1. Introduction
Definition: The citric acid cycle is a central metabolic pathway that takes place in the mitochondrial matrix, serving as a hub for the oxidation of acetyl-CoA derived from various nutrient sources.
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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