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Oxidative Phosphorylation ( Respiratory Chain)

Oxidative Phosphorylation ( Respiratory Chain). FADH 2 2ADP. FAD 2ATP. NADH, H + + 1/2 O 2 + 3ADP, P i. NAD + + H 2 O + 3ATP. Electron transport. Where – mitochondria Why – make ATP When – supply (ADP) and demand (ATP). H +. III. I’. II. ATP syn.

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Oxidative Phosphorylation ( Respiratory Chain)

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  1. Oxidative Phosphorylation(Respiratory Chain) FADH2 2ADP FAD 2ATP NADH, H+ + 1/2 O2+ 3ADP, Pi NAD+ + H2O + 3ATP Electron transport Where – mitochondria Why – make ATP When – supply (ADP) and demand (ATP)

  2. H+ III I’ II ATP syn I H+ Oxidative Phosphorylation Electon Transport creates a Proton Gradient ATP synthase utilizes the gradient to fuel ATP production H+

  3. DG˚′ = -nFDE˚′ The Oxidative phosphorylation pathway exchanges the free energy provided by redox reactions into a proton gradient. The electric potential of the gradient drives the spontaneous production of ATP from ADP,Pi.

  4. I I’ II III Electron Transport Complexes H+ Succinate-CoQreductase (FADH2) 140k FADH2 + CoQ→ FAD + CoQH2 CoQ-Cytochrome C oxidoreductase250k CoQH2+ 2 CytC(Fe3+) → 2H+ + 2 CytC(Fe2+)+ CoQ H+ Cytochrome C Oxidase160k 6 CytC(Fe2+) + O2 → 2 H2O + 6 CytC(Fe3+) H+

  5. H+ H+ H+ c Q III I IV H+ H+ H+ CoQH2+ 2 CytC(Fe3+) → 2H+ + 2 CytC(Fe2+)+ CoQ 6 CytC(Fe2+) + O2 → 2 H2O + 6 CytC(Fe3+) NADH, H+ + CoQ→ NAD+ + CoQH2 Coenzyme Q is … a) polar b) nonpolar c) ionic

  6. I NADH dehydrogenase: NADH, H+ + CoQ→ NAD+ + CoQH2 II Succinate dehydrogenase: FADH2+ CoQ→ FAD + CoQH2 III CoQ:cytochrome C oxidoreductase : CoQH2+ 2 CytC(Fe3+) → 2H+ + 2 CytC(Fe2+) + CoQ IV Cytochrome Oxidase 4 CytC(Fe2+) + O2 → 2 H2O + 4CytC(Fe3+)

  7. CoQ and cytochrome C (Fe3+/Fe2+) are ‘mobile’ electron carriers in Oxidative Phosphorylation

  8. DpH = -1.4 III I’ II ATP syn I H+ • Oxidative Phosphorylation • The pH of the inner membrane space will be …. • > than b) < than c) = to • The pH of the mitochondrial matrix? H+

  9. Transport of ADP and Pi into the Matrix

  10. Proton Gradient = Energy Graient

  11. H+  ATP H+ ATP synthase Fo F1 ADP + Pi

  12. The proton gradient turns the transmembrane portion of ATP synthase (F0) creating a pinwheel effect that leads to ATP generation. The turning of the transmembrane portion of ATP synthase leads to the release of H+ into the matrix and ATP production. At any time a b subunit can have ADP/Pi, ATP, or nothing bound (1 of each).

  13. ATP a g b b a a b Asp- + H+outAsp Conformational D Asp  Asp- + H+in F1-ATP Synthase ATP A key aspartic acid residue facilitates the H+ driven ‘spinner’ ADP,Pi

  14. ATP a ATP g b b a a b F1-ATP Synthase ATP ADP,Pi ADP,Pi

  15. g ATP F1-ATP Synthase a ADP,Pi ATP b b a a b

  16. Transport of ADP and Pi into the Matrix

  17. Summary of the Electron Flow in the Respiratory Chain

  18. Metabolic Mainstreet Glucose + 2ADP + 2NAD+ Glycolysis 2Pyruvate + + 2ATP + 2NADH in cytosol Bridging Rx. How? AcetylCoA NAD+/FAD NADH/FADH2 C6 C4 OP Krebs Cycle ADP O2 C5 C4 ATP

  19. The Glycerol Phosphate shuttle allows NADH produced in the cytosol to Produce aerobic ATP in the matrix without actually entering the mitochondria. Muscle ― 2 ATP per Glycolysis NADH Liver ― 3 ATP per Glycolysis NADH

