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8d- BCC Oxidaitve Metabolism Handout

Oxidative Metabolism Energy Flow

  • Acetyl-CoA Production: Derived from carbohydrates, fatty acids, and amino acids.

  • Acetyl-CoA Oxidation: Occurs in the citric acid cycle.

  • Electron Transfer: Establishes proton-motive force and leads to oxidative phosphorylation.

Stages of Oxidative Metabolism

  • Location: All stages occur in mitochondria:

    • Stages 1 & 2: Mitochondrial matrix.

    • Stage 3: Inner mitochondrial membrane.

Pyruvate Dehydrogenase Complex

  • Function: Oxidizes pyruvate in the presence of oxygen.

    • Net Reaction: Oxidative decarboxylation of pyruvate, where CO2 is released, making it thermodynamically favorable and irreversible.

    • Connects glycolysis to the citric acid cycle by converting pyruvate to acetyl-CoA.

Structure of Pyruvate Dehydrogenase Complex

  • Components:

    • Pyruvate dehydrogenase (E1)

    • Dihydrolipoyl transacetylase (E2)

    • Dihydrolipoyl dehydrogenase (E3)

  • Coenzymes:

    • Tightly bound (TPP, lipoamide, FAD+) considered prosthetic groups.

    • Mobile carriers (CoA-SH, NAD+).

Regulation of Pyruvate Dehydrogenase

  • Activation: Pyruvate, ADP, AMP, CoA, NAD+, Ca2+, Insulin.

  • Inhibition: ADP, NADH, acetyl-CoA.

Deficiency of Pyruvate Dehydrogenase Complex

  • Lactic Acidosis: Common genetic disorder due to mutations lowering PDH complex activity.

  • Consequence:

    • Decreased oxidative metabolism and ATP production.

    • Increased glycolysis (~15x more glucose consumption).

    • Accumulation of lactic and pyruvic acids causing lactic acidosis.

  • High ATP Demand Effects: Notable impacts on high ATP demand tissues like the brain, leading to retardation.

Thiamine Pyrophosphate Deficiency

  • Condition: Leads to beriberi due to inactive pyruvate dehydrogenase.

    • Central nervous problems from inadequate ATP production.

    • Related to other conditions like Wernicke-Korsakoff syndrome in severe thiamine deficiency due to alcoholism.

Tricarboxylic Acid Cycle (TCA)

  • Krebs Cycle: A central metabolic pathway.

  • Historical Evidence: Confirmed through experiments involving succinate, fumarate, and malate's effect on oxygen consumption.

Citric Acid Cycle Steps

  1. C-C Bond Formation: Acetyl-CoA and oxaloacetate form citrate.

  2. Isomerization: Converts citrate to isocitrate.

  3. Oxidative Decarboxylation: Produces NADHs, converting isocitrate to ◽α-ketoglutarate.

  4. Second Oxidative Decarboxylation: Converts ◽α-ketoglutarate to succinyl-CoA.

  5. Substrate-level Phosphorylation: Produces GTP from succinyl-CoA.

  6. Oxidation of Succinate: Converts succinate to fumarate.

  7. Hydration of Fumarate: Forms malate.

  8. Final Oxidation: Oxidizes malate back to oxaloacetate, completing the cycle.

Overview of Citric Acid Cycle

  • Energy Yield:

    • 2 carbon atoms enter (from acetyl-CoA) and 2 carbon atoms leave (as CO2).

    • 4 pairs of hydrogen leave through oxidation, reducing 3 NAD+ and 1 FAD.

    • Produces 1 GTP.

  • Full Glucose Oxidation: Requires 2 turns of the cycle.

Regulation of the Citric Acid Cycle

  • Key Control Points:

    • Controlled at exergonic steps involving citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase complex.

    • Regulation affected by substrate availability, product inhibition, and intermediates.

  • Activation: By ADP, NAD+, and CoA; inhibited by ATP and NADH.

Electron Transport Chain (ETC)

  • Function: Transfers electrons through carriers to O2, producing ATP in the process.

  • ETC Complexes:

    1. Complex I: NADH to ubiquinone, transported electrons with protons released into the intermembrane space.

    2. Complex II: Succinate to ubiquinone, does not pump protons.

    3. Complex III: Transfers electrons from CoQH2 to cytochrome c.

    4. Complex IV: Reduces oxygen to water using electrons from cytochrome c and pumps additional protons.

ATP Synthesis – Oxidative Phosphorylation

  • Chemiosmotic Theory: Proton gradient drives ATP synthesis by ATP synthase.

  • ATP Synthase:

    • F0 (proton channel) and F1 (catalytic part), facilitating ADP phosphorylation to ATP.

Regulation of Oxidative Phosphorylation

  • Cellular Energy Needs:

    • High energy demand favors ADP and NAD+ activation, low favors ATP and NADH inhibition.

  • Inhibitors of Oxidative Phosphorylation:

    1. ATP synthase inhibitors.

    2. ADP/ATP translocase inhibitors.

    3. ETC inhibitors (uncouplers disrupt proton-motive force).

Clinical Correlations

  • Coenzyme Q10: Essential for energy metabolism; deficiency linked to heart failure and aging.

  • Uncoupling: Important in brown adipose tissue for thermoregulation.

  • Mitochondrial Shuttle Systems: For oxidizing cytosolic NADH; include Glycerol 3-P and Malate-Aspartate shuttles.

