One Turn Of Citric Acid Cycle Produces

The citric acid cycle, also known as the Krebs cycle or tricarboxylic acid (TCA) cycle, is a central metabolic pathway in all aerobic organisms. Its primary role is to oxidize acetyl-CoA, derived from carbohydrates, fats, and proteins, into carbon dioxide (CO2), while generating high-energy electron carriers like NADH and FADH2, and a small amount of ATP or GTP. Understanding what one turn of the citric acid cycle produces is crucial for grasping cellular respiration and energy metabolism.

The Citric Acid Cycle: An Overview

The citric acid cycle takes place in the mitochondrial matrix of eukaryotic cells and the cytoplasm of prokaryotic cells. It is a cyclical series of eight enzymatic reactions, each catalyzed by a specific enzyme. The cycle begins with the condensation of acetyl-CoA with oxaloacetate, a four-carbon molecule, to form citrate, a six-carbon molecule. Through a series of redox, dehydration, hydration, and decarboxylation reactions, citrate is progressively transformed back into oxaloacetate, completing the cycle.

Key Objectives of the Citric Acid Cycle

1. Oxidation of Acetyl-CoA: The primary goal is to completely oxidize the two-carbon acetyl group of acetyl-CoA into two molecules of carbon dioxide.
2. Energy Generation: The cycle produces high-energy molecules such as NADH and FADH2, which are essential for the electron transport chain and oxidative phosphorylation, the main ATP-producing pathway in aerobic respiration.
3. Precursor Synthesis: The cycle generates several intermediate compounds that serve as precursors for the biosynthesis of amino acids, fatty acids, and other essential molecules.

Products of One Turn of the Citric Acid Cycle

One complete turn of the citric acid cycle results in the following products per molecule of acetyl-CoA:

• 2 molecules of carbon dioxide (CO2)
• 3 molecules of NADH
• 1 molecule of FADH2
• 1 molecule of GTP (or ATP in some organisms)

Let's break down each of these products and their significance:

1. Carbon Dioxide (CO2)

Role in the Cycle: Two decarboxylation reactions occur during the citric acid cycle, releasing two molecules of CO2.

• The first decarboxylation occurs when isocitrate is oxidized and decarboxylated to α-ketoglutarate, catalyzed by isocitrate dehydrogenase.
• The second decarboxylation occurs when α-ketoglutarate is converted to succinyl-CoA, catalyzed by the α-ketoglutarate dehydrogenase complex.

Significance: CO2 is a waste product of cellular respiration and is eventually exhaled. The release of CO2 signifies the complete oxidation of the carbon atoms from the original acetyl-CoA molecule.

2. NADH

Role in the Cycle: Three NADH molecules are produced during one turn of the citric acid cycle.

• The first NADH is generated during the conversion of isocitrate to α-ketoglutarate, catalyzed by isocitrate dehydrogenase.
• The second NADH is produced during the conversion of α-ketoglutarate to succinyl-CoA, catalyzed by the α-ketoglutarate dehydrogenase complex.
• The third NADH is formed during the oxidation of malate to oxaloacetate, catalyzed by malate dehydrogenase.

Significance: NADH is a crucial electron carrier. Each NADH molecule carries two high-energy electrons to the electron transport chain (ETC), where they are used to generate ATP via oxidative phosphorylation. Each NADH molecule can potentially yield approximately 2.5 ATP molecules.

3. FADH2

Role in the Cycle: One FADH2 molecule is generated during the citric acid cycle.

• FADH2 is produced during the conversion of succinate to fumarate, catalyzed by succinate dehydrogenase.

Significance: FADH2 is another essential electron carrier. It carries two high-energy electrons to the electron transport chain. However, FADH2 enters the ETC at a later stage than NADH, resulting in a lower ATP yield. Each FADH2 molecule can potentially yield approximately 1.5 ATP molecules.

4. GTP (or ATP)

Role in the Cycle: One GTP (guanosine triphosphate) molecule is produced during the cycle.

• GTP is generated during the conversion of succinyl-CoA to succinate, catalyzed by succinyl-CoA synthetase.

Significance: GTP is energetically equivalent to ATP. In some organisms, ATP is directly produced instead of GTP by the same enzyme. GTP can be readily converted to ATP by nucleotide diphosphate kinase, which catalyzes the transfer of a phosphate group from GTP to ADP. This single GTP molecule represents a small but immediate energy gain from the cycle.