  20. II Glycerol – Phosphate Shuttle NADH,H+ NAD+ Glycerol-3-P Dehydrogenase (cytosol) DHAP Glycerol-3-P Glycerol-3-P Dehydrogenase (mt) E-FADH2 E-FAD Q QH2

  21. PathwayDirectOP 2NADH out  2FADH2 in = 4 2NADH = 6 6NADH = 18 2FADH2 = 4 Glycolysis Bridging Rx Krebs Cycle 2ATP none 2GTP Gross muscle ATP output – Additional loss of ATP due to ‘overhead’

  22. Metabolic Mainstreet Glucose 2 ATP ― anaerobic 34 ATP ― aerobic Bridging Rx + Krebs + OP Glycolysis Pyruvate Bridging Rx. AcetylCoA NAD+/FAD NADH/FADH2 C6 oxaloacetate OP Krebs Cycle ADP O2 C5 C4 ATP

  23. OP UncouplersWhat would happen if H+ entered mitochondria without going through ATP synthase?a) ATP would be produced b) heat would be produced c) both of above d) neither of above Transport H+ across membrane without generating ATP • 2,4 – dinitrophenol • a weak nonnpolaracid • UCP (uncoupler Protein) • a passive H+ transport

  24. O- NO2 OH NO2 O- NO2 H+ pH ~ 5.5 NO2 ATP synthase Fo NO2 F1 pH ~ 7.0 ADP + Pi ATP + H+ NO2

  25. ATP synthase Fo F1 UCP H+ ADP + Pi > ATP

  26. Hibernating animals use UCP to stay room in winter in lieu of ATP production for muscle activity.

  27. Superoxide ion •O2- Hydroxide radical OH• Nitric oxide NO• Defenses against ROS Superoxide Dismutase (SOD) 2H+ + O2- H2O2 Glutathione Peroxidase Glutathione (GSH) is the tripeptidegGlu-Cys-Gly 2GSH + H2O2 2 H2O + GS-SG Degrades lipid peroxides as well as H2O2 to minimize lipid damage Glutathione Reductase GS-SG + 2NADPH  2 GSH + 2NADP+ Hydrogen peroxide H2O2

  28. Antioxidants Vitamin E and Vitamin C Flavinoids: green tea, red wine, chocolate …. Carotinoids: fruits and veggies ….. What do they do? 1) Directly scavenge free radicals 2) Inhibit enzymes that can generate ROS 3) Combination of above. Caution: Antioxidants can produce FR themselves and excesses may have pro-oxidant rather than antioxidant activity. Some clinical studies show excessive supplements cause more harm than good.

  29. Resveratrol Catechin Found in skin of red grapes & red wine. May activate sirtuin which is implicated in the epigenetic control of gene expression. May up-regulate SOD expression. Found in cocoa and white/green tea. Antioxidants These molecules taken as are considered beneficial components of fruits and vegetables etc. They may function to supplement the bodies normal defense against ROS. This could happen by serving as targets for ROS oxidation but also may involve enzyme expression or inhibition. Studies using pure forms of these compounds show mixed results. Epigallocatechin 3-O-gallate EGCG

  30. Pentose Phosphate Pathway Glucose-6-P + 2 NADP+ + H2O Ribose-5-P + CO2 + 2 NADPH, H+ Why? Production of NADPH as reducing agent fatty acid synthesis & glutathione recycling particularly important Where? Liver and adipose – neurons (brain) When? NADP+ stimulates – NADPH inhibits mass action signals need for production

  31. Transketolase (TPP cofactor) & Transaldolase TK 2C5↔ C7 + C3 TA C7 + C3 ↔ C6 + C4 TK C5 + C4↔ C6 + C3 Net 3C5Û 2C6 + C3 or ….6C5Û 5C6 What? – Reversible exchange of ribose/glucose Why? – Retain proper balance of ribose/glucose Where? – Liver, adipose, neurons (brain) When? – As needed – regulated by mass action (equilibrium) DG = DG°´ + RT ln Q

  32. NADP+ PPP Fat Synthesis & Glutathione Reductase NADPH + R-5-P (C5) + CO2 TK TA Nucleic Acids Glycolysis --- Gluconeogenesis Glucose ↓↑ Glucose-6-P ↓↑ C3 Intermediate ↓↑ Pyruvate

  33. Pentose Phosphate Pathway

  34. v Thiamine deficiency Normal [TPP] [TPP] Wernicke Korsakoff Syndrome Lesions in Wernicke’s area of brain - left posterior of temporal lobe – probably due to neuron death. Causes speech comprehension problems, amnesia, peripheral neuritis. Genetics (‘nature’) TK binding to TPP 10x weaker more common in “Europeans” Environment (‘nurture’) Exacerbated by thiamine deficiency – common in alcoholics. TK mutation

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