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Overview of the Krebs Cycle

The Krebs cycle, also known as the citric acid cycle or tricarboxylic acid (TCA) cycle, is a fundamental metabolic pathway that plays a crucial role in cellular respiration. It occurs in the mitochondrial matrix and is essential for the aerobic oxidation of carbohydrates, fats, and proteins into carbon dioxide and water, while generating energy in the form of ATP, NADH, and FADH₂.

Key Steps of the Krebs Cycle

1. Formation of Citrate: The cycle begins with the condensation of acetyl-CoA (derived from carbohydrates, fats, or proteins) with oxaloacetate to form citrate, catalyzed by the enzyme citrate synthase.
2. Isomerization to Isocitrate: Citrate is then converted to isocitrate by the enzyme aconitase.
3. Oxidative Decarboxylation: Isocitrate is oxidized to α-ketoglutarate, producing NADH and releasing CO₂ through the action of isocitrate dehydrogenase.
4. Second Decarboxylation: α-Ketoglutarate is further oxidized to succinyl-CoA, generating another NADH and releasing another CO₂ molecule, catalyzed by α-ketoglutarate dehydrogenase.
5. Conversion to Succinate: Succinyl-CoA is converted to succinate, producing GTP (or ATP) through substrate-level phosphorylation, catalyzed by succinyl-CoA synthetase.
6. Oxidation to Fumarate: Succinate is oxidized to fumarate, generating FADH₂ via the enzyme succinate dehydrogenase.
7. Hydration to Malate: Fumarate is hydrated to malate by the enzyme fumarase.
8. Regeneration of Oxaloacetate: Finally, malate is oxidized to regenerate oxaloacetate, producing another NADH, catalyzed by malate dehydrogenase. This completes the cycle, allowing it to begin anew with another acetyl-CoA.

Energy Yield

For each turn of the Krebs cycle, the following energy carriers are produced:

• 3 NADH
• 1 FADH₂
• 1 GTP (or ATP)
• 2 CO₂ (as waste products)

Each NADH can generate approximately 2.5 ATP, and each FADH₂ can generate about 1.5 ATP in the electron transport chain, leading to a total yield of approximately 10 ATP per acetyl-CoA molecule entering the cycle.

Regulation of the Krebs Cycle

The Krebs cycle is tightly regulated by the availability of substrates and the energy needs of the cell. Key regulatory enzymes include:

• Citrate Synthase: Regulated by the concentration of acetyl-CoA and oxaloacetate.
• Isocitrate Dehydrogenase: Activated by ADP and inhibited by ATP and NADH.
• α-Ketoglutarate Dehydrogenase: Inhibited by succinyl-CoA and NADH, and activated by calcium ions.

Clinical Relevance

Disruptions in the Krebs cycle can lead to various metabolic disorders and are implicated in diseases such as cancer, where altered metabolism supports rapid cell growth. For instance, mutations in Krebs cycle enzymes like succinate dehydrogenase and fumarate hydratase have been linked to hereditary cancers, highlighting the cycle's role in tumor suppression and metabolic regulation Krebs cycle enzymes as tumor suppressors.

Conclusion

The Krebs cycle is a vital metabolic pathway that not only generates energy but also provides intermediates for various biosynthetic processes. Understanding its regulation and function is crucial for insights into metabolic health and disease.

Further Exploration

For more detailed insights into the Krebs cycle and its implications in health and disease, consider exploring the following: