U01.01.093 TCA cycle

The TCA (Tricarboxylic Acid) Cycle, also known as the Krebs Cycle or Citric Acid Cycle, is a crucial metabolic pathway that occurs in the mitochondria. It plays a vital role in cellular respiration, where energy is produced in the form of ATP, NADH, FADH2, and GTP. The cycle processes Acetyl-CoA (derived from carbohydrates, fats, and proteins) to generate energy, which is essential for the cell’s functions.

Key Components of the TCA Cycle

Acetyl-CoA (2C): The starting molecule that enters the cycle.
NADH: Electron carrier that is produced during the cycle.
Malate (4C): One of the intermediate compounds in the cycle.
Fumarate (4C): Another intermediate compound in the cycle.
Succinate (4C): Formed during the TCA cycle.
Succinyl-CoA (4C): Intermediate that is converted into succinate.
α-Ketoglutarate (5C): A key intermediate involved in energy production.
Isocitrate (6C): Formed from citrate and undergoes decarboxylation.
Citrate (6C): The starting point of the cycle.
Oxaloacetate (4C): The final compound that combines with acetyl-CoA to form citrate.
Pyruvate (3C): Precursor molecule converted into acetyl-CoA.

Key Enzymes in the TCA Cycle

Citrate Synthase
Catalyzes the reaction of Acetyl-CoA with oxaloacetate to form citrate.
Aconitase
Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
Isocitrate Dehydrogenase
Converts isocitrate to α-ketoglutarate, producing NADH and CO2.
α-Ketoglutarate Dehydrogenase Complex
Converts α-ketoglutarate to succinyl-CoA, producing NADH and CO2.
Succinyl-CoA Synthetase
Converts succinyl-CoA to succinate, producing GTP.
Succinate Dehydrogenase
Converts succinate to fumarate, producing FADH2.
Fumarase
Catalyzes the conversion of fumarate to malate.
Malate Dehydrogenase
Converts malate to oxaloacetate, producing NADH.

Key Reactions and Products

Step	Reaction	Products
1. Acetyl-CoA + Oxaloacetate	Forms Citrate	No energy output
2. Citrate → Isocitrate	Isomerization by Aconitase	No energy output
3. Isocitrate → α-Ketoglutarate	Decarboxylation by Isocitrate Dehydrogenase	1 NADH, 1 CO2
4. α-Ketoglutarate → Succinyl-CoA	Decarboxylation by α-Ketoglutarate Dehydrogenase	1 NADH, 1 CO2
5. Succinyl-CoA → Succinate	Conversion by Succinyl-CoA Synthetase	1 GTP
6. Succinate → Fumarate	Dehydrogenation by Succinate Dehydrogenase	1 FADH2
7. Fumarate → Malate	Hydration by Fumarase	No energy output
8. Malate → Oxaloacetate	Dehydrogenation by Malate Dehydrogenase	1 NADH

Key Points to Remember

ATP Yield: Each Acetyl-CoA that enters the cycle produces 10 ATP (3 NADH, 1 FADH2, 1 GTP, 2 CO2). As two molecules of acetyl-CoA are produced from one glucose, the total yield per glucose is 20 ATP.
TCA Cycle Location: The TCA cycle takes place in the mitochondria of the cell.
Irreversible Enzymes: The enzymes in the TCA cycle that catalyze irreversible steps are:
- Citrate Synthase
- Isocitrate Dehydrogenase
- α-Ketoglutarate Dehydrogenase
Cofactors for α-Ketoglutarate Dehydrogenase: This enzyme complex requires the same cofactors as the Pyruvate Dehydrogenase Complex:
- Vitamin B1 (Thiamine)
- Vitamin B2 (Riboflavin)
- Vitamin B3 (Niacin)
- Vitamin B5 (Pantothenic acid)
- Lipoic acid

Learning Objective

Students should be able to:

Understand the overall function and energy production of the TCA cycle.
Recognize the key enzymes and their roles in the cycle.
Calculate the energy yield per glucose molecule from the TCA cycle.
Identify the irreversibility of key steps in the cycle.
Link the TCA cycle to other metabolic pathways such as glycolysis and oxidative phosphorylation.

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