Biochemistry · MU Pleven

15. Citric Acid Cycle (Krebs Cycle). Reactions, Regulation, Energetic and Metabolic Balance. Connection with Other Metabolic Pathways.

Covers the citric acid (Krebs) cycle as the central oxidative pathway in mitochondria, taking the eight enzymatic steps in order from citrate synthase to malate dehydrogenase, with cofactors and regulatory signals noted at each step. It then gives the energy yield per acetyl-CoA and per glucose, the cycle's regulation, its amphibolic role as a source of biosynthetic precursors, and its links to carbohydrate, lipid, amino acid and heme metabolism, plus brief clinical notes on thiamine deficiency, arsenic poisoning and hypoxia.

Inside: 11 sections · 12 labelled pictures · 10 flashcards · 6 min

Topic 15 of 76 in the MU Pleven syllabus for Biochemistry (Medicine, Year 2). The free AceMed note covers it in 11 sections, about 849 words (6 min of reading), with 10 flashcards.

In this note

  1. Citric Acid Cycle (Krebs Cycle).
  2. Overview
  3. Main Function
  4. Entry into the Cycle
  5. Reactions of the Citric Acid Cycle
  6. Summary of Energy Yield (Per Acetyl-CoA)
  7. Regulation of the TCA Cycle
  8. Energetic and Metabolic Balance
  9. Amphibolic Nature of the TCA Cycle
  10. Connection with Other Metabolic Pathways
  11. Clinical and Physiological Aspects

Citric Acid Cycle (Krebs Cycle).

Citric Acid Cycle (Krebs Cycle / Tricarboxylic Acid Cycle)

Overview

  • The Citric Acid Cycle (TCA Cycle) is the central pathway of aerobic metabolism, where acetyl-CoA is completely oxidized to CO₂, producing energy in the form of NADH, FADH₂, and GTP (ATP equivalent).
  • It occurs in the mitochondrial matrix.
  • It is called the Krebs cycle, after Hans Krebs, who discovered it.
  • It serves as a metabolic hub, connecting carbohydrate, lipid, and amino acid metabolism.

Main Function

  • To oxidize acetyl-CoA to CO₂ and capture energy in the form of high-energy electron carriers (NADH, FADH₂) and GTP.
  • The reduced coenzymes then enter the electron transport chain to generate ATP.

Entry into the Cycle

  • Acetyl-CoA is formed from pyruvate (via Pyruvate Dehydrogenase Complex), fatty acid β-oxidation, and amino acid degradation.
  • The two-carbon acetyl group condenses with oxaloacetate (4C) to form citrate (6C) — beginning the cycle.

Reactions of the Citric Acid Cycle

Each turn of the cycle oxidizes one acetyl-CoA to two CO₂ molecules and produces three NADH, one FADH₂, and one GTP.

Step 1: Condensation

  • Enzyme: Citrate synthase
  • Reaction: Oxaloacetate + Acetyl-CoA → Citrate + CoA-SH
  • Importance: Initiates the cycle by forming a 6-carbon compound (citrate).
  • Regulation: Inhibited by ATP, NADH, and Succinyl-CoA.

Step 2: Isomerization

  • Enzyme: Aconitase
  • Reaction: Citrate ↔ Isocitrate
  • Mechanism: Dehydration followed by rehydration to shift the hydroxyl group position.
  • Purpose: Converts citrate into a form (isocitrate) that can be oxidized.

Step 3: First Oxidative Decarboxylation

  • Enzyme: Isocitrate dehydrogenase
  • Reaction: Isocitrate → α-Ketoglutarate + CO₂ + NADH
  • Importance: First NADH produced, first CO₂ released.
  • Regulation: Activated by ADP and Ca²⁺; inhibited by ATP and NADH.
  • Rate-limiting step of the TCA cycle.

Step 4: Second Oxidative Decarboxylation

  • Enzyme: α-Ketoglutarate dehydrogenase complex
  • Reaction: α-Ketoglutarate + CoA + NAD⁺ → Succinyl-CoA + CO₂ + NADH
  • Coenzymes required: TPP (B1), Lipoic acid, CoA (B5), FAD (B2), NAD⁺ (B3).
  • Regulation: Inhibited by NADH and Succinyl-CoA; activated by Ca²⁺.

Step 5: Substrate-Level Phosphorylation

  • Enzyme: Succinyl-CoA synthetase (Succinate thiokinase)
  • Reaction: Succinyl-CoA + GDP + Pi → Succinate + GTP + CoA-SH
  • Importance: Direct generation of GTP (which can be converted to ATP).
  • This is the only substrate-level phosphorylation in the cycle.

Step 6: Dehydrogenation

  • Enzyme: Succinate dehydrogenase
  • Reaction: Succinate → Fumarate + FADH₂
  • Location: Embedded in the inner mitochondrial membrane (complex II of ETC).
  • Importance: FAD accepts electrons instead of NAD⁺ due to lower energy of succinate oxidation.

Step 7: Hydration

  • Enzyme: Fumarase
  • Reaction: Fumarate + H₂O → Malate
  • Importance: Addition of water across the double bond to form malate.

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