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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
• Glycogenolysis (glycogen metabolism)
• Glycolysis
• Citric Acid Cycle
• Oxidative Phosphorylation
Identification of Potential Control Sites in Electron Transport and Oxidative
Phosphorylation
Complex I and III
1/2 NADH + Cytochrome c (Fe3+) + ADP + Pi
——> 1/2 NAD+ + Cytochrome c (Fe2+) +
ATP
∆G’ = ~0
(reversible)
Complex I and III Equilibrium
Keq =
[NAD][NADH]
12 [Cytochrome c (Fe2 )]
[Cytochrome c (Fe3 )]
[ATP][ADP][Pi]
ATP Mass Action Ratio
(compare with Energy Charge)
Cytochrome c OxidaseComplex IV
Irreversible
Regulatory Site
Control by Substrate Availability
Inverse ATP Mass Action Ratio
[NADH] and [ATP] reduced Cytc c
Effectors of Electron Transport - Oxidative
Phosphorylation
• ATP mass action ratio– Availability of ADP and Pi
• Stimulation by Ca2+
• IF1: inhibitor of F1–ATPase
IF1
(Inhibitor of F1–ATPase)
Inactive(high pH)
Active(low pH)
Inactive during active respiration
Traps ATP bound to DP
Prevents ATPase activity when [O2] is low
Sources of Electrons for Mitochondrial Electron
Transport
• Glycolysis (or glycogenolysis)
• Fatty acid degradation
• Citric Acid Cycle
• Amino acid degradation
Figure 17-1
Metabolic Relationships
Figure 17-16
Regulation of the Citric Acid Cycle
Inhibition of ETC NADH
Coordinate Regulation of Citric Acid Cycle
Coordinate Regulation of Glycolysis and Pyruvate
Dehydrogenase
Citrate
Inhibition of Phosphofructokinase by
Citrate
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
Regulation of Central Metabolic Pathways
Consequence
Enzyme or Process Negative Positive of Inhibition
Electron Transport ATP ADP + Pi Accum of NADH
-ketoglutarate DHase NADH No Oxaloacetate
Isocitrate DHase NADH Accum of Citrate ATP
Citrate Synthase NADH Accum of Acetyl-SCoA Citrate
Substrate Availability
Acetyl-SCoA Oxaloacetate
Pyruvate DHase NADH ADP Acetyl-SCoA
Pyruvate Kinase ATP PEP Citrate F-1,6-bisP
Phosphofructokinase ATP AMP No F-1,6-bisP Citrate F-2,6-bisP
Hexokinase Glc-6-P
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
Drawbacks or Disadvantages of Aerobic Metabolism
Sensitivity to O2 Deprivation
Production of Reactive Oxygen Species (ROS)
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
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
Partial Oxygen Reduction Produces Reactive Oxygen
Species (ROS)
O2 + eĞ Ñ >
O2
[
O2 + H+ Ñ >
HO2 ] (strong oxidant)
H2O2 + Fe2+ Ñ >
OH + OHĞ + Fe3+ Or
O2 + H2O2 Ñ > O2 + H2O +
OH
Superoxide Radical
Hydroxyl Radical
Radicals Extract Electrons (Oxidize) Various
Biomolecules
• Polyunsaturated Lipids — disrupts biological membranes
• DNA — point mutations
• Proteins — enzyme inactivation
Free Radical Theory of Aging
Aging occurs, in part, from damage caused by reactive
oxygen species arising during normal oxidative metabolism
Cells are Equipped with Antioxidant Mechanims
• Superoxide Dismutase
• Catalase
• Glutathione Peroxidase
• Plant-derived Compounds
– Ascorbate (vitamin C), α-tocopherol
2
O2 + 2 H+ Ñ > H2O2 + O2
2 H2O2 —> 2 H2O + O2
2 GSH + H2O2 —> GSSG + 2 H2O
Oxidative Stress in Aging
Buffenstein, R et al; AGE 2008, 30:99-109
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