:WileyNisbetEE& SleepNH (2001)Thehabitatand narureof earlylife Nature409:10813091RackerE (l9BO)FromPasteurto Mitchell:a hundredyearsofn l n t r n t r r ^ o l r r c L o / 1p t ^ .
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