The Citric Acid Cycle Overview

The Citric Acid Cycle (CAC) or Krebs Cycle

• The Citric Acid Cycle (CAC) or Krebs cycle breaks down Acetyl-CoA to carbon dioxide and water releasing energy.
• It occurs in the mitochondrial matrix and captures energy by transferring electrons to NADH and FADH2.
• The CAC is also a major source of NADH and FADH2 which are important electron carriers.
• NADH and FADH2 donate their electrons to the respiratory chain to generate the majority of ATP in the process of oxidative phosphorylation.

Reactions of the Citric Acid Cycle

• Step 1: Acetyl-CoA (2C) condenses with Oxaloacetate (4C) to produce Citrate (6C) catalyzed by Citrate Synthase.
  • This reaction is highly exergonic due to the high standard free energy of hydrolysis in Acetyl-CoA.
  • This helps drive the reaction forward despite the low concentration of Oxaloacetate.
• Step 2: Citrate is transformed into Isocitrate via the formation of Cis-Aconitate catalyzed by Aconitase.
  • This reaction is reversible; it involves dehydration to form Cis-Aconitate followed by hydration to form Isocitrate.
  • The hydroxyl group is moved from Carbon 2 to Carbon 3.  
• Step 3: Isocitrate is oxidized to form α-Ketoglutarate (5C) and CO2 involving oxidative decarboxylation catalyzed by Isocitrate Dehydrogenase.
  • NAD+ or NADP+ (depending on the isozyme) is reduced to NADH or NADPH.
• Step 4: α-Ketoglutarate is oxidized to form Succinyl-CoA and CO2 involving oxidative decarboxylation catalyzed by the α-Ketoglutarate dehydrogenase complex.
  • NAD+ is reduced to NADH and energy is conserved in the thioester bond of Succinyl-CoA.
• Step 5: Succinyl-CoA is converted to Succinate, a reversible reaction catalyzed by Succinyl-CoA Synthetase.
  • The high energy thioester bond is used to produce GTP or ATP (energetically equivalent) in a process called Substrate Level Phosphorylation.
• Step 6: Succinate is oxidized to form Fumarate in a dehydrogenation reaction catalyzed by Succinate Dehydrogenase.
  • FAD is reduced to FADH2.
  • Succinate dehydrogenase is bound to the inner mitochondrial membrane and directly transfers electrons to the Electron Transport Chain.
• Step 7: Fumarate undergoes a reversible hydration reaction to form Malate catalyzed by Fumarase.
• Step 8: Malate is oxidized by oxaloacetate catalyzed by Malate Dehydrogenase, reducing NAD+ to NADH.
  • Oxaloacetate can then condense with Acetyl-CoA to form Citrate and continue the cycle.
  • The highly exergonic first reaction helps drive the cycle forward despite the low concentration of Oxaloacetate.

Remembering the Intermediates

• A mnemonic to remember the intermediates of the citric acid cycle is "The CIA Sings Country Songs For Me On-Stage."
  • C - Citrate, I - Isocitrate, A - Alpha-Ketoglutarate, Sings Country - Succinyl-CoA, Songs - Succinate, For - Fumarate, Me - Malate, On-Stage - Oxaloacetate.

Energy Yield of the Citric Acid Cycle

• For each NADH molecule, 2.5 ATP equivalents are produced.
• For each FADH2 molecule, 1.5 ATP equivalents are produced.
• Each turn of the citric acid cycle produces:
  • 3 NADH
  • 1 FADH2
  • 1 GTP (equivalent to ATP).
• The cycle runs twice per molecule of Glucose, producing 6 NADH, 2 FADH2, and 2 ATP.
• The total ATP equivalents generated per glucose molecule during the citric acid cycle is 20.

Total ATP Generation

• The total ATP equivalents produced per glucose molecule under aerobic conditions are 32. This calculation factors the energy yield of glycolysis, conversion of pyruvate to Acetyl-CoA and the Citric Acid Cycle, as follows:
  • Glycolysis: 2 ATP (net) + 2 NADH (5 ATP equivalents) = 7 ATP equivalents
  • Pyruvate to Acetyl-CoA: 2 NADH (5 ATP equivalents) = 5 ATP equivalents
  • Citric Acid Cycle: 20 ATP equivalents
  • Total: 7 + 5 + 20 = 32 ATP equivalents

Test your knowledge on the Citric Acid Cycle (CAC) or Krebs Cycle, a biochemical pathway crucial for energy production. This quiz covers key reactions, electron carriers, and the role of Acetyl-CoA in metabolic processes. Understand how the CAC contributes to ATP generation and its importance in cellular respiration.