8885dc19690-7503/1/0411:32 AM Page699 6mac76:385 19.1 Electron-Transfer Reactions in Mitochondria FIGURE 19-10 Structure of Complex ll(succinate dehydrogenase of E coli(PDB ID 1NEK) zyme has two transmembrane sub- units, C(green)and D(blue); the cytoplasmic extensions contain sub- units B(orange)and A (purple). Just behind the FAD in subunit A (gold) the binding site for succinate(occupied in this crystal structure by the inhibitor oxaloacetate, green). Subunit B has three sets of Fe-S cen- ters(yellow and red); ubiquinone (yellow)is bound to subunit C; and heme b(purple) is sandwiched between subunits C and D. A cardi- FAD lipin molecule is so tightly bound to subunit C that it shows up in the crystal structure (gray spacefilling). Electrons move(blue arrows) from succinate to FAD, then through the three Fe-S centers to ubiquinone. The heme b is not on the main path of electron transfer but protects against the formation of reactive oxygen species(ROS)by electrons that go astray. B Cytoplasm flavoprotein acyl-CoA dehydrogenase(see Fig 17-8) (N side) involves transfer of electrons from the substrate to the FAD of the dehydrogenase, then to electron-transferring flavoprotein (Etf), which in turn passes its electrons to e Ubiquinone enzyme transfers electrons into the respiratory chain by reducing ubiquinone Glycerol 3-phosphate, formed ei- Heme b ther from glycerol released by triacylglycerol breakdown or by the reduction of dihydroxyacetone phosphate from glycolysis, is oxidized by glycerol 3-phosphate dehydrogenase(see Fig 17-4). This enzyme is a flavo- protein located on the outer face of the inner mito- chondrial membrane, and like succinate dehydrogenase and acyl-CoA dehydrogenase it channels electrons into the respiratory chain by reducing ubiquinone (Fig B.The of glycerol hydrogenase in shuttling reducing equivalents from cytosolic NADH into the mitochondrial matrix is de- scribed in Section 19. 2(see Fig. 19-28). The effect of each of these electron-transferring enzymes is to con- The heme b of Complex I is apparenty not in tribute to the pool of reduced ubiquinone QH, from all the direct path of electron transfer; it may ser these reactions is reoxidized by Complex II instead to reduce the frequency with which electrons leak"out of the system, moving from succinate to mo- Complex II: Ubiquinone to Cytochrome c The next respi- lecular oxygen to produce the reactive oxygen species ratory complex, Complex Ill, also called cytochrome (ROS) hydrogen peroxide(h202)and the superoxide bci complex or ubiquinone: cytochrome c oxidore- radical (O2)described in Section 19.5. Humans with ductase, couples the transfer of electrons fror point mutations in Complex II subunits near heme b or ubiquinol(QH2) to cytochrome c with the vectorial the quinone-binding site suffer from hereditary para- transport of protons from the matrix to the intermem- ganglioma. This inherited condition is characterized by brane space. The determination of the complete struc benign tumors of the head and neck, commonly in the ture of this huge complex (Fig. 19-11) and of Complex carotid body, an organ that senses O2 levels in the blood. IV (below) by x-ray crystallography, achieved between These mutations result in greater production of ROS 1995 and 1998, were landmarks in the study of mito- and perhaps greater tissue damage during succinate chondrial electron transfer, providing the structural oxidation.