TCA cycle
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TCA cycle steps enzymes NADH FADH2 summary
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Here is a complete, textbook-based overview of the TCA cycle.
The TCA (Citric Acid / Krebs) Cycle
Location: Mitochondrial matrix (enzymes free or attached to the inner mitochondrial membrane)
Function: Oxidizes acetyl-CoA (2C) to CO2, capturing energy as reducing equivalents (NADH, FADH2) and GTP. It is the central hub of metabolism - both catabolic and synthetic - making it amphibolic.
The Cycle Diagram
Harper's Illustrated Biochemistry, 32nd Ed - Fig 16-3: Full TCA cycle with enzymes, cofactors, and sites of inhibition
Entry Point: Pyruvate to Acetyl-CoA
Before entering the cycle, pyruvate (from glycolysis) is decarboxylated to acetyl-CoA by the pyruvate dehydrogenase complex, releasing one CO2 and producing one NADH. Acetyl-CoA (C2) is then the substrate that enters the TCA cycle.
The 8 Steps
| Step | Reaction | Enzyme | Cofactors / Products |
|---|---|---|---|
| 1 | Oxaloacetate (C4) + Acetyl-CoA (C2) → Citrate (C6) | Citrate synthase | H2O consumed; CoA released |
| 2 | Citrate → cis-Aconitate → Isocitrate (C6) | Aconitase (aconitate hydratase) | Fe2+ required; inhibited by fluoroacetate |
| 3 | Isocitrate → Oxalosuccinate → α-Ketoglutarate (C5) | Isocitrate dehydrogenase | NAD+ → NADH; CO2 released; Mg2+/Mn2+ required |
| 4 | α-Ketoglutarate (C5) → Succinyl-CoA (C4) | α-Ketoglutarate dehydrogenase complex | NAD+ → NADH; CO2 released; thiamin-PP, lipoate, FAD, CoA; inhibited by arsenite |
| 5 | Succinyl-CoA → Succinate (C4) | Succinate thiokinase (succinyl-CoA synthetase) | ADP/GDP → ATP/GTP (substrate-level phosphorylation - the only one in the cycle) |
| 6 | Succinate → Fumarate (C4) | Succinate dehydrogenase | FAD → FADH2; inhibited by malonate; Fe-S protein; directly reduces ubiquinone |
| 7 | Fumarate + H2O → L-Malate (C4) | Fumarase (fumarate hydratase) | H2O added |
| 8 | L-Malate → Oxaloacetate (C4) | Malate dehydrogenase | NAD+ → NADH; cycle regenerates OAA |
Net Yield Per Turn (per acetyl-CoA)
| Product | Number | ATP equivalent (via ox. phosphorylation) |
|---|---|---|
| NADH | 3 | 3 × 2.5 = 7.5 ATP |
| FADH2 | 1 | 1 × 1.5 = 1.5 ATP |
| GTP/ATP | 1 | 1 ATP |
| Total | ~10 ATP per acetyl-CoA |
Since one glucose yields 2 acetyl-CoA, the cycle contributes ~20 ATP per glucose (before accounting for pyruvate dehydrogenase). NADH and FADH2 are reoxidized by the respiratory chain - this process requires oxygen, making the TCA cycle strictly aerobic.
- Harper's Illustrated Biochemistry, 32nd Ed, p. 168-170
Vitamins Required as Cofactors
Four B-vitamins are indispensable:
| Vitamin | Active Form | Role in TCA |
|---|---|---|
| Niacin (B3) | NAD+ | Electron acceptor for isocitrate DH, α-KG DH, malate DH |
| Riboflavin (B2) | FAD | Cofactor for succinate dehydrogenase |
| Thiamin (B1) | Thiamin diphosphate | Decarboxylation at α-KG dehydrogenase (and pyruvate DH) |
| Pantothenic acid (B5) | Coenzyme A | Forms acetyl-CoA and succinyl-CoA |
- Harper's Illustrated Biochemistry, 32nd Ed, p. 171
Regulation
The cycle is controlled at three main points - all three regulated by the energy charge of the cell (high NADH, ATP inhibit; ADP, Ca2+ activate):
- Citrate synthase - inhibited by ATP, NADH, succinyl-CoA, and citrate itself
- Isocitrate dehydrogenase - activated by ADP and Ca2+; inhibited by ATP, NADH
- α-Ketoglutarate dehydrogenase complex - inhibited by succinyl-CoA, NADH, ATP; activated by Ca2+
Anaplerosis and Cataplerosis
The cycle needs OAA replenishment when intermediates are drained for biosynthesis. Key anaplerotic reactions:
- Pyruvate carboxylase (pyruvate + CO2 → OAA) - the main anaplerotic enzyme, activated by acetyl-CoA
- Glutamate → α-ketoglutarate (via transamination)
Conversely, cycle intermediates leave (cataplerosis) as precursors for:
- Gluconeogenesis - OAA → phosphoenolpyruvate
- Fatty acid synthesis - citrate exported to cytosol → acetyl-CoA
- Amino acid synthesis - α-KG → glutamate, OAA → aspartate
- Porphyrin/heme synthesis - succinyl-CoA + glycine → δ-aminolevulinic acid
Clinical Connections
| Poison/Drug | Target | Effect |
|---|---|---|
| Fluoroacetate | Aconitase (via fluorocitrate) | Citrate accumulates; lethal in animals |
| Arsenite | α-Ketoglutarate DH (lipoate) | α-KG accumulates |
| Malonate | Succinate dehydrogenase | Competitive inhibition; succinate accumulates |
Thiamin (B1) deficiency impairs both pyruvate DH and α-KG DH, causing lactic acidosis and neurological damage (beriberi, Wernicke's encephalopathy) because the cycle cannot process pyruvate or α-KG normally.
The TCA cycle sits at the intersection of carbohydrate, fat, and protein catabolism - all three macronutrients ultimately converge on acetyl-CoA or cycle intermediates, making this pathway the central axis of aerobic energy metabolism.
- Harper's Illustrated Biochemistry, 32nd Ed (primary source)
- Guyton and Hall Textbook of Medical Physiology
- Ganong's Review of Medical Physiology, 26th Ed
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