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8d- BCC Oxidaitve Metabolism Handout

Oxidative Metabolism Energy Flow

  • Acetyl-CoA Production: Derived from carbohydrates, fatty acids, and amino acids.

  • Acetyl-CoA Oxidation: Occurs in the citric acid cycle.

  • Electron Transfer: Establishes proton-motive force and leads to oxidative phosphorylation.

Stages of Oxidative Metabolism

  • Location: All stages occur in mitochondria:

    • Stages 1 & 2: Mitochondrial matrix.

    • Stage 3: Inner mitochondrial membrane.

Pyruvate Dehydrogenase Complex

  • Function: Oxidizes pyruvate in the presence of oxygen.

    • Net Reaction: Oxidative decarboxylation of pyruvate, where CO2 is released, making it thermodynamically favorable and irreversible.

    • Connects glycolysis to the citric acid cycle by converting pyruvate to acetyl-CoA.

Structure of Pyruvate Dehydrogenase Complex

  • Components:

    • Pyruvate dehydrogenase (E1)

    • Dihydrolipoyl transacetylase (E2)

    • Dihydrolipoyl dehydrogenase (E3)

  • Coenzymes:

    • Tightly bound (TPP, lipoamide, FAD+) considered prosthetic groups.

    • Mobile carriers (CoA-SH, NAD+).

Regulation of Pyruvate Dehydrogenase

  • Activation: Pyruvate, ADP, AMP, CoA, NAD+, Ca2+, Insulin.

  • Inhibition: ADP, NADH, acetyl-CoA.

Deficiency of Pyruvate Dehydrogenase Complex

  • Lactic Acidosis: Common genetic disorder due to mutations lowering PDH complex activity.

  • Consequence:

    • Decreased oxidative metabolism and ATP production.

    • Increased glycolysis (~15x more glucose consumption).

    • Accumulation of lactic and pyruvic acids causing lactic acidosis.

  • High ATP Demand Effects: Notable impacts on high ATP demand tissues like the brain, leading to retardation.

Thiamine Pyrophosphate Deficiency

  • Condition: Leads to beriberi due to inactive pyruvate dehydrogenase.

    • Central nervous problems from inadequate ATP production.

    • Related to other conditions like Wernicke-Korsakoff syndrome in severe thiamine deficiency due to alcoholism.

Tricarboxylic Acid Cycle (TCA)

  • Krebs Cycle: A central metabolic pathway.

  • Historical Evidence: Confirmed through experiments involving succinate, fumarate, and malate's effect on oxygen consumption.

Citric Acid Cycle Steps

  1. C-C Bond Formation: Acetyl-CoA and oxaloacetate form citrate.

  2. Isomerization: Converts citrate to isocitrate.

  3. Oxidative Decarboxylation: Produces NADHs, converting isocitrate to ◽α-ketoglutarate.

  4. Second Oxidative Decarboxylation: Converts ◽α-ketoglutarate to succinyl-CoA.

  5. Substrate-level Phosphorylation: Produces GTP from succinyl-CoA.

  6. Oxidation of Succinate: Converts succinate to fumarate.

  7. Hydration of Fumarate: Forms malate.

  8. Final Oxidation: Oxidizes malate back to oxaloacetate, completing the cycle.

Overview of Citric Acid Cycle

  • Energy Yield:

    • 2 carbon atoms enter (from acetyl-CoA) and 2 carbon atoms leave (as CO2).

    • 4 pairs of hydrogen leave through oxidation, reducing 3 NAD+ and 1 FAD.

    • Produces 1 GTP.

  • Full Glucose Oxidation: Requires 2 turns of the cycle.

Regulation of the Citric Acid Cycle

  • Key Control Points:

    • Controlled at exergonic steps involving citrate synthase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase complex.

    • Regulation affected by substrate availability, product inhibition, and intermediates.

  • Activation: By ADP, NAD+, and CoA; inhibited by ATP and NADH.

Electron Transport Chain (ETC)

  • Function: Transfers electrons through carriers to O2, producing ATP in the process.

  • ETC Complexes:

    1. Complex I: NADH to ubiquinone, transported electrons with protons released into the intermembrane space.

    2. Complex II: Succinate to ubiquinone, does not pump protons.

    3. Complex III: Transfers electrons from CoQH2 to cytochrome c.

    4. Complex IV: Reduces oxygen to water using electrons from cytochrome c and pumps additional protons.

ATP Synthesis – Oxidative Phosphorylation

  • Chemiosmotic Theory: Proton gradient drives ATP synthesis by ATP synthase.

  • ATP Synthase:

    • F0 (proton channel) and F1 (catalytic part), facilitating ADP phosphorylation to ATP.

Regulation of Oxidative Phosphorylation

  • Cellular Energy Needs:

    • High energy demand favors ADP and NAD+ activation, low favors ATP and NADH inhibition.

  • Inhibitors of Oxidative Phosphorylation:

    1. ATP synthase inhibitors.

    2. ADP/ATP translocase inhibitors.

    3. ETC inhibitors (uncouplers disrupt proton-motive force).

Clinical Correlations

  • Coenzyme Q10: Essential for energy metabolism; deficiency linked to heart failure and aging.

  • Uncoupling: Important in brown adipose tissue for thermoregulation.

  • Mitochondrial Shuttle Systems: For oxidizing cytosolic NADH; include Glycerol 3-P and Malate-Aspartate shuttles.

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