Harpers

THE RESPIRATORY CHAIN & OXIDATIVE PHOSPHORYLATION / 95OH(H + + e – )OHH(H + + e – )CH 3 OCH 3 OOHCH 3 CH 3[CH 2 CHCCH 2 ] n HOFully oxidized orquinone form• OSemiquinone form(free radical)OHReduced or quinol form(hydroquinone)Figure 12–5. Structure of ubiquinone (Q). n = Number of isoprenoid units, which is10 in higher animals, ie, Q 10 .the cell approaches state 3 or state 5 when either the capacityof the respiratory chain becomes saturated or thePO 2 decreases below the K m for cytochrome a 3 . There isalso the possibility that the ADP/ATP transporter (Figure12–9), which facilitates entry of cytosolic ADP intoand ATP out of the mitochondrion, becomes ratelimiting.Thus, the manner in which biologic oxidativeprocesses allow the free energy resulting from the oxidationof foodstuffs to become available and to be capturedis stepwise, efficient (approximately 68%), andcontrolled—rather than explosive, inefficient, and uncontrolled,as in many nonbiologic processes. The remainingfree energy that is not captured as high-energyphosphate is liberated as heat. This need not be considered“wasted,” since it ensures that the respiratory systemas a whole is sufficiently exergonic to be removedfrom equilibrium, allowing continuous unidirectionalflow and constant provision of ATP. It also contributesto maintenance of body temperature.PrPrCysCysSSSFeFeSSCysSSPrCysFigure 12–6. Iron-sulfur-protein complex (Fe 4 S 4 ). S ,acid-labile sulfur; Pr, apoprotein; Cys, cysteine residue.Some iron-sulfur proteins contain two iron atoms andtwo sulfur atoms (Fe 2 S 2 ).FeFeSPrMANY POISONS INHIBIT THERESPIRATORY CHAINMuch information about the respiratory chain has beenobtained by the use of inhibitors, and, conversely, thishas provided knowledge about the mechanism of actionof several poisons (Figure 12–7). They may be classifiedas inhibitors of the respiratory chain, inhibitors of oxidativephosphorylation, and uncouplers of oxidativephosphorylation.Barbiturates such as amobarbital inhibit NADlinkeddehydrogenases by blocking the transfer fromFeS to Q. At sufficient dosage, they are fatal in vivo.Antimycin A and dimercaprol inhibit the respiratorychain between cytochrome b and cytochrome c. Theclassic poisons H 2 S, carbon monoxide, and cyanideinhibit cytochrome oxidase and can therefore totally arrestrespiration. Malonate is a competitive inhibitor ofsuccinate dehydrogenase.Atractyloside inhibits oxidative phosphorylation byinhibiting the transporter of ADP into and ATP out ofthe mitochondrion (Figure 12–10).The action of uncouplers is to dissociate oxidationin the respiratory chain from phosphorylation. Thesecompounds are toxic in vivo, causing respiration to becomeuncontrolled, since the rate is no longer limitedby the concentration of ADP or P i . The uncoupler thathas been used most frequently is 2,4-dinitrophenol,but other compounds act in a similar manner. The antibioticoligomycin completely blocks oxidation andphosphorylation by acting on a step in phosphorylation(Figures 12–7 and 12–8).THE CHEMIOSMOTIC THEORY EXPLAINSTHE MECHANISM OF OXIDATIVEPHOSPHORYLATIONMitchell’s chemiosmotic theory postulates that theenergy from oxidation of components in the respiratorychain is coupled to the translocation of hydrogen ions(protons, H + ) from the inside to the outside of theinner mitochondrial membrane. The electrochemicalpotential difference resulting from the asymmetric dis-