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Portrait of The Krebs cycle

Science · Biology

The Krebs cycle

1937

Biology — biochemistry and metabolism

The Krebs cycle, also called the citric acid cycle or tricarboxylic acid (TCA) cycle, is the eight-step sequence of reactions in the mitochondrial matrix that completes the oxidation of food molecules. Acetyl-CoA condenses with oxaloacetate to form citrate; the cycle then strips off two carbons as carbon dioxide and regenerates oxaloacetate, harvesting electrons as NADH and FADH2 which feed the electron transport chain. Hans Krebs worked it out at Sheffield in 1937 and shared the 1953 Nobel Prize in Physiology or Medicine with Fritz Lipmann.

How to spot them

  • ▸Eight steps, running in the mitochondrial matrix, regenerating its own starting compound
  • ▸Acetyl-CoA joins oxaloacetate to make citrate
  • ▸Per turn: three NADH, one FADH2, one GTP and two molecules of carbon dioxide
  • ▸The paper describing it was rejected by Nature in 1937
  • ▸Its discoverer also worked out the urea cycle and won the 1953 Nobel Prize

Key facts

Worked out at Sheffield in 1937 by a German-born biochemist who had been dismissed from his post in 1933 and taken in by Frederick Gowland Hopkins at Cambridge (1937)

Hans Krebs, with his student William Arthur Johnson.

Rejected by Nature for lack of space in 1937 and published instead in the Dutch journal Enzymologia (1937)

Nature called the rejection an 'egregious error' in a 1988 letter.

Its discoverer shared the 1953 Nobel Prize in Physiology or Medicine with Fritz Lipmann, who had found coenzyme A (1953)

Lipmann's discovery supplied the two-carbon fragment that feeds the sequence.

Begins when a two-carbon acetyl group condenses with the four-carbon oxaloacetate to form the six-carbon citrate

Catalysed by citrate synthase; citrate is the tricarboxylic acid that gives the pathway another of its names.

Yields three NADH, one FADH2, one GTP and two carbon dioxide molecules per turn

The reduced coenzymes are cashed in by oxidative phosphorylation for roughly ten ATP.

Its intermediates fumarate and succinate are also tumour suppressors whose loss causes cancer

Mutations in fumarate hydratase and succinate dehydrogenase cause inherited cancer syndromes.

The same discoverer earlier worked out, with Kurt Henseleit in 1932, the pathway that turns ammonia into urea (1932)

The urea cycle — the first metabolic cycle ever described.

Key ideas

  • The trick is that it is a cycle: the acceptor molecule, oxaloacetate, is regenerated at the end, so a tiny catalytic pool can process an unlimited amount of fuel.
  • It is amphibolic — as well as burning fuel it supplies carbon skeletons for amino acids, haem and fatty acids, which is why intermediates must be topped up by 'anaplerotic' reactions.

Quick-fire facts

  • •Three names in common use: the Krebs cycle, the citric acid cycle and the tricarboxylic acid (TCA) cycle.
  • •Hans Krebs was born in Hildesheim in 1900 and lost his post at Freiburg in 1933 under the Nazi laws on Jewish civil servants; he was knighted in Britain in 1958.
  • •Succinate dehydrogenase is the one enzyme of the sequence embedded in the inner mitochondrial membrane, and is also Complex II of the electron transport chain.
  • •The eight intermediates in order: citrate, isocitrate, alpha-ketoglutarate, succinyl-CoA, succinate, fumarate, malate, oxaloacetate.
  • •Arsenic and fluoroacetate (the poison '1080') kill by blocking it — fluoroacetate becomes fluorocitrate, which jams aconitase.
  • •It requires oxygen indirectly: no oxygen means no way to reoxidise NADH, so the whole sequence stalls.
  • •The related glyoxylate cycle lets plants, fungi and bacteria — but not animals — convert fat into sugar.
  • •Common misconception: it does not itself use oxygen at any step; oxygen is consumed downstream, at the end of the electron transport chain.

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