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Transcript
720 CHAPTER 23 Energyand Life Fouow-upro rHECRselt Poltr: A mysteriousfatigue After eiiminating usual causes of fatigue, the medical researchers who investigated Emily's condition sought the source of her problem in the biochemical processes of energy productlon: oxygen del.ivery,formaLion of NADH and FADH2, the respiratory chain, and oxidative phosphoryiation. They found that oxygen uptake by her tissues was normal. This eliminated the posslbility of a flawed delivery of oxygen to the tissues. Her body cells' levels of NADH, NAD | , FADH2, and FAD also were normal, suggesting that enough reducing power was avarlable to the respiratory chain and that the respiratory chain was operative. Her cellular ATP levels were considerably lower than norma_l. The researchers concluded that Emrly was suffering from an exf,remely rare defect of oxidative phosphorylation: The respiratory chain and the production of ATP were partially uncoupled. In such a situation, oxygen uptake, cellular respuation, and levels of NADH, NAD r, FADH2, and FAD would be normal. However, AIP ievels would be iow, leading to chronic fatigue. The molecular basis of the defect was noi determined, but a mutant gene could be responsihle for the defective expression of the ATP synthase that couples the respiratory chain to the production of ATP in oxidative phosphorylation. A flawed AIP synthase would result in impaired ATP producfion. 2t.7 Cellularwork AIMS: Todescribethe threemoior typesof work done by cells. Toshow how coupled reactionsenoble o cell to corry out chemicolwork. Focus Energy conserved inATP drives cellular processes. We have seen that cleavageof the phosphoric acid anhydride bonds in the ATP molecule releasesfree energy that can do cellular work. Cells do three major kinds of work chemical, osmotic, and mechanical. In this section we will examine each kind of work and seehowATP is involved. Chemical work ATPoften supplies energy to chemical reactions that need energyto make a product. Most of these reactionsinvolve AIP as a phosphorylating agent. That is, becauseof its very reactivephosphoric acid anhydride functional groups, AIP readily transfers phosphoryl o -P-OH I OH oq less commonly, plrophosphoryl oo iltl -P-O-P-OH groups to other molecules.Justas reducing power is the ability of NADH and FADH2to transfer electronsin reduction reactions,phosphorylatingpower zs the ability of ATP to transferphosphorylgroups in phosphorylationreactions. 25.7 CellularWork 721 Some phosphorylated enzyme substrates are activated for subsequent reactions they would not ordinarily undergo. The process of activation often involves a coupled reaction-an energeticallyunfauorable reaction is made to occur by being linked to a reaction that is energetically ueryfauorable (uery exergonic).In a coupled reaction, the net energy change for the linked reactions is favorable (exergonic).For example,liver cells need to use ammonia and carbon dioxide to make citrulline from the amino acid ornithine. (This reaction is important in the urea cycle, and we will return to it in Chapter 26.)A hypothetical equation for this reaction can be written: o- c H I NHO ll CHT+C l-l + NH3 + ,/ \ NH, NH 9H, + H2O I CH, CH, O t- I CHr CHr I I H2N-CH H2N-CH I I co2H c02H omithine Ammonia Citrulline Water :rT::: Figure 25.12 Thedirectconversion of ammonia to citrullineis not a favorable process(a).Whenthe reaction is coupledwith the breakdown of ATBhowever,it is exergonic (favorable) (b). This hypothetical reaction is energetically unfavorable (Fig. 23.12a).The equilibrium position greatly favors the reactants over the product. lVhat about using an enzJrmeto catalyze the reaction? This would not make the reaction exergonic.As catalysts, enzymes only speed up reactions that are already exergonic; they do not alter the position of equilibrium. Cells are not stymied by this state of affaits, however,becausethey have AIP on their side. They carry out an exergonic reaction instead, forming a molecule of carbamoyl phosphate by using one molecule of ammonia, one of carbon Citrulline (product) Energyreleasedby conversionofATP to ADP makes formation of carbamoyl phosphate energeticallyfavorable {exergonic). bo Freeenergy change is unfavorable. Formation of citrulline does not occur. m 0) o q) 0 oo il[ NH2-c-o-1-oH+6$tr I OH Carbamoyl phosphate Formation of citnrlline from carbamoyiphosphate and ornithine is energetically favorable (exergonic). Ornithine + CO2+ NH3 (reactants) I f +Omithine I i Citrulline f 722 CHAPTER 25 Energyand Life dioxide,and two ofAIP (Fig.23.12b).An enzymespeedsup the reaction. oo E*"'so'i", NH3+ CO2+ 2ATp NU2-a-O-J-O" I + 2ADp+ p' OH ;ilxlHJj The structure of carbamoyl phosphate contains a mixed anhydride linkage, one formed from a carboxylic acid and phosphoric acid. This linkage is very energetic. Carbamoyl phosphate readily reacts with ornithine to produce citrulline in another exergonic enzyme- cata\rzed reaction (Fig. 23.I 2b). Mived anhridride _t*fq_ oo tl NH,-C-O-P-OH ,rN''t O:C .*" NH, T OH Exergonic l,, UHr+CH,*P' t-t- CH, tl CHI tl H2N-CH co2H Carbamoyl phosphate Ornithine I CHI CH' H2N-CH co2H Citrulline ATP appearsin the equation for the overall reaction for the formation of citrulline, and it looks as if it were used up, as it is in hydrolysis. ornithine + co2 + NH3 + 2ATp Exergonic, citrulline + 2ADp + zpi + HzO The reality is quite different. The free energy stored in the energetic anhydride bonds of two AIP molecules was unleashed by breaking these bonds, but some was consewed in the anhydride bond of carbamoyl phosphate. By expending the phosphorylating power of AIP to make carbamoyl phosphate, liver cells boosted the reactivity of ammonia and carbon dioxide and achieved the synthesis of citrulline. In our example, an energetically unfavorable reaction-the formation of citrulline from ammonia, carbon dioxide, and ornithine-could not occur without coupling the reaction to the favorable breakdor,rmof ATP Sometimesthe route to energetically activated molecules requires several chemical steps, but the principle is the same. The inevitable result of substrate phosphorylation is the production of a more reactive molecule. Like substrates,some enzyrnesare also phosphorylated by ATP Phosphorylation often makes the difference between an active'and inactive enzyrne.A good example of enzyme activation caused by phosphoq4ation comes from catabolism and involves phosphorylase, the errzyrnethat catalyzesthe breakdor,rmof stored glycogen.The inactive form of phosphorylase (phosphorylase b) is a dimer consisting of identical protein subunits. 23.7 CellularWork PO.z-, t: o Figure25.15 Phosphorylase is convertedfrom an inactiveto an activeform upon phosphorylation. Inactive phosphorylase b dimers 72t Po:zl' o Active phosphorylase a The active form of phosphorylase (phosphorylase a) is a tetramer of these identical subunits. PhosphoryIation of the hydroxyl groups of a single serine residue in the amino acid sequenceof each subunit causestwo inactive phosphorylase b dimers to form the active phosphorylase a tetramer (Fig. 23.L3).The phosphorylase a can now go about the work nature intended: the breakdor.nrn of glycogen.It may appear that the phosphorylation of phosphorylase, a catabolic enzSrme, violates the rule that catabolism produces ATP However,one molecule of phosphorylase acatalyzes the cleavageof glycogen into many molecules of glucose.And aswe will seein Chapter 24, the complete oxidation of only one glucosemolecule freed by the action of phosphorylase a on glycogen gives a return of ATP many times greater than the four molecules of AIP it takes to phosphorylate the en4rrne. Osmotic work Cellscontain molecularpumps that transportions and moleculesthrough cell membranes. Thesepumps work against the normal concentration gradient-the transport is from a lower to a higher concentration of the substance being transported-and require the expenditure of energy in the form of ATP Such pumps often require the phosphorylation of transport proteins embeddedin the cell membrane. Mechanical work At this point we understand that AIP is a phosphorylating agent in the chemical and osmotic work done by cells.But in mechanical work-that is, cellular movements including muscle contraction-ATP is hydrolyzed rather than acting as a phosphorylating agent. The sliding-filament model is the generally accepted depiction of muscle contraction. In this model, muscles contract when thick and thin filaments slide past each otherffth AIP providing the energy of propulsion (Fig. 23.141. Muscle contraction requires so much ATP that muscle cells cannot keep enough on hand. Nature usesATPto transmit energy,not to store it. In 724 23 Energyand Life CHAPTER Thick filament (myosin) Thin filament (actin) Baseplate (a) Restingmuscle Figure25.14 Musclefibers contractwhen thick filamentsmade of myosinand thin filamentsmade of actin slide past each other,propelledby energy releasedin the hydrolysisof ATP. (b) Contractedmuscle resting muscle, the phosphorylating power ofAIP is stored in another highenergy compound called creatine phosphate, or phosphocreatine. On demand, the phosphoryl groups of creatine phosphate are transferred back to ADP NHr I I T .C +/\ HzN T-t"' cH2co2H ATD ntr - fot' I NH Resting muscle Active muscle I + ADP C +/\ H -"Nl N-CH" cH2co2H creatine of;:".XtiT" The enz].,rneinvolved in this reversible reaction is creatine phosphokinase. (Enzymesthat catalyze the transfer of a phosphoryl group to or from AIP are called kinases.)As soon as the demand forAIP exceedsthe supply, as in heavy exercise,muscles become tired and weak. ,. -: PRACIICE EXERCISE 2I.8 Outline the steps to showwhy the body's need for oxygen incrgdes as ,' physical activity increases.\Mhathappens to muscleswhen the demand ,i: forAIP exceedsthe supply?