Kreb's cycle

The citric acid cycle is a mitochondrial set of reactions with two major roles:

• Large amounts of energy are released from the metabolism of pyruvate or other intermediates.
• Intermediates in the cycle act as precursors or end points for other pathways, such as the metabolism of certain amino acids.

Key Steps in the Citric Acid Cycle:

1. Formation of Citrate:
   • Acetyl-CoA (2C) combines with oxaloacetate (4C) to form citrate (6C), catalyzed by citrate synthase.
   • Clinical relevance: Disruption can affect energy production, especially in disorders like pyruvate dehydrogenase deficiency.
2. Isomerization of Citrate:
   • Citrate is converted into isocitrate (6C) by aconitase.
3. Oxidative Decarboxylation of Isocitrate:
   • Isocitrate is oxidized to α-ketoglutarate (5C) by isocitrate dehydrogenase, producing NADH and releasing CO2.
   • Rate-limiting step regulated by ADP and calcium.
   • Clinical relevance: Enzyme defects affect aerobic respiration, important in mitochondrial diseases (e.g., Leigh's disease).
4. Formation of Succinyl-CoA:
   • α-Ketoglutarate undergoes decarboxylation by the α-ketoglutarate dehydrogenase complex to form succinyl-CoA (4C), producing NADH and releasing CO2.
   • Clinical relevance: Inhibitors of α-ketoglutarate dehydrogenase (e.g., arsenic) impair the cycle.
5. Conversion to Succinate:
   • Succinyl-CoA is converted to succinate (4C) by succinyl-CoA synthetase, generating GTP (substrate-level phosphorylation).
6. Oxidation of Succinate:
   • Succinate is oxidized to fumarate (4C) by succinate dehydrogenase, producing FADH2.
   • Clinical relevance: Succinate dehydrogenase defects are linked to mitochondrial dysfunction and tumorigenesis (e.g., pheochromocytoma).
7. Conversion to Malate:
   • Fumarate is hydrated to malate (4C) by fumarase.
8. Regeneration of Oxaloacetate:
   • Malate is oxidized to oxaloacetate (4C) by malate dehydrogenase, producing NADH.
   • Clinical relevance: Malate dehydrogenase is key in maintaining cycle continuity.

Each cycle generates 3 NADH, 1 FADH2, 1 GTP, and 2 CO2, ultimately leading to 10 ATP equivalents per acetyl-CoA.

Regulated by availability of substrates (NAD+, FAD) and feedback from ATP, NADH, ADP, and Ca²⁺.

Isocitrate dehydrogenase and α-ketoglutarate dehydrogenase are major control points.

Mutations in succinate dehydrogenase and fumarase are linked to certain tumors.