Citric Acid Cycle (Krebs Cycle or Tricarboxylic Acid Cycle): Pathway, energetics and significance

1. Introduction of Citric Acid Cycle

The Citric Acid Cycle (CAC), also known as the Krebs Cycle or the Tricarboxylic Acid (TCA) Cycle, is a fundamental metabolic pathway that plays a central role in cellular respiration. It is an essential process occurring in the mitochondrial matrix of eukaryotic cells and the cytoplasm of prokaryotic cells, where it functions as a key energy-generating system. This cycle is responsible for the oxidation of acetyl-CoA, a metabolic intermediate derived from carbohydrates, fatty acids, and amino acids, to produce energy-rich molecules such as NADH, FADH₂, and ATP (or GTP).

Key Molecules: The involvement of tricarboxylic acids often earns the citric acid cycle the name TCA (Tricarboxylic Acid) cycle.

2. Key Steps in the Citric Acid Cycle

Step 1: Acetyl-CoA Entry:

Enzyme: Citrate synthase

Reaction: Acetyl-CoA combines with oxaloacetate to form citrate.

Importance: Initiates the cycle by incorporating the two-carbon acetyl unit.

Step 2: Citrate Isomerization:

Enzyme: Aconitase

Reaction: Citrate is isomerized to isocitrate.

Significance: Rearranges the structure for subsequent reactions.

Step 3: Isocitrate Oxidation:

Enzyme: Isocitrate dehydrogenase

Reaction: Isocitrate is oxidized to alpha-ketoglutarate, producing NADH and CO2.

NADH Production: First instance of NADH generation in the cycle.

Step 4: Alpha-Ketoglutarate Decarboxylation:

Enzyme: Alpha-ketoglutarate dehydrogenase complex

Reaction: Decarboxylating alpha-ketoglutarate forms succinyl-CoA, generating NADH and CO2.

Similarity to Pyruvate Decarboxylation: Resembles the pyruvate decarboxylation step in glycolysis.

Step 5: Succinyl-CoA Synthesis:

Enzyme: Succinyl-CoA synthetase

Reaction: Succinyl-CoA is formed with the concurrent conversion of GDP to GTP.

Energy Transfer: Represents substrate-level phosphorylation.

Step 6: Succinate Dehydrogenation:

Enzyme: Succinate dehydrogenase (part of the electron transport chain)

Reaction: Succinate is oxidized to fumarate, transferring electrons to FAD to form FADH2.

Unique Feature: The only enzyme of the cycle embedded in the inner mitochondrial membrane.

Step 7: Fumarate Formation:

Enzyme: Fumarase

Reaction: Fumarate is hydrated to form malate.

Hydration Reaction: Adds water to the double bond in fumarate.

Step 8: Malate Oxidation:

Enzyme: Malate dehydrogenase

Reaction: Malate is oxidized to reform oxaloacetate, generating NADH.

Regeneration of Oxaloacetate: Completes the cycle by reforming the initial substrate.

3. Energetics and Regulation

Energy Yield: The cycle generates 3 NADH, 1 FADH2, and 1 GTP (or ATP) and releases 2 CO2 molecules per turn.

Regulation: Allosteric regulation of key enzymes, especially isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase.

4. Amphibolic Nature of the Citric Acid Cycle

Anabolic Functions: Provides intermediates for biosynthetic pathways, including amino acid synthesis.

Catabolic Functions: Oxidizes acetyl-CoA to produce reducing equivalents (NADH and FADH2) for ATP synthesis.

5. Connection to Electron Transport Chain (ETC)

Electron Carrier Production: NADH and FADH2 generated in the cycle donate electrons to the ETC, contributing to ATP production.

6. Role in Nutrient Metabolism

Glucose Metabolism: Accepts acetyl-CoA derived from glucose through glycolysis.

Amino Acid Metabolism: Intermediates participate in amino acid synthesis and degradation.

7. Physiological Conditions Affecting the Citric Acid Cycle

Oxygen Availability: The cycle is most efficient in the presence of oxygen, as NADH and FADH2 can donate electrons to the ETC.

Nutrient Availability: The availability of acetyl-CoA precursors, such as glucose or fatty acids, influences the cycle’s activity.

8. Disorders Related to the Citric Acid Cycle

Genetic Deficiencies: Rare genetic disorders affecting enzymes of the cycle can lead to metabolic diseases.

9. Significance in Cellular Respiration

Integration with Glycolysis: The citric acid cycle is the convergence point for the oxidation of various fuel molecules, linking glycolysis and the breakdown of fatty acids.

The citric acid cycle is a central metabolic pathway with catabolic and anabolic functions. Its role in generating reducing equivalents for ATP synthesis, providing biosynthetic intermediates, and participating in the overall metabolism of nutrients underscores its significance in cellular energy production and nutrient homeostasis.

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