Citric Acid Cycle Detailed Study Notes

Overview of the Citric Acid Cycle

• The Citric Acid Cycle is part three, stage three of aerobic cellular respiration.

• It is called the Citric Acid Cycle because the first product of the enzymatic reaction is citric acid.

• Citric acid is known as a tricarboxylic acid (TCA cycle).

• Sometimes referred to as the Krebs cycle, named after Hans Krebs, who discovered this pathway in cells.

• It is important to be familiar with all three terms as they are often used interchangeably in textbooks and discussions.

Process of the Citric Acid Cycle

• Each acetyl coenzyme A (Acetyl CoA) molecule entering the cycle will:

  • Be oxidized.

  • Result in the release of two molecules of carbon dioxide (CO₂) for each acetyl group.

• The pathway must be traversed twice for each glucose molecule that enters glycolysis, leading to a total release of six carbon atoms per glucose as CO₂.

Oxidation and Energy Production

• During the cycle:

  • Potential energy released from oxidation reactions is used to:

  • Reduce NAD⁺ to NADH.

  • Reduce FAD to FADH₂.

  • Produce ATP or GTP through substrate-level phosphorylation.

• ATP is mainly produced in bacteria and plants, while GTP forms in some animal cells, depending on the enzyme isoform involved.

Structure of the Citric Acid Cycle

• The cycle can be divided into three main segments:

  1. Formation of Citrate: Acetyl group from Acetyl CoA combines with oxaloacetate (a four-carbon molecule) to form citrate (six carbon molecule).

  • Key Reaction: Acetyl CoA + Oxaloacetate → Citrate

  • Enzyme: Citrate Synthase (first enzyme, irreversible reaction, often regulated).

  1. Oxidation and Decarboxylation: Involves multiple reactions producing CO₂ and reducing coenzymes:

  • First, citrate converts to isocitrate via the enzyme aconitase.

  • Isocitrate is oxidized (NAD⁺ to NADH) and decarboxylated, resulting in α-ketoglutarate.

    • Enzyme: Isocitrate Dehydrogenase.

  • α-Ketoglutarate undergoes further decarboxylation and is converted to succinyl-CoA, with NAD⁺ being reduced to NADH.

    • Enzyme: α-ketoglutarate Dehydrogenase.

  1. Regeneration of Oxaloacetate:

  • Succinyl-CoA is converted to succinate, with ATP or GTP being generated from substrate-level phosphorylation.

    • Enzyme: Succinyl-CoA Synthetase.

  • Succinate is oxidized to fumarate (FAD to FADH₂), catalyzed by succinate dehydrogenase.

  • Water is added to fumarate to form malate (catalyzed by fumarate hydratase), which is then oxidized back to oxaloacetate (NAD⁺ to NADH).

    • Final Enzyme: Malate Dehydrogenase.

Key Enzymes and Their Functions

• The Citric Acid Cycle involves eight enzymatic reactions throughout these segments:

  • Citrate Synthase: Converts Acetyl CoA and oxaloacetate to citrate.

  • Aconitase: Converts citrate to isocitrate.

  • Isocitrate Dehydrogenase: Converts isocitrate to α-ketoglutarate, reducing NAD⁺ to NADH.

  • α-ketoglutarate Dehydrogenase: Converts α-ketoglutarate to succinyl-CoA, reducing NAD⁺ to NADH.

  • Succinyl-CoA Synthetase: Converts succinyl-CoA to succinate, generating ATP/GTP.

  • Succinate Dehydrogenase: Converts succinate to fumarate, reducing FAD to FADH₂.

  • Fumarate Hydratase: Converts fumarate to malate by adding water.

  • Malate Dehydrogenase: Converts malate back to oxaloacetate, reducing NAD⁺ to NADH.

Study Tips for Memorization

• Memorization of intermediate names and enzyme names is essential:

  • A mnemonic for remembering succinate's order is that "Succinate is always late".

• Continuous writing and repetition will enhance recall.

• Understanding the cycle structure may help, but specific structure recognition is not strictly required for the exam.

Regulation and Other Considerations

• Identify which enzymes in the cycle are subject to regulation (still to be discussed in the following slides).

• Note the importance of the TCA cycle in both the Krebs cycle and electron transport chain, particularly with succinate dehydrogenase being a pivotal enzyme in both processes.

Recap

• The main focus points of the Citric Acid Cycle:

  • Function and terminology (Citric Acid, TCA, Krebs cycle).

  • Energy production and reduction of coenzymes throughout the cycle.

  • Detailed knowledge of enzyme names, derivatives, and regulatory aspects.