Citric Acid Cycle

Introduction to the Citric Acid Cycle

  • The citric acid cycle (CAC) occurs in the mitochondria following the entry of acetyl CoA, as well as fatty acid CoA or fatty acyl CoA.

  • Major products produced from this pathway are carbon dioxide (CO₂) and electron carriers NADH and FADH₂.

Overview of Initial Substrate and Product Formation

  • Initial Reaction:

    • Combines acetyl CoA with oxaloacetate (OAA).

    • This reaction is a condensation reaction and the catalyst for this process.

    • Product: Citrate (also known as citric acid).

    • Difference between citrate and citric acid:

      • Presence of hydronium on the carboxylic acids (at biological pH, citrate is deprotonated).

    • Notable Structure: Contains three carboxylic acid functional groups.

Alternative Terminology

  • Citric acid cycle is often referred to as TCA (tricarboxylic or tricarboxylate cycle).

Step-by-Step Mechanism of the Cycle

Reaction 1: Isomerization

  • Converts citrate to isocitrate through an isomerization process.

  • Enzyme Involved: Isomerase

    • Hydroxyl group moves from carbon 3 to carbon 2.

    • Significance: Facilitates the decarboxylation process (removal of CO₂) and enables the coupling of NADH production.

  • Water is used as an intermediate; it's removed as hydroxyl and added back in a different position.

Reaction 2: Oxidative Decarboxylation

  • Enzyme Involved: Isocitrate dehydrogenase

  • Process:

    • This reaction is identified as oxidative decarboxylation.

    • Products: NADH and CO₂.

    • Isocitrate is oxidized while NAD⁺ is reduced.

    • Final product is alpha-ketoglutarate.

    • Note: Two NADH produced for each glucose molecule; equivalently one NADH per acetyl CoA.

Reaction 3: Formation of Succinyl CoA

  • Conversion of alpha-ketoglutarate to succinyl CoA.

  • Enzyme Involved: Alpha-ketoglutarate dehydrogenase complex

    • Similar to the pyruvate dehydrogenase complex, coupling decarboxylation with NADH formation.

    • Additional product produced is CO₂.

  • This step is recognized as the second energy-generating reaction of CAC.

  • Total NADH produced thus far: Two per each acetyl CoA.

Reaction 4: Conversion to Succinate

  • Behavior: Removal of coenzyme A from succinyl CoA.

  • Product Formed: GTP through substrate-level phosphorylation (direct energy production).

    • GTP considered equivalent to ATP.

    • Enzyme Involved: Succinyl CoA synthetase.

  • Structural similarity noted between ATP and GTP; both are purines and share energy equivalence.

Reaction 5: Reduction of Fumarate

  • This reaction involves producing FADH₂.

  • Produced through the formation of a carbon-carbon double bond.

  • CO-Factor: FAD (Flavin adenine dinucleotide) is essential when producing carbon-carbon double bonds, in contrast to NADH, which is used to form carbonyl compounds.

Reaction 6: Addition of Water

  • Reaction: Water is added to incorporate an alcohol group, producing malate.

    • Malate is noted to have an L isomer, which is atypical among biologically active molecules.

Reaction 7: Oxidation of Malate

  • Enzyme Involved: Malate dehydrogenase

  • Process:

    • Oxidation of malate occurs here, removing two hydrogens.

    • Final product being oxaloacetate, thus completing the cycle.

  • Total products from one acetyl CoA:

    • Three NADH, one FADH₂, and one GTP.

Conclusion of Energy Yields

  • The outputs from the citric acid cycle will be analyzed to determine ATP equivalents produced from both glucose and fatty acids as the discussion moves forward.

  • Highlighting the cyclic nature of the citric acid cycle, oxaloacetate condenses with acetyl CoA again at the cycle's initiation, symbolizing the completion and renewal of the cycle.