[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Biochemistry](https://durgical.com/en/biochemistry/) › Krebs cycle (citric acid cycle) [Biochemistry](https://durgical.com/en/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 ## Interactive map **Balance:** NADH +8 FADH₂ +2 GTP +2 CO₂ +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)](https://durgical.com/en/biochemistry/enzymes/pyruvate-dehydrogenase-complex/)** irreversible [Pyruvate](https://durgical.com/en/biochemistry/molecules/pyruvate/) + coenzyme A + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) → [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) + CO₂ + NADH The 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 →](https://durgical.com/en/conditions/pyruvate-dehydrogenase-deficiency/) - **Step 1 · [Citrate synthase](https://durgical.com/en/biochemistry/enzymes/citrate-synthase/)** irreversible [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) + oxaloacetate + H₂O → [Citrate](https://durgical.com/en/biochemistry/molecules/citrate/) + coenzyme A Joins 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 →](https://durgical.com/en/conditions/fluoroacetate-poisoning/) - **Step 2 · Aconitase** [Citrate](https://durgical.com/en/biochemistry/molecules/citrate/) ⇌ isocitrate Moves 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 →](https://durgical.com/en/conditions/fluoroacetate-poisoning/) - **Step 3 · [Isocitrate dehydrogenase](https://durgical.com/en/biochemistry/enzymes/isocitrate-dehydrogenase/)** irreversible isocitrate + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) → α-ketoglutarate + CO₂ + NADH The 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](https://durgical.com/en/biochemistry/enzymes/ketoglutarate-dehydrogenase/)** irreversible α-ketoglutarate + coenzyme A + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) → succinyl-CoA + CO₂ + NADH PDH'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) →](https://durgical.com/en/conditions/wernicke-encephalopathy/) - **Step 5 · Succinyl-CoA synthetase** succinyl-CoA + phosphate (Pi) ⇌ succinate + coenzyme A + GTP The 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)](https://durgical.com/en/biochemistry/enzymes/succinate-dehydrogenase/)** succinate + [FAD](https://durgical.com/en/biochemistry/molecules/fad/) ⇌ fumarate Oxidises 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) →](https://durgical.com/en/conditions/hereditary-paraganglioma-and-pheochromocytoma/) - **Step 7 · Fumarase (fumarate hydratase)** fumarate + H₂O ⇌ malate Adds 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 →](https://durgical.com/en/conditions/fumarase-deficiency/) - **Step 8 · Malate dehydrogenase** malate + [NAD⁺](https://durgical.com/en/biochemistry/molecules/nad/) ⇌ oxaloacetate + NADH Regenerates 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](https://durgical.com/en/conditions/pyruvate-dehydrogenase-deficiency/) - [Wernicke encephalopathy (thiamine deficiency)](https://durgical.com/en/conditions/wernicke-encephalopathy/) - [Fumarase deficiency](https://durgical.com/en/conditions/fumarase-deficiency/) - [Hereditary paraganglioma and pheochromocytoma (SDH)](https://durgical.com/en/conditions/hereditary-paraganglioma-and-pheochromocytoma/) - [Fluoroacetate poisoning](https://durgical.com/en/conditions/fluoroacetate-poisoning/) - [Diabetic ketoacidosis](https://durgical.com/en/conditions/diabetic-ketoacidosis/) - [Arsenic poisoning](https://durgical.com/en/conditions/arsenic-poisoning/) - [Lactic acidosis](https://durgical.com/en/conditions/lactic-acidosis/) ## Related - [Acetyl-CoA](https://durgical.com/en/biochemistry/molecules/acetyl-coa/) - [Citrate](https://durgical.com/en/biochemistry/molecules/citrate/) - [Pyruvate](https://durgical.com/en/biochemistry/molecules/pyruvate/) - [NAD⁺ (nicotinamide adenine dinucleotide)](https://durgical.com/en/biochemistry/molecules/nad/) - [ATP (adenosine triphosphate)](https://durgical.com/en/biochemistry/molecules/atp/) - [Pyruvate dehydrogenase complex (PDH)](https://durgical.com/en/biochemistry/enzymes/pyruvate-dehydrogenase-complex/) - [Citrate synthase](https://durgical.com/en/biochemistry/enzymes/citrate-synthase/) - [Isocitrate dehydrogenase](https://durgical.com/en/biochemistry/enzymes/isocitrate-dehydrogenase/) - [α-Ketoglutarate dehydrogenase](https://durgical.com/en/biochemistry/enzymes/ketoglutarate-dehydrogenase/) - [Succinate dehydrogenase (complex II)](https://durgical.com/en/biochemistry/enzymes/succinate-dehydrogenase/) - [Glycolysis](https://durgical.com/en/biochemistry/pathways/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. [Add to my cards (4)](https://durgical.app/estudiar/?add=/en/biochemistry/pathways/krebs-cycle/) Educational information, not medical advice. For any symptom, see a health professional. Sources: [Citric acid cycle (TCA cycle)](https://reactome.org/PathwayBrowser/#/R-HSA-71403) (Reactome, 2026); [Pyruvate metabolism](https://reactome.org/PathwayBrowser/#/R-HSA-70268) (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011). [← All of biochemistry](https://durgical.com/en/biochemistry/) ## **Spotted a mistake?** We are always improving for the community. Tell us what is wrong and our team will review it. Report a mistake Representative model, for educational purposes only. --- Source: https://durgical.com/en/biochemistry/pathways/krebs-cycle/ License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/biochemistry/pathways/krebs-cycle/