Introduction
The Citric Acid Cycle, also known as the Tricarboxylic Acid (TCA) or Krebs cycle, is a vital metabolic pathway occurring within the mitochondria of eukaryotic cells. This cycle plays a crucial role in cellular respiration, oxidizing acetyl-CoA derived from carbohydrates, lipids, and proteins. This oxidation process generates carbon dioxide (CO2), water (H2O), and reduced electron carriers (NADH and FADH2). These carriers then fuel the electron transport chain, ultimately leading to the production of ATP, the cell’s primary energy currency.
Location:
The Citric Acid Cycle takes place within the mitochondria, specifically:
- Mitochondrial Matrix: Most cycle enzymes reside here.
- Inner Mitochondrial Membrane: Succinate dehydrogenase, an exception, is embedded here.
Regulation of the Citric Acid Cycle
The Citric Acid Cycle is tightly regulated to match energy demands.
Respiratory Control:
The primary control mechanism is linked to the electron transport chain (ETC) and oxidative phosphorylation.
Key Enzyme Regulation:
Several enzymes within the cycle also exert control:
- Citrate Synthase: Inhibited by ATP and long-chain Acyl-CoA.
- Mitochondrial Isocitrate Dehydrogenase: Activated by ADP, inhibited by ATP and NADH.
- α-Ketoglutarate Dehydrogenase: Inhibited by succinyl-CoA, NADH + H+, and ATP.
Succinate Dehydrogenase Regulation:
- Inhibited by oxaloacetate (OAA).
- OAA availability is controlled by malate dehydrogenase, which is influenced by the NADH/NAD+ ratio.
Functions of the Citric Acid Cycle
The Citric Acid Cycle serves several essential functions:
- Energy Production: It’s the primary energy source for cells containing mitochondria.
- Succinyl-CoA Synthesis: This molecule is crucial for:
- Porphyrin and Hemoglobin synthesis
- Ketone body activation
- Conversion to OAA, which can be further converted to glucose
- Detoxification: Involves conjugation reactions.
- Synthetic Functions:
- Fasting State: Oxaloacetate can be converted into glucose.
- Fed State: Citric acid can be used to synthesize fatty acids.
- Cycle intermediates contribute to amino acid synthesis (transamination).
- Anaplerotic Reactions: Replenish cycle intermediates:
- OAA from pyruvate and aspartate.
- Fumarate from phenylalanine and tyrosine.
- Succinyl-CoA from valine, isoleucine, methionine, and threonine.
- α-ketoglutarate from glutamic acid.
Inhibitors of the Citric Acid Cycle
Several substances can inhibit the Citric Acid Cycle:
- Fluoroacetate: Reacts with oxaloacetate to form fluorocitrate, inhibiting aconitase.
- Arsenite: Inhibits α-ketoglutarate dehydrogenase.
- Malonate: Acts as a competitive inhibitor of succinate dehydrogenase.
Roles of Vitamins in the Citric Acid Cycle
B-complex vitamins are essential for the cycle’s function:
- Riboflavin (FAD): Involved in electron transfer.
- Niacin (NAD): Also participates in electron transfer.
- Thiamin: A component of the α-ketoglutarate dehydrogenase complex.
- Pantothenic Acid: A component of Coenzyme A.
| Step | Enzyme | ATP Yield |
|---|---|---|
| 2(NADH → NAD+) | α-ketoglutarate dehydrogenase complex | 6ATP |
| Substrate level phosphorylation | Succinate thiokinase (2GTP or 2ITP → 2ATP) | 2ATP |
| 2(FADH2 → FAD) | Succinate dehydrogenase | 4ATP |
| 2(NADH → NAD+) | Malate dehydrogenase | 6ATP |
| TOTAL | 24ATP |
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