Biochemistry · Metabolic pathway
Krebs cycle (citric acid cycle) !
The Krebs cycle burns the acetyl of acetyl-CoA in the mitochondria: it releases CO₂ and loads the NADH and FADH₂ that later yield most of the ATP.
Updated 2026-10-31
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Balance: NADH +8FADH₂ +2GTP +2CO₂ +6
Key facts
- It takes place in the mitochondrial matrix; succinate dehydrogenase sits in the inner membrane and is also complex II.
- Per acetyl-CoA: 3 NADH, 1 FADH₂, 1 GTP (or ATP) and 2 CO₂; about 10 ATP after the respiratory chain.
- Oxaloacetate is regenerated each turn: the cycle is catalytic and does not use up its intermediates.
- It needs oxygen indirectly: without the respiratory chain NAD⁺ and FAD are not regenerated.
- Pyruvate dehydrogenase links glycolysis to the cycle; four B vitamins work in it (B1, B2, B3, B5).
- Also called
- Tricarboxylic acid (TCA) cycle
Regulation
- It is set by energy charge: high NADH and ATP slow it; ADP and Ca²⁺ (muscle contraction) speed it up.
- Control points: pyruvate dehydrogenase, citrate synthase, isocitrate dehydrogenase and α-ketoglutarate dehydrogenase.
- Insulin switches on PDH phosphatase; fasting and fatty acids switch PDH off through PDH kinase.
The steps, one by one
- Link (PDH) · Pyruvate dehydrogenase complex (PDH) irreversible Pyruvate + coenzyme A + NAD⁺ → Acetyl-CoA + CO₂ + NADHThe bridge from glycolysis to the cycle: removes a CO₂ from pyruvate and joins the acetyl to coenzyme A.If it fails: PDH deficiency (PDHA1 gene, X-linked): lactic acidosis and Leigh syndrome. Thiamine deficiency has the same effect. Pyruvate dehydrogenase deficiency →
- Step 1 · Citrate synthase irreversible Acetyl-CoA + oxaloacetate + H₂O → Citrate + coenzyme AJoins the acetyl (2 C) to oxaloacetate (4 C) to make citrate (6 C); hydrolysis of the thioester drives it.If it fails: Citrate that leaves for the cytosol activates fatty acid synthesis and slows PFK-1. Fluoroacetate poisoning →
- Step 2 · Aconitase Citrate ⇌ isocitrateMoves the OH group (via cis-aconitate) so the carbon can be oxidised in the next step.If it fails: Fluoroacetate poisoning: citrate builds up, binds calcium and the heart and brain run out of energy. Fluoroacetate poisoning →
- Step 3 · Isocitrate dehydrogenase irreversible isocitrate + NAD⁺ → α-ketoglutarate + CO₂ + NADHThe cycle's first oxidative decarboxylation and its rate-limiting step: the first CO₂ leaves and NADH is made.If it fails: IDH1/IDH2 mutations (other isoforms, with NADP⁺) make 2-hydroxyglutarate in gliomas and leukemias.
- Step 4 · α-Ketoglutarate dehydrogenase irreversible α-ketoglutarate + coenzyme A + NAD⁺ → succinyl-CoA + CO₂ + NADHPDH's twin: the second decarboxylation, the second CO₂ and another NADH.If it fails: In thiamine deficiency it fails together with PDH; the brain suffers most (Wernicke). Wernicke encephalopathy (thiamine deficiency) →
- Step 5 · Succinyl-CoA synthetase succinyl-CoA + phosphate (Pi) ⇌ succinate + coenzyme A + GTPThe cycle's only substrate-level phosphorylation: the thioester's energy makes GTP (or ATP).If it fails: SUCLA2/SUCLG1 defects: mitochondrial DNA depletion, encephalomyopathy and mild methylmalonic aciduria.
- Step 6 · Succinate dehydrogenase (complex II) succinate + FAD ⇌ fumarateOxidises succinate to fumarate and passes the electrons through its FAD straight to the respiratory chain's ubiquinone.If it fails: SDHB, SDHD and other mutations: hereditary paragangliomas and pheochromocytomas (stored succinate mimics hypoxia). Hereditary paraganglioma and pheochromocytoma (SDH) →
- Step 7 · Fumarase (fumarate hydratase) fumarate + H₂O ⇌ malateAdds water across fumarate's double bond to make L-malate.If it fails: With both copies lost: severe newborn encephalopathy. With one damaged copy: leiomyomas and hereditary kidney cancer. Fumarase deficiency →
- Step 8 · Malate dehydrogenase malate + NAD⁺ ⇌ oxaloacetate + NADHRegenerates oxaloacetate and makes the third NADH; it runs uphill, but citrate synthase uses the product at once.If it fails: Malate dehydrogenase also moves NADH from cytosol to mitochondria (the malate–aspartate shuttle).
Clinical notes
- Thiamine deficiency (alcohol use, malnutrition) blocks PDH and α-ketoglutarate dehydrogenase: lactic acidosis and Wernicke encephalopathy.
- Arsenite binds the lipoic acid of the same two enzymes.
- SDH and fumarase mutations turn succinate and fumarate into 'oncometabolites': paragangliomas and kidney cancer.
- IDH1/IDH2 mutations make 2-hydroxyglutarate, a hallmark of some gliomas and acute myeloid leukemia.
Related conditions
- Pyruvate dehydrogenase deficiency
- Wernicke encephalopathy (thiamine deficiency)
- Fumarase deficiency
- Hereditary paraganglioma and pheochromocytoma (SDH)
- Fluoroacetate poisoning
- Diabetic ketoacidosis
- Arsenic poisoning
- Lactic acidosis
Related
- Acetyl-CoA
- Citrate
- Pyruvate
- NAD⁺ (nicotinamide adenine dinucleotide)
- ATP (adenosine triphosphate)
- Pyruvate dehydrogenase complex (PDH)
- Citrate synthase
- Isocitrate dehydrogenase
- α-Ketoglutarate dehydrogenase
- Succinate dehydrogenase (complex II)
- Glycolysis
Test yourself
Think of the answer, then tap the question to see it.
How much NADH, FADH₂ and GTP does one turn of the Krebs cycle make?
3 NADH, 1 FADH₂ and 1 GTP per acetyl-CoA, plus 2 CO₂.
Which cycle enzyme sits in the inner membrane?
Succinate dehydrogenase, which is also complex II of the respiratory chain.
Which two enzymes share thiamine pyrophosphate and lipoic acid?
Pyruvate dehydrogenase and α-ketoglutarate dehydrogenase.
Which classic competitive inhibitor blocks succinate dehydrogenase?
Malonate, which looks like succinate.
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Citric acid cycle (TCA cycle) (Reactome, 2026); Pyruvate metabolism (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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Representative model, for educational purposes only.