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Coordination of Intermediary Metabolism

Coordination of Intermediary Metabolism. ATP Homeostasis. Energy Consumption (adult woman/day) 6300-7500 kJ (>200 mol ATP) Vigorous exercise: 100x rate of ATP utilization Steady-State ATP: <0.1 mol 0.05% daily usage <1 min supply Strict Coordinate Control. Strict Coordinate Control.

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Coordination of Intermediary Metabolism

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  1. Coordination of Intermediary Metabolism

  2. ATP Homeostasis • Energy Consumption (adult woman/day) • 6300-7500 kJ (>200 mol ATP) • Vigorous exercise: 100x rate of ATP utilization • Steady-State ATP: <0.1 mol • 0.05% daily usage • <1 min supply Strict Coordinate Control

  3. Strict Coordinate Control • Glycogenolysis (glycogen metabolism) • Glycolysis • Citric Acid Cycle • Oxidative Phosphorylation

  4. Identification of Potential Control Sites in Electron Transport and Oxidative Phosphorylation

  5. Complex I and III 1/2 NADH + Cytochrome c (Fe3+) + ADP + Pi——> 1/2 NAD+ + Cytochrome c (Fe2+) + ATP ∆G’ = ~0 (reversible)

  6. Complex I and III Equilibrium ATP Mass Action Ratio (compare with Energy Charge)

  7. Cytochrome c OxidaseComplex IV Irreversible Regulatory Site

  8. Control by Substrate Availability Inverse ATP Mass Action Ratio [NADH] and [ATP]  reduced Cytc c

  9. Effectors of Electron Transport - Oxidative Phosphorylation • ATP mass action ratio • Availability of ADP and Pi • Stimulation by Ca2+ • IF1: inhibitor of F1–ATPase

  10. IF1(Inhibitor of F1–ATPase) Inactive during active respiration Traps ATP bound to DP Prevents ATPase activity when [O2] is low

  11. Sources of Electrons for Mitochondrial Electron Transport • Glycolysis (or glycogenolysis) • Fatty acid degradation • Citric Acid Cycle • Amino acid degradation

  12. Metabolic Relationships Figure 17-1

  13. Regulation of the Citric Acid CycleInhibition of ETC  NADH Figure 17-16

  14. Coordinate Regulation of Citric Acid Cycle

  15. Coordinate Regulation of Glycolysis and Pyruvate Dehydrogenase Citrate

  16. Inhibition of Phosphofructokinase by Citrate

  17. Decline in Demand for ATP(ATP and ADP) • Isocitrate Dehydrogenase: not activated by ADP • α-Ketoglutarate Dehydrogenase: inhibited by ATP • Citrate Accumulates • Citrate transport system • Inhibition of Phosphofructokinase

  18. Regulation of Central Metabolic Pathways

  19. Advantages of Aerobic Metabolism Anaerobic glycolysis: 2 ATP C6H12O6 + 2 ADP + 2 Pi—> 2 Lactate + 2 H+ + 2 H2O + 2 ATP Aerobic metabolism of glucose: 32 ATP C6H12O6 + 32 ADP + 32 Pi + 6 O2—> 6 CO2 + 38 H2O + 32 ATP

  20. Drawbacks or Disadvantages of Aerobic Metabolism Sensitivity to O2 Deprivation Production of Reactive Oxygen Species (ROS)

  21. Oxygen Deprivation inHeart Attack and Stroke Myocardial Infarction: interuption of the blood (O2) supply to a portion of the heart Stroke: interuption of the blood (O2) supply to a portion of the brain

  22. Consequences of O2 Limitation • Disruption of osmotic balance (ion pumps) • Swelling of cells and organelles — increased permeability • Acidification (anaerobic lactic acid production) — activity of leaked lysosomal enzymes

  23. Partial Oxygen Reduction Produces Reactive Oxygen Species (ROS) Superoxide Radical Hydroxyl Radical

  24. Radicals Extract Electrons (Oxidize) Various Biomolecules • Polyunsaturated Lipids — disrupts biological membranes • DNA — point mutations • Proteins — enzyme inactivation

  25. Free Radical Theory of Aging Aging occurs, in part, from damage caused by reactive oxygen species arising during normal oxidative metabolism

  26. Cells are Equipped with Antioxidant Mechanims • Superoxide Dismutase • Catalase • Glutathione Peroxidase • Plant-derived Compounds • Ascorbate (vitamin C), α-tocopherol 2 H2O2—> 2 H2O + O2 2 GSH + H2O2—> GSSG + 2 H2O

  27. Oxidative Stress in Aging ? Buffenstein, R et al; AGE 2008, 30:99-109

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