■ framework to integrate the many biochemical observa- Other substrates for mitochondrial dehydrogenases tions on the functions of the respiratory complexes pass electrons into the respiratory chain at the level of Based on the structure of Complex II and detailed ubiquinone, but not through Complex II. The first step biochemical studies of the redox reactions, a reasonable in the B oxidation of fatty acyl-CoA, catalyzed by the model has been proposed for the passage of electronsflavoprotein acyl-CoA dehydrogenase (see Fig. 17–8), involves transfer of electrons from the substrate to the FAD of the dehydrogenase, then to electron-transferring flavoprotein (ETF), which in turn passes its electrons to ETF : ubiquinone oxidoreductase (Fig. 19–8). This enzyme transfers electrons into the respiratory chain by reducing ubiquinone. Glycerol 3-phosphate, formed ei￾ther from glycerol released by triacylglycerol breakdown or by the reduction of dihydroxyacetone phosphate from glycolysis, is oxidized by glycerol 3-phosphate dehydrogenase (see Fig. 17–4). This enzyme is a flavo￾protein located on the outer face of the inner mito￾chondrial membrane, and like succinate dehydrogenase and acyl-CoA dehydrogenase it channels electrons into the respiratory chain by reducing ubiquinone (Fig. 19–8). The important role of glycerol 3-phosphate de￾hydrogenase in shuttling reducing equivalents from cytosolic NADH into the mitochondrial matrix is de￾scribed in Section 19.2 (see Fig. 19–28). The effect of each of these electron-transferring enzymes is to con￾tribute to the pool of reduced ubiquinone. QH2 from all these reactions is reoxidized by Complex III. Complex III: Ubiquinone to Cytochrome c The next respi￾ratory complex, Complex III, also called cytochrome bc1 complex or ubiquinone:cytochrome c oxidore￾ductase, couples the transfer of electrons from ubiquinol (QH2) to cytochrome c with the vectorial transport of protons from the matrix to the intermem￾brane space. The determination of the complete struc￾ture of this huge complex (Fig. 19–11) and of Complex IV (below) by x-ray crystallography, achieved between 1995 and 1998, were landmarks in the study of mito￾chondrial electron transfer, providing the structural framework to integrate the many biochemical observa￾tions on the functions of the respiratory complexes. Based on the structure of Complex III and detailed biochemical studies of the redox reactions, a reasonable model has been proposed for the passage of electrons 19.1 Electron-Transfer Reactions in Mitochondria 699 The heme b of Complex II is apparently not in the direct path of electron transfer; it may serve instead to reduce the frequency with which electrons “leak” out of the system, moving from succinate to mo￾lecular oxygen to produce the reactive oxygen species (ROS) hydrogen peroxide (H2O2) and the superoxide radical (O2 ) described in Section 19.5. Humans with point mutations in Complex II subunits near heme b or the quinone-binding site suffer from hereditary para￾ganglioma. This inherited condition is characterized by benign tumors of the head and neck, commonly in the carotid body, an organ that senses O2 levels in the blood. These mutations result in greater production of ROS and perhaps greater tissue damage during succinate oxidation. ■ Other substrates for mitochondrial dehydrogenases pass electrons into the respiratory chain at the level of ubiquinone, but not through Complex II. The first step in the
oxidation of fatty acyl–CoA, catalyzed by the FIGURE 19–10 Structure of Complex II (succinate dehydrogenase) of E. coli (PDB ID 1NEK). The enzyme has two transmembrane sub￾units, C (green) and D (blue); the cytoplasmic extensions contain sub￾units B (orange) and A (purple). Just behind the FAD in subunit A (gold) is the binding site for succinate (occupied in this crystal structure by the inhibitor oxaloacetate, green). Subunit B has three sets of Fe-S cen￾ters (yellow and red); ubiquinone (yellow) is bound to subunit C; and heme b (purple) is sandwiched between subunits C and D. A cardi￾olipin molecule is so tightly bound to subunit C that it shows up in the crystal structure (gray spacefilling). Electrons move (blue arrows) from succinate to FAD, then through the three Fe-S centers to ubiquinone. The heme b is not on the main path of electron transfer but protects against the formation of reactive oxygen species (ROS) by electrons that go astray. Substrate binding site Cytoplasm (N side) C B D A FAD Fe-S centers Periplasm (P side) Cardiolipin Ubiquinone QH2 Heme b 8885d_c19_690-750 3/1/04 11:32 AM Page 699 mac76 mac76:385_reb: