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t , ) : 2 l O - 2 I 5SchrodingerE (1944& 1958)Whatis Life?:ThePhysicaiAspectof theL i v i n gC eI a n dM i n da n dM a t t e r1, 9 9 2c o m b i n e ded Cambridge:CambridgeUniversityPressvan HoldeKE,JohnsonWC& Ho PS(2005)Principlesof PhysicalBiochemistry,2nd ed UpperSaddleRiver,NJ:PrenticeHalWalshC (2001)Enablingthe chemistryof life Nature409.226-23iWestheimerFH(1982)Why naturechosephosphatesScience235.11/3-1t78YouvanDC& MarrsBL(1987)MolecularmechanismsofphotosynthesisSciAm 256:4249How CellsObtain Energyfrom FoodCramerWA & KnaffDB(1990)EnergyTransductionin BioogicalMembranes,NewYork:Springer-Verlag,DismukesGC,KlimovW, BaranovSVet al (2001)Theoriginofatmosphericoxygenon Earth:Theinnovationof oxygenicphotosyntheisPracNatAcadSciUSA9821702175Fel D (l 997)Understandingthe Controlof MetabolismLondon:Portand PressF att JP(1995)Useand storageof carbohydrateand fat Am J ClinNutr61,95259595.FriedmannHC(2004)FromButybacteriumto E.coli:An essayon unityin biochemistryPerspectBiollrled47:47-66Fothergill-GilmoreLA (,1986)Theevolutionof the glycolyticpathwayTrendsBiochemSci11:475lHeinrichR,Melendez-HeviaE,MonteroF et al (,1999)Thestructuraldesignof glycolysis:An evo utionaryapproachBiochemSocTrans27:294-298HuynenMA,DandekarT & BorkP (1999)Variarionand evolutionof thecitricacidcycle:a genomicperspective,TrendsMicrobroll:281-291KornbergHL(2000)Krebsand histrinityof cyclesNatureRevMolCellBiol1.225-228KrebsHA& MartinA (1981)Reminiscencesand ReflectionsOxford/NewYork:ClarendonPress/OxfordUniversityPress,KrebsHA (l 970)The historyof the tricarboxylicacidcycle perspectBiolMed14.154-17aMartlnBR(1987)MetabolicRegulation:A MolecularApproachOxford:BlackwellScientificMcGilveryRW(,1983)Biochemistry:A FunctionalApproach,3rdedP h i l a d e l p hSi aa:u n d e r sMorowitzHJ(1993)Beginningsof CellularLife:MetabolismRecapitulatesBiogenesisNewHaven:YaleUniversityPressNewsholmeEA& StarkC (1973)Regulationof MetabolismNewYork.Wiley,gzl'suorrerlaJqqe Jraq] srsrz-g a.rntlc pue seJnronJlsc..uorerreqt s^aoqs(6ZI-8ZI'dd) f-g larrud 'uo os pue 'spuoq tualeloc urrog ,{lrpeararuos 'pa8reqc dlanrlrsodro dyanrle8aueJesJeqlo '(,,3upeay-ra1e,,rn,,)crqoqdorpl.qpue reloduou eJe sureqo aprs asaq] Jo auros '(I-t arnt1fl suleqc epls prJeourue lueJeJJrp0Z aql :saruadord anbrun slr prJEourrue qrea arr€ leqt pue puoqappdad u Suqeru ur pallolur lou aJp leql sprJp ourup aql Jo suoruod asoq]erp urcqr anppadar sq] ol peqJeDV'auoqlJuq eppdad,tod aql sB 01 parreJersr ureqJ apltdaddlod eq] Jo eroo aqt Suop sruole;o acuanbas Surleadar aql'acuanbas prJE ourrue relnrrged uir,rosll qlp/r qf,Ea 'suralord luaragrp Jo spuesnoql dueur eJe ereq] pue 'spr3e ourrueyo acuanbas anbrun e seq uraloJd yo addr qteg'saptldadt1od se u,\i\oDl ospaJoJereqleJe sureloJd 'puoq apudad luapnoc