Table of contents · 7 sections
The Krebs cycle (tricarboxylic acid cycle, citric acid cycle) is a central metabolic pathway that integrates the catabolism of carbohydrates, fats, and proteins. Understanding this cycle is the foundation of energy metabolism biochemistry, essential for every medical student preparing for exams and mastering clinical pathology.
Core and Biological Significance of the Krebs Cycle
The Krebs cycle takes place in the mitochondrial matrix. Its main functions are:
- Energetic — generation of reduced coenzymes (NADH, FADH₂) that transfer electrons to the respiratory chain
- Amphibolic — participation in both catabolism and anabolism (intermediates are used for the synthesis of amino acids, glucose, and heme)
- Integrative — the "metabolic crossroad" where pathways of glucose, fatty acid, and amino acid oxidation converge
One turn of the cycle yields: 3 NADH, 1 FADH₂, 1 GTP (≈ ATP), and 2 CO₂. Calculated in terms of ATP via oxidative phosphorylation, this is ~10 ATP per one acetyl-CoA.
Reactions of the Krebs Cycle: Step-by-Step Breakdown
The cycle includes 8 consecutive reactions. The following mnemonic helps remember their order: "Citrate Is Krebs' Starting Substrate For Making Oxaloacetate" (Citrate → Aconitate → Isocitrate → α-ketoglutarate → Succinyl-CoA → Succinate → Fumarate → Malate → Oxaloacetate).
| № | Reaction | Enzyme | Product | Cofactor / Yield |
|---|---|---|---|---|
| 1 | Acetyl-CoA + OAA → citrate | Citrate synthase | Citrate (6C) | — |
| 2 | Citrate → isocitrate | Aconitase | Isocitrate (6C) | — |
| 3 | Isocitrate → α-ketoglutarate | Isocitrate dehydrogenase | α-ketoglutarate (5C) | NADH + CO₂ |
| 4 | α-KG → succinyl-CoA | α-Ketoglutarate dehydrogenase complex | Succinyl-CoA (4C) | NADH + CO₂ |
| 5 | Succinyl-CoA → succinate | Succinyl-CoA synthetase | Succinate (4C) | GTP (substrate-level phosphorylation) |
| 6 | Succinate → fumarate | Succinate dehydrogenase (complex II) | Fumarate (4C) | FADH₂ |
| 7 | Fumarate → malate | Fumarase | L-malate (4C) | H₂O |
| 8 | Malate → oxaloacetate | Malate dehydrogenase | OAA (4C) | NADH |
Key Enzymes and Regulation
Three reactions are irreversible and serve as regulation points:
| Enzyme | Activators | Inhibitors |
|---|---|---|
| Citrate synthase | ADP, substrates | ATP, NADH, citrate, succinyl-CoA |
| Isocitrate dehydrogenase | ADP, Ca²⁺ | ATP, NADH |
| α-Ketoglutarate dehydrogenase | Ca²⁺ | ATP, NADH, succinyl-CoA |
Core principle: a high energy charge (ATP/NADH) inhibits the cycle, while a low charge (ADP/NAD⁺) accelerates it. Calcium activates the cycle during muscle contraction when energy demand is highest.
Connection to the Electron Transport Chain and ATP
Reduced coenzymes transfer electrons to the electron transport chain (ETC) located on the inner mitochondrial membrane:
- 1 NADH → complex I → ~2.5 ATP
- 1 FADH₂ → complex II → ~1.5 ATP
Total per one turn of the cycle: 3 NADH × 2.5 = 7.5 ATP + 1 FADH₂ × 1.5 = 1.5 ATP + 1 GTP = ~10 ATP. Complete oxidation of a single glucose molecule (glycolysis + 2 turns of the TCA cycle + ETC) yields ~30–32 ATP.
Anaplerotic Reactions
Normal functioning of the cycle requires a continuous supply of intermediates:
- Pyruvate carboxylase: pyruvate + CO₂ → oxaloacetate (the principal anaplerotic reaction)
- Glutamate dehydrogenase: glutamate → α-ketoglutarate
- Aminotransferases: aspartate → OAA (via AST)
If OAA "leaks" into gluconeogenesis (via PEPCK), anaplerotic reactions replenish its levels.
Clinical correlations
- Thiamine (B₁) deficiency — thiamine is a component of TPP, a cofactor for α-ketoglutarate dehydrogenase and pyruvate dehydrogenase. Deficiency → beriberi, Wernicke encephalopathy
- Fluoroacetate poisoning — fluorocitrate blocks aconitase → cycle arrest
- Succinate dehydrogenase (SDH) mutations — associated with paragangliomas and pheochromocytomas (succinate accumulation activates HIF-1α)
- Lactic acidosis — during hypoxia, the TCA cycle slows down → pyruvate does not enter the cycle → converts to lactate
- Oncometabolites — isocitrate dehydrogenase (IDH1/2) mutations in gliomas → 2-hydroxyglutarate is produced instead of α-KG
Frequently asked questions
Why doesn't the Krebs cycle work without oxygen?
The cycle itself does not consume O₂ directly, but without oxygen the electron transport chain stops → NADH and FADH₂ are not oxidized back → NAD⁺ and FAD are not regenerated → TCA cycle enzymes cannot function (they need oxidized coenzymes as acceptors).
How many ATP molecules does one glucose molecule yield?
A maximum of ~30–32 ATP: glycolysis yields 2 ATP + 2 NADH, pyruvate dehydrogenase gives 2 NADH, two turns of the TCA cycle give 6 NADH + 2 FADH₂ + 2 GTP. Everything adds up via the ETC. The exact number depends on the shuttle mechanism (malate-aspartate → 2.5 ATP/NADH, glycerophosphate → 1.5 ATP/NADH).
How to memorize the cycle reactions?
Mnemonic based on the first letters of the substrates: «Citrate Is Krebs' Starting Substrate For Making Oxaloacetate» (Citrate, cis-Aconitate, Isocitrate, α-Ketoglutarate, Succinyl-CoA, Succinate, Fumurate, Malate, Oxaloacetate). Also remember «3-4-5-6»: three irreversible reactions, four oxidative steps, five carbon acids/intermediates, six carbon atoms in citrate.
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