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Cytosolic-derived NADH must be shuttled into the mitochondria

Cytosolic-derived NADH must be shuttled into the mitochondria.

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Cytosolic-derived NADH must be shuttled into the mitochondria

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  1. Cytosolic-derived NADH must be shuttled into the mitochondria • Although citric acid cycle and fatty acid oxidation occur in the “right” place (mitochondrial matrix), glycolysis is cytoplasmic and NADH from this pathway must be shuttled into the matrix of the mitochondria (membrane is impermeable to this compound; no transporter) • Glycerol-3-phosphate shuttle • Malate-Aspartate shuttle

  2. Glycerol 3 Phosphate shuttle

  3. Malate-Aspartate Shuttle

  4. Malate-Aspartate shuttle

  5. General class of transporters

  6. Electron transport is accomplished by multienzyme complexes

  7. NADH:ubiquinone oxidoreductase utilizes NADH generated from catabolic reactions • This is a huge protein complex ~900,000 kDa • Electron transfer from NADH to ubiquinone is coupled to the translocation of protons through the protein, with a stoichiometry of 2H+/e- • NADH + H+ + Q  NAD+ + QH2

  8. An electron’s path through this complex • Oxidation of NADH transfers two electrons to FMN bound to the enzyme, and releases a proton into the matrix • The electrons are passed from FMN through a series of Fe-S centers the last one being called N-2 (Six in the case of the mitochondrial enzyme, but only four appear to be universally conserved) • N-2 reduces ubiquinone

  9. Proton pumping by this complex • Experiments suggest one proton is pumped into the intermembrane space during NADH to N-2 transfer of one electron, and a second proton during N-2 to ubiquinone transfer of one electron • Recall the stoichiometry, 2 protons per electron – this means four protons in total are pumped for each NADH oxidation

  10. Ubiquinone transfers electrons to the cytochrome bc1 complex

  11. Cytochrome bc1 • Contains two types of cytochromes (two types of heme), as well as a FeS protein (Rieske) • Since ubiquinol is a two electron carrier and cytochromes are one electron carrier, electron transfer within the bc1 complex is complicated.

  12. There are two Q binding sites (N and P), and three hemes in bc1

  13. The Q cycle • The Q cycle reveals the two electron reductant QH2 is oxidized in one electron steps. • The cycle begins with ubiquinol binding to the P center of the enzyme. • One electron is passed to the iron-sulfur cluster, then passed to cytochrome c1, then the soluble cytochrome c.

  14. The Q cycle • The second electron from ubiquinol oxidation is transferred to heme bL, then to heme bH, where it is used to reduce another molecule of ubiquinone at the N site to its semiquinone form.

  15. The Q cycle • The two protons released during the oxidation of the quinol molecule are released on the cytoplasm side of the membrane. • To complete the reaction cycle, a second molecule of ubiquinol is oxidized at the P center with the associated release of two protons to the cytoplasm side of the membrane. (Again, one electron makes its way to soluble cytochrome c, and the other electron to the N site where it reduces the semiquinone to ubiquinol with uptake of two protons from the matrix side.

  16. The Q cycle • The full cycle consists of the oxidation of two molecules of ubiquinol with the associated release of four protons to the cytoplasmic side of the membrane, the reduction of one molecule of ubiquinone, coupled to the uptake of two electrons from the matrix, and reduction of two molecules of soluble c type cytochrome.

  17. The Q cycle • 2QH2 + 2 cytc+3 + Q + 2H+(matrix)  2 Q + 2 cytc+2 + QH2 + 4H+(cytosol)

  18. Lehninger highlights the net Q cycle

  19. The outcome of the Q cycle includes reduced soluble cytochrome c • Soluble (not always, but here I am drawing a distinction with cytochrome c1) cytochrome c acts as a shuttle between the bc1 complex and cytochrome c oxidase • Cytochrome c oxidase catalyzes the transfer of electrons from soluble cytochrome c to dioxygen in the terminal step of respiration. • 4 cytc+2 + O2 + 8 H+ (matrix) 4 cytc+3 + H2O + 4 H+(cytosol)

  20. Proton transfer by cytochrome c oxidase • Four protons are taken up from the matrix side of the membrane to form water, while four protons are pumped from matrix to the cytoplasm • Unlike bc1, cytochrome c oxidase does not utilize a small molecule for proton transport, but relies on transmembrane ion channels

  21. Cytochrome c oxidase – the enzyme • Contains four redox centers [2 containing Cu, 2 hemes (a, a3)]

  22. Branches in Electron transport • Succinate dehydrogenase and other electron donors • Distinct terminal electron acceptors • Distinct (multiple) cytochrome oxidases • For example, cytochrome bo and bd in E. coli

  23. Other ways of getting electrons into the electron transport chain

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