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The citric acid cycle is the part of respiration students most often memorise without understanding. It helps to know how Hans Krebs found it, because each clue he used explains a feature of the cycle. This post covers his life, the experiments that revealed the loop, a worked count of what one glucose yields, and the habits a student can borrow from him.
Who was Hans Krebs?
Krebs was born in Hildesheim, Germany, on 25 August 1900. His Nobel biography records that he studied medicine, then from 1926 to 1930 worked as assistant to Otto Warburg in Berlin. In June 1933 the National Socialist government ended his appointment at Freiburg. At the invitation of Frederick Gowland Hopkins he moved to Cambridge, and in 1935 to the University of Sheffield, where the cycle was worked out. He later moved to Oxford and was knighted in 1958. He also studied how the liver makes urea.
The 1953 Nobel Prize in Physiology or Medicine gave Krebs half the prize "for his discovery of the citric acid cycle". The other half went to Fritz Lipmann.
Why was the cycle so hard to find?
In his Nobel lecture, Krebs explains that by the early 1930s the steps of fermentation, sugar to lactic acid or ethanol, were well mapped, partly by the Coris. Oxidation was a different matter. Oxidative reactions could not be obtained in cell-free extracts, and they faded quickly once tissue was minced.
Three clues came from other labs:
Albert Szent-Györgyi found in 1935 that pigeon breast muscle, the powerful flight muscle, keeps its oxidising power after mincing. He confirmed that succinic, fumaric, malic and oxaloacetic acids are oxidised rapidly, and concluded that part of their action was catalytic.
Stare and Baumann proved the catalytic effect in December 1936: tiny amounts of these acids increased respiration by a multiple of the oxygen needed to oxidise the added acid itself, and the acid was not used up.
In March 1937 Martius and Knoop worked out how citrate is oxidised, through cis-aconitate and isocitrate to α-ketoglutarate.
How did Krebs close the loop?
Early in 1937 the Sheffield lab found that citrate also acts as a catalyst, just like succinate. Between March and June came the decisive observation: citrate was not only broken down quickly but also formed in muscle when oxaloacetate was added. Krebs explained this by supposing that oxaloacetate combines with something derived from carbohydrate, such as pyruvate or acetate, to make citrate. The acids then pass through a series of steps that oxidise one acetic acid equivalent and regenerate oxaloacetate.
That explained why tiny amounts of the acids acted as catalysts: they are regenerated each turn. Krebs and W.A. Johnson published the scheme in 1937, and the name "citric acid cycle" was proposed that year.
How did an inhibitor prove it?
The lecture describes a third line of evidence using malonate, which blocks the enzyme succinic dehydrogenase. Malonate prevents succinate from binding because the two molecules have similar structures. If succinate is an intermediate in the main pathway, blocking that enzyme should make succinate pile up. It does, even when malonate is injected into a living animal.
You have met this exact example. The NCERT Class 11 chapter Biomolecules uses inhibition of succinic dehydrogenase by malonate as its example of a competitive inhibitor. Our post on enzymes for NEET covers competitive inhibition in more depth.
Worked example: what does one glucose give in the cycle?
The NCERT chapter Respiration in Plants gives everything you need. Glycolysis splits one glucose into two pyruvic acid molecules, so count per pyruvate and then double.
Link reaction, per pyruvate: pyruvic acid + CoA + NAD⁺ gives acetyl CoA + CO₂ + NADH + H⁺.
Carbon check: acetyl (2 C) + oxaloacetate (4 C) = citric acid (6 C). Two decarboxylations later the cycle is back to a 4-carbon acid.
NCERT's summary for one pyruvate, link reaction included: 3 CO₂, 4 NADH + H⁺, 1 FADH₂ and 1 ATP (via GTP).
Per glucose, double it: 6 CO₂, 8 NADH, 2 FADH₂, 2 ATP. Six carbons in glucose, six CO₂ out, so the carbon balances.
To reach NCERT's balance sheet, add glycolysis (2 ATP and 2 NADH) and use its rule that each NADH gives 3 ATP and each FADH₂ gives 2:
NADH: 8 + 2 = 10, giving 30 ATP.
FADH₂: 2, giving 4 ATP.
Direct ATP: 2 from glycolysis + 2 from the cycle = 4.
Total: 30 + 4 + 4 = 38 ATP, the figure NCERT gives.
Common mistakes:
One turn per glucose. There are two, one for each pyruvate.
Dropping the link reaction NADH. It is easy to count only the three NADH made inside the cycle.
Treating 38 as a measured value. NCERT says it rests on assumptions that do not really hold in a living cell.
For how the NADH is turned into ATP, see our post on Peter Mitchell and chemiosmosis.
What can a student take from Krebs's way of working?
Krebs did not discover most of the individual reactions. He took results from Szent-Györgyi, Stare and Baumann, and Martius and Knoop, added his own key observation, and found the pattern that tied them together. Then he tested it with an inhibitor that should produce a specific, checkable effect.
A routine built on that:
Collect the clues. For a pathway, write each known fact on its own line before trying to connect them.
Look for what is regenerated. In any cycle, find the molecule that comes back at the end.
Predict a test. Ask what would happen if one step were blocked, then check your notes or textbook for the answer.
If one step of the cycle will not stay in your head, revise it on its own. The Fermi Concept Library has every concept in biology and chemistry with its own lesson, so you can fix one step and go back to the pathway.
Close your book now and write the cycle from acetyl CoA to oxaloacetate, counting carbons at each step.