e q8norq] roqq8rau slr ol pa{urlqJpe 'sproeourrup asaqlJo uuqc Suoye tuo4 eperu sr elnJalou ugalord V'serua-dord pcruraqc lualaJJrpqllm qJEe 'suralord ur sprJeounuu;o saddl 0Z eJeaJaqJe)uenbesp!)V oulr,uvsll ^q palJ!)adssl ulelorde Jo adeqsaql'lleJeuruorlJuryslr seurru-Jelap alnJelour uralord qJee adeqs asrcardaql rtoq aqrJosepolJola^al Jnuoleeqt te eJn]f,nr1suralord;o Surpuelsrapun srql esn alvrtaldeqc aqt ur Jale'I 'adeqspuolsuolulp-eerqt sll saurruJalep uralord p sruJoJleq] sprJe ourrue ;o 3uu1s3uo1aql ur prJ€ ourrue qcea Jo uouelol eql ,lrroqJeprsuooa^ 'uorloes srq] uI'Eurzeute ,{pr1 ruaas uec suralord;o flqqesran alqe{JeueJ eql 'suedxeol uala '1atr'&o1srq ,{.reuor1n1ona;o sreaf Jo suoilrq JeAopeun]-eug pue pado-la^epuaeqseq uratord qJeaJo frlsruraqc pup eJnlJnJlsaql leq] ezlleat ellr eJuo'Sursrrdrns1ou sdeqrad sl sHI'umou) se1ncelotupalecqsrqdosl.lpuorlcurg puexaldruoc rtlernpnrls lsotu eq] re; dq are suralord '^aet,tJolurod pcnuaqJ E ruoJCSNI]]OUdIO ]UNDNU]SCNV]dVHS3HIL)INOtr)NnlNElOUdsNE1OUdlo tunl)nutsSZLC N V ] d V H S] H Iraldeq) s$ll ul'suralord;o Surpuelsrapun daap B urpllplsnur a^a'uorlJunJ serpoq Jno ,t,roqro 'dolanap so,,fuqrua^r,roq'dlrculcele lJnpuocselreu ^ oq 'lJeJluoc salcsnur ntoq '{{Jomsaua8 anoq pue}sJepun o1 adoq uece.nAaJoJag'aJuaJseurrunlJosaJJnosro'sadol 'sJeqgJIlsEIa'salnceloruezee4rlup'sauoruJoq 'sulxol 'sarpoqque sE'selnoeloru]Je suralord pazqurcads JaqloVNCI palloul afuelun ue) asolautostodol iutseldofc aqr q8norql salaue8rosladord 'aldruexa rc! 'u6au!q :sped Sulrour qlIM saurqcptu relncaloru LuqsE elJas sJeqlo la;'snalcnu ilac aq] ol eueJqruau eruseydaqt tuo4 pJE^ut spu-8rs;o,te1arpu8rsslassrolerSalursB lJe Jo taqloue o] IIef, euo uror; sa8esleql-saur .d.rrucsuralord Jaqlo 'lleo aqlJo lno pue olut selnoeloru IIErusJo a8essedeq] IoJtuoJ teqt sdund pue slauueqJ ruJoJauerqruaru eruseld aqt ur peppaquasuralord 'suor]3eal IEJrueqJ r{ueru slr alourord tEq} IIaJ e ur seJeJJnsJEInJeloIualeJrrlur aq] apnord saudzua 'snql 'suorlJunJ s,llal eql IIE dpeau elnJexaosp ,taql ls{Jolq Surplnq s,lleJ eql ,i.Iuo 1ou are .,(aq; 'ssuru 'fup s,llar e Jo lsoualnlrlsuoc suraloJd 'suralord Suurrasqo 'eJuesse ur 'eJe al'- ',Qnrloe IeJrruaqJ-orq Jo lef,rJlJelas1razdpue ro adocsorcnu e q8norqlIIeJ u lp {ool a a uaq \su!elold126Chapter3: Proteinsmethionine (Met)TfOll/zH-:N-C-C|H(il\i.()leucine(Leu)(f 'lt,/o()tl(.'1()lHoooH:N-c-c\._oI\JIC.U, oHI+\^OH( |l,I I-^N - c tlHIoC\HoI( H,('HIH,('5//\tyrosine (Tyr)Cl-JJ(-H,HzoH:O( ) tlp o l y p e p t i d eb a c k b o n es i d ec h a i n sI IHHOa m i n ot e r m i n u sor N-terminusov^tttlHei-i-3rlHlC\o(H,Ioono(-H,IH,(-5( l-lI(H,p o l y p e p t i d eb a c k b o n eSCHEMATICSEQUENCEMetAspTyrAs discussedin chapter 2, atoms behave almost as if they were hard sphereswith a definite radius (their uan derwaals radius).
