The Citric Acid Cycle - Lecture 17 Review

Lecture Overview

• Focus on the citric acid cycle, also known as the tricarboxylic acid cycle.
• Key topics include:
  • Conversion of pyruvate to acetyl-CoA.
  • Pathway structure: key enzymes and degradative products.
  • Regulation of the cycle via allosteric inhibitors.
• Ignore sections on the glyoxylate cycle (less relevant for human biology).

Citric Acid Cycle - Overview

Importance of Citric Acid

• Citric acid: First intermediary in the citric acid cycle.
• Overall pathway begins after the production of pyruvate:
  1. Creation of acetyl-CoA from pyruvate, generating reduced electron carriers.
  2. Oxidation of carbon atoms to form CO2 and further reduce electron carriers.
  3. Transport of electrons for oxidative phosphorylation.

Key Stages of Metabolism

1. Conversion of pyruvate to acetyl-CoA.
2. The Citric Acid Cycle.
3. Oxidative Phosphorylation.

• Note: In unicellular organisms without mitochondria, oxidative phosphorylation takes place at the cell surface.

Mitochondrial Function

• Location: Eukaryotic processes occur in the mitochondria, which have:
  • Outer and inner membranes, essential in ATP conversion.
  • H+ ion gradients in the intermembrane space facilitate ATP production.
• Cristae: Membrane folds increase surface area for ATP synthase and proton pumps.

Electron Transport and ATP Synthesis

• Electrons from glycolysis and the citric acid cycle flow through inner membrane proteins.
• Oxygen acts as the final electron acceptor, forming water and enabling ATP synthesis via ATP synthase due to the H+ gradient.

Detailed Steps of the Citric Acid Cycle

1. Acetyl-CoA + oxaloacetate → Citrate (catalyzed by citrate synthase).
2. Citrate → Isocitrate (via aconitase; temporary water removal).
3. Isocitrate → a-Ketoglutarate (oxidized, producing NADH and CO2).
4. a-Ketoglutarate → Succinyl-CoA (produces NADH and CO2; catalyzed by a-ketoglutarate dehydrogenase).
5. Succinyl-CoA → Succinate (producing GTP).
6. Succinate → Fumarate (by succinate dehydrogenase producing FADH2).
7. Fumarate → Malate (hydration reaction).
8. Malate → Oxaloacetate (regenerated, producing NADH).

Energetics and Stoichiometry of the Cycle

• Starting materials:
  • Acetyl-CoA + 2H2O + 3NAD + FAD + GDP + Pi
• Products:
  • 2CO2 + 3NADH/H+ + FADH2 + CoA + GTP.
• Overall reaction encapsulating glycolysis to the citric acid cycle:
  $ext{Big king glucose} + 2H2O + 10NAD^+ + 2FAD + 4ADP + 4Pi <br /> ightarrow 6CO2 + 10NADH/H^+ + 2FADH2 + 4ATP$

Regulation of the Citric Acid Cycle

1. Pyruvate to Acetyl-CoA conversion (main control point).
2. Conversion of Acetyl-CoA to Citrate.
3. Conversion of Isocitrate to a-Ketoglutarate.
4. Conversion of a-Ketoglutarate to Succinyl-CoA.

Activators/Regulators

• Acetyl-CoA: Downregulated by NADH and Succinyl-CoA.
• Isocitrate: Upregulated by ADP and Ca2+, downregulated by NADH and ATP.
• a-Ketoglutarate: Upregulated by Ca2+, downregulated by Succinyl-CoA and NADH.

Pyruvate Oxidation Control Methods

1. Feedback inhibition via Acetyl-CoA and NADH.
2. Phosphorylation control: Inactive at high ATP levels; activated by Ca2+ and Mg2+.

Lecture Summary

• Next lecture: Review of energy production, metabolism, oxidative phosphorylation, and mitochondrial diseases.