TCA Cycle: A Key Metabolic Pathway in Cellular Respiration

Posted on Jan 8, 2025 in Biochemistry

The Tricarboxylic Acid (TCA) Cycle

The Tricarboxylic Acid (TCA) cycle, also known as the citric acid cycle or Krebs cycle, is a central metabolic pathway that plays a crucial role in the aerobic respiration of eukaryotic cells and many bacteria. It is named after Sir Hans Krebs, who elucidated its key features in the 1930s and 1940s. The TCA cycle takes place in the mitochondria of eukaryotic cells and the cytoplasm of prokaryotic cells.

Detailed Description of the TCA Cycle

  1. Acetyl-CoA Entry:
    • The TCA cycle begins with the entry of acetyl-CoA, a two-carbon molecule derived from the breakdown of carbohydrates, fats, and proteins in various metabolic pathways.
    • Before entering the cycle, each pyruvate molecule (the end product of glycolysis) is converted to acetyl-CoA in a reaction catalyzed by the enzyme pyruvate dehydrogenase.
  2. Citrate Formation:
    • Acetyl-CoA combines with a four-carbon molecule called oxaloacetate to form citrate, a six-carbon compound.
    • This reaction is catalyzed by the enzyme citrate synthase.
  3. Isocitrate Formation:
    • Citrate is isomerized into isocitrate through the action of aconitase, an enzyme that rearranges the carbon atoms within the citrate molecule.
  4. α-Ketoglutarate Formation:
    • Isocitrate undergoes oxidative decarboxylation, where a molecule of carbon dioxide is released, and NAD+ is reduced to NADH.
    • The resulting molecule is α-ketoglutarate, a five-carbon compound.
  5. Succinyl-CoA Formation:
    • α-Ketoglutarate is further decarboxylated with the release of carbon dioxide and the reduction of NAD+ to NADH.
    • The product is succinyl-CoA, a four-carbon compound.
  6. Succinate Formation:
    • Succinyl-CoA undergoes a substrate-level phosphorylation reaction, where a phosphate group is transferred to GDP to form GTP. This reaction is catalyzed by succinyl-CoA synthetase.
    • GTP can later donate its phosphate to ADP to form ATP.
  7. Fumarate Formation:
    • Succinate is oxidized to fumarate, and FAD (flavin adenine dinucleotide) is reduced to FADH2.
    • This reaction is catalyzed by succinate dehydrogenase, which is embedded in the inner mitochondrial membrane and is also part of the electron transport chain.
  8. Malate Formation:
    • Fumarate is hydrated to form malate.
    • The enzyme responsible for this reaction is fumarase.
  9. Regeneration of Oxaloacetate:
    • Malate is oxidized to oxaloacetate, with the reduction of NAD+ to NADH.
    • This reaction is catalyzed by malate dehydrogenase, completing the TCA cycle.

The TCA cycle is essential for the generation of high-energy molecules such as NADH and FADH2, which play crucial roles in the electron transport chain, the final stage of aerobic respiration. The cycle also produces ATP through substrate-level phosphorylation and provides precursors for the synthesis of various biomolecules. It is a central hub in cellular metabolism, connecting pathways involved in the breakdown of carbohydrates, fats, and proteins.