Step-by-Step Breakdown of the Citric Acid Cycle

To fully understand the products, let's walk through each step of the citric acid cycle:

1. Step 1: Formation of Citrate

   • Reactants: Acetyl-CoA (2 carbons) + Oxaloacetate (4 carbons)
   • Enzyme: Citrate synthase
   • Product: Citrate (6 carbons)
   • CoA is released.
   • Significance: This step initiates the cycle by combining acetyl-CoA with oxaloacetate to form citrate.

2. Step 2: Isomerization of Citrate to Isocitrate

   • Reactant: Citrate
   • Enzyme: Aconitase
   • Intermediate: cis-Aconitate
   • Product: Isocitrate
   • Significance: This isomerization rearranges the citrate molecule, preparing it for the subsequent decarboxylation reactions.

3. Step 3: Oxidation and Decarboxylation of Isocitrate to α-Ketoglutarate

   • Reactant: Isocitrate
   • Enzyme: Isocitrate dehydrogenase
   • Product: α-Ketoglutarate (5 carbons) + CO2 + NADH
   • Significance: This is the first redox reaction in the cycle, producing NADH and releasing the first molecule of CO2.

4. Step 4: Oxidation and Decarboxylation of α-Ketoglutarate to Succinyl-CoA

   • Reactant: α-Ketoglutarate
   • Enzyme: α-Ketoglutarate dehydrogenase complex
   • Product: Succinyl-CoA (4 carbons) + CO2 + NADH
   • CoA is added.
   • Significance: This is the second redox reaction, producing NADH and releasing the second molecule of CO2. This step is similar to the pyruvate dehydrogenase complex reaction.

5. Step 5: Conversion of Succinyl-CoA to Succinate

   • Reactant: Succinyl-CoA
   • Enzyme: Succinyl-CoA synthetase
   • Product: Succinate (4 carbons) + GTP (or ATP) + CoA
   • Significance: This substrate-level phosphorylation step generates one molecule of GTP (or ATP), providing a small but immediate energy gain.

6. Step 6: Oxidation of Succinate to Fumarate

   • Reactant: Succinate
   • Enzyme: Succinate dehydrogenase
   • Product: Fumarate (4 carbons) + FADH2
   • Significance: FADH2 is produced, carrying electrons to the electron transport chain. Succinate dehydrogenase is bound to the inner mitochondrial membrane.

7. Step 7: Hydration of Fumarate to Malate

   • Reactant: Fumarate
   • Enzyme: Fumarase
   • Product: Malate (4 carbons)
   • Significance: Water is added to fumarate, preparing it for the final oxidation step.

8. Step 8: Oxidation of Malate to Oxaloacetate

   • Reactant: Malate
   • Enzyme: Malate dehydrogenase
   • Product: Oxaloacetate (4 carbons) + NADH
   • Significance: This final redox reaction produces NADH and regenerates oxaloacetate, allowing the cycle to continue.

Regulation of the Citric Acid Cycle

The citric acid cycle is tightly regulated to meet the energy demands of the cell. Several factors influence the cycle's activity:

• Availability of Substrates: The concentrations of acetyl-CoA and oxaloacetate can limit the cycle's rate.
• Energy Charge: High levels of ATP and NADH inhibit the cycle, while high levels of ADP and NAD+ stimulate it.
• Calcium Ions: In muscle cells, calcium ions (Ca2+) stimulate the cycle by activating pyruvate dehydrogenase, isocitrate dehydrogenase, and α-ketoglutarate dehydrogenase.
• Feedback Inhibition: Certain intermediates of the cycle, such as citrate and succinyl-CoA, can inhibit specific enzymes in the cycle.

Key regulatory enzymes include:

• Citrate Synthase: Inhibited by ATP, NADH, succinyl-CoA, and citrate.
• Isocitrate Dehydrogenase: Activated by ADP and Ca2+, inhibited by ATP and NADH.
• α-Ketoglutarate Dehydrogenase Complex: Inhibited by succinyl-CoA and NADH, activated by Ca2+.

The Link Between Glycolysis, Pyruvate Decarboxylation, and the Citric Acid Cycle

The citric acid cycle is closely linked to glycolysis and pyruvate decarboxylation. Glycolysis is the breakdown of glucose into pyruvate. Under aerobic conditions, pyruvate is transported into the mitochondria and converted to acetyl-CoA by the pyruvate dehydrogenase complex.

Pyruvate Decarboxylation:

• Reactant: Pyruvate
• Enzyme: Pyruvate dehydrogenase complex
• Products: Acetyl-CoA + CO2 + NADH

The acetyl-CoA produced from pyruvate then enters the citric acid cycle. Thus, glycolysis provides the initial substrate (glucose), which is broken down to pyruvate, then converted to acetyl-CoA for the citric acid cycle.