The requirement that no twoatoms overlap limits greatly the possible bond angles in a pollpeptide chain(Figure 3-3). This constraint and other steric interactions severely restrict thepossible three-dimensional arrangements of atoms (or conformaflons). Nevertheless, a long flexible chain, such as a protein, can still fold in an enormousnumber of ways.The folding of a protein chain is, however, further constrained by many different sets of weak noncoualent bonds that form between one part of the chainand another. These involve atoms in the polypeptide backbone, as well as atomsin the amino acid side chains. There are three tlpes of weak bonds: hydrogenbonds, electrostatic attractions, and uan der waals .tttractions, as explained inchapter 2 (see p.
54). Individual noncovalent bonds are 30-300 times weakerthan the tlpical covalent bonds that create biological molecules. But manyweakbonds acting in parallel can hold two regions of a polypeptide chain tightlytogether. In this way, the combined strength of large numbers of such noncovalent bonds determines the stability of each folded shape (Figure 3-4).Figure3-1 The componentsof a protein.
A proteinconsistsof a polypeptidebackbonewith attachedsioechains.Eachtype of proteindiffersin its sequenceandnumberof aminoacids;therefore,it is the sequenceof the chemicallydifferentsidechainsthat makeseachc a r b o x ytl e r m i n u s proteindistinct.Thetwo endsor C-terminusof a polypeptidechainarechemicallydifferent:the endcarryingthe freeaminogroup(NH3+,alsowrittenNH2)istheaminoterminus,orN-terminus,and that carryingthe free carboxylgroup(COO-,alsowritten COOH)isthe carboxylterminusorC-terminus.Theaminoacidsequenceof a proteinisalwayspresentedin theN-to-Cdirection,readingfrom left to rioht.127THESHAPEAND STRUCTUREOF PROTEINSA M I N OA C I DAsparticacidG l u t a m i ca c i dArginineLysineHistidineAsparagineGlutamineSerineThreonineTyrosineAspGluArgLysHisAsnGlnSerThrTyrS I D EC H A I NA M I N OA C I DDERKHNaSTYAlaAlanineGlyGlycineValValineLeuLeucinellelsoleucineProProlineP h e n y l a l a n i n eP h eMetMethionineTrpTryptophanCysCysteinenegativenegativepositivepositivepositivepolarunchargedpolarunchargedunchargepdolarpolarunchargedpolarunchargedAGVLIPFMWCnonpolarnonpolarnonpolarnonpolarnonpolarnonpolarnonpolarnonpolarnonpolarnonpolarFigure3-2 The 20 aminoacidsfound in proteins.Eachaminoacidhasa three-letterand a one-letterabbreviation.Thereareequalnumbersofp o l a ra n d n o n p o l asr i d echains;howevetsomesidechainslistedhereas polararelargeenoughto havesomenon-polarproperties(forexample,Tyr,Thr,Arg,Lys).ForseePanetatomicstructures,3-1 (pp.128-129).A fourth weak force also has a central role in determining the shape of a protein.