The Electron Transport Chain and Oxidative Phosphorylation

The NADH and FADH2 produced during the citric acid cycle are crucial for the electron transport chain (ETC) and oxidative phosphorylation, which are the primary means of ATP production in aerobic respiration.

Electron Transport Chain (ETC):

• NADH and FADH2 donate their electrons to a series of protein complexes embedded in the inner mitochondrial membrane.
• As electrons are transferred through these complexes, protons (H+) are pumped from the mitochondrial matrix to the intermembrane space, creating an electrochemical gradient.
• The final electron acceptor is oxygen (O2), which is reduced to water (H2O).

Oxidative Phosphorylation:

• The electrochemical gradient drives protons back into the mitochondrial matrix through ATP synthase, a protein complex that synthesizes ATP from ADP and inorganic phosphate.
• This process is called chemiosmosis, and it is the primary mechanism by which ATP is generated in aerobic respiration.

Significance in Energy Production

One turn of the citric acid cycle generates a small amount of ATP directly (1 GTP or ATP). However, its main contribution to energy production lies in the generation of NADH and FADH2, which drive the electron transport chain and oxidative phosphorylation.

Theoretical ATP Yield:

• 3 NADH x 2.5 ATP/NADH = 7.5 ATP
• 1 FADH2 x 1.5 ATP/FADH2 = 1.5 ATP
• 1 GTP = 1 ATP
• Total ATP yield per turn of the citric acid cycle ≈ 10 ATP

Since each glucose molecule yields two pyruvate molecules, and each pyruvate is converted into one acetyl-CoA, two turns of the citric acid cycle are required per glucose molecule. Therefore, the total ATP yield from the citric acid cycle per glucose molecule is approximately 20 ATP.

Combining this with the ATP produced during glycolysis (2 ATP and 2 NADH, which yield about 5 ATP) and pyruvate decarboxylation (2 NADH, which yield about 5 ATP), the total ATP yield from the complete oxidation of one glucose molecule is approximately 32 ATP.

Anaplerotic Reactions: Replenishing Citric Acid Cycle Intermediates

The intermediates of the citric acid cycle are not only used for energy production but also serve as precursors for various biosynthetic pathways. To ensure that the cycle can continue functioning even when intermediates are drawn off for biosynthesis, anaplerotic reactions replenish these intermediates.

Examples of anaplerotic reactions include:

• Pyruvate Carboxylation: Pyruvate is converted to oxaloacetate by pyruvate carboxylase, using ATP and CO2. This reaction is particularly important in the liver and kidneys.
• Phosphoenolpyruvate (PEP) Carboxylation: PEP is converted to oxaloacetate by PEP carboxylase.
• Malic Enzyme: Pyruvate is converted to malate by malic enzyme, using NADPH.
• Glutamate Deamination: Glutamate is converted to α-ketoglutarate by glutamate dehydrogenase.

Clinical Significance

The citric acid cycle plays a vital role in human health and disease. Dysregulation of the cycle can lead to various metabolic disorders and diseases.

• Cancer: Cancer cells often have altered metabolism, including changes in the citric acid cycle. Some cancer cells rely heavily on glycolysis (the Warburg effect) and may have mutations in genes encoding enzymes of the citric acid cycle, such as succinate dehydrogenase (SDH) and fumarate hydratase (FH).
• Mitochondrial Disorders: Mutations in genes encoding enzymes of the citric acid cycle or the electron transport chain can cause mitochondrial disorders, which can affect multiple organ systems and lead to severe health problems.
• Diabetes: Insulin resistance and type 2 diabetes can affect the citric acid cycle, leading to impaired glucose metabolism and increased fatty acid oxidation.
• Neurodegenerative Diseases: Impaired mitochondrial function, including dysregulation of the citric acid cycle, has been implicated in neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease.

Conclusion

One turn of the citric acid cycle produces 2 molecules of CO2, 3 molecules of NADH, 1 molecule of FADH2, and 1 molecule of GTP (or ATP). While the direct ATP yield from the cycle is relatively small, the NADH and FADH2 generated are crucial for the electron transport chain and oxidative phosphorylation, the primary means of ATP production in aerobic respiration. The citric acid cycle is a central metabolic pathway that plays a vital role in energy production, biosynthesis, and overall cellular function. Understanding its products and regulation is essential for comprehending cellular metabolism and its implications for health and disease. The cycle’s intricate coordination with glycolysis, pyruvate decarboxylation, and the electron transport chain highlights its significance in the broader context of cellular respiration.