As described in Chapter 2, hydrophobic molecules, including the nonpolarside chains of particular amino acids, tend to be forced together in an aqueousenvironment in order to minimize their disruptive effect on the hydrogenbonded network of water molecules (see p. 54 and Panel 2-2, pp. f08-109).Therefore, an important factor governing the folding of any protein is the distribution of its polar and nonpolar amino acids.The nonpolar (hydrophobic) sidechains in a protein-belonging to such amino acids as phenylalanine, leucine,valine, and tryptophan-tend to cluster in the interior of the molecule (just ashydrophobic oil droplets coalesce in water to form one large droplet).
Thisenables them to avoid contact with the water that surrounds them inside a cell.In contrast, polar groups-such as those belonging to arginine, glutamine, andhistidine-tend to arrange themselves near the outside of the molecule, wherethey can form hydrogen bonds with water and with other polar molecules (Figure 3-5). Polar amino acids buried within the protein are usually hydrogenbonded to other polar amino acids or to the polypeptide backbone.(A)(B) +180a m i n oa c i doHC.
l- ' ciR2nIIN,,\,'I-CoR1p e p t i d eb o n d s-1800+18(ohlthreebondsFigure3-3 Stericlimitationson the bond anglesin a polypeptidechain.(A)Eachaminoacidcontributes(red)to the backboneofthe chain.Thepeptidebond is planar(grayshading)and doesnot permitrotation.By contrast,rotationcanoccuraboutthe Co-Cbond,whoseangleof rotationis calledpsi (V),and aboutthe N-Cobond,whoseanglean R group is often usedto denotean aminoacidsidechain(greencircles).of rotationis calledphi (Q).BVconvention,(B)Theconformationatomsin a proteinis determinedby one pairof Q and ry anglesfor eachaminoacid;of the main-chainbetweenatomswithin eachaminoacid,most pairsof Q and ry anglesdo not occur.In this sobecauseof stericcollisionsplot,eachdot representsan observedpairof anglesin a protein.Theclusterof dots in the bottomcalledRamachandran(seeFigure3-7A)'(8,fromquadrantthatarelocatedin cr-helixstructurestheaminoacidsleftrepresentsall offrom AcademicPress.)1981.WlthpermissionJ.
Richardson,Adv.Prot.Chem.34:174-175,THEAMINO ACIDOPTICALISOMERSTheo,-carbonatomisasymmetric,whichallowsfor two mirrorimage(or stereo-)rsomers,LanoD.T h e g e n e r a fl o r m u l ao f a n a m i n oa c i di s||,/ c-carbonatomI t't'amtno^ ^O^H. . c a r b o' x v l-CI -COgroup H:NgioufRgroupside-chainR is commonlyone of 20 different sidechains.At pH 7 both the amino and carboxylgroupsareionized.Proteinsconsistexclusivelvof l-amino acids.F A M I L I EOSFA M I N OA C I D SBASICS I D EC H A I N Shistidine(Hiso, r H)T h e c o m m o na m i n oa c i d sare grouped accordingtow h e t h e rt h e i r s i d ec h a i n sareH-N-Ctla c i di cbasicu n c h a r g e dp o l a rnonpolarHHOI-CH,ICH,ICH,T h e s e2 0 a m i n o a c i d sare given both three-letterand one-letterabbreviations.HOltlC-CICH:ICH.,I9H,ICH,ttl-N-C-CHIHN./INH,T h u s :a l a n i n e= A l a = A/tr/\Ct-C.//\NHNHrCH,HC:CHNHtThesenitrogenshavearelativelyweak affinity for anH+and are only partly positiveat neutral pH.P E P T I DBEO N D SA m i n o a c i d sa r e c o m m o n l yj o i n e dt o g e t h e rb y a n a m i d el i n k a g e ,c a l l e da p e p t i d eb o n d .\l//Ho-fN-C-C/l\ROH\l//RPeptidebond: The four atoms in eachgray box form a rigidplanar unit.
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