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From Proteopedia

The discovery of the Krebs cycle

The degradation pathway of glucose to pyruvate or lactate is known in his roughly sequence since the 1930s. However, the fact that six molecules of carbon dioxide and six molecules of water from can be obtained out of one molecule of glucose, was not known at that time. Although some researchers indicated the presence of dicarboxylic acids, but the structure of these compounds cold not be correlated with the structure of glucose.

In 1935, Albert Szent-Györgyi did some experiments with freshly prepared breast muscles. He discovered that the oxygen consumption increased as soon as succinate, fumarate, malate or oxaloacetate have been added. However, the comsumption of oxygen was much higher than usual. In addition, Szent Györgyi found that succinate was still present in the tissue. Therefore he suggested that succinate served as a catalyst. From his experiments, he derived the following reaction sequence:

Figure 1: Reaction sequence of Szent-Györgyi (1935)

For his work in the field of cellular respiration and the catalytic role of fumarate in biological combustion processes, Alber Szent-Györgyi was awarded the 1937 Nobel Prize in Physiology.

At the same time and independent from Szent-Györgyi, Franz Knoop and Carl Martius presendet the following reaction sequence in 1937. They also discovered that the decomposition of citric acid is done by an enzyme.

Figure 2: Reaction sequence of Knoop and Martius

Hans Krebs could prove the reaction sequence of Knoop and Martius working with freshly prepared pigeon breast muscle and additionally realised that the α-ketoglutarate was converted into succinate. With this knowledge, Krebs could complete the reaction sequence of the cycle:

Citrate → Aconitate → Isocitrate → Ketoglutarate → Succinate → Fumarate → Malate → Oxalacetate

The only two pieces that was now missing in the puzzle was the reaction that it returns to the beginning of the reaction sequence: the reaction that leads from oxalacetate to citrate, and how this cycle relates to the glycolysis. The essential information for the discovery of the citric acid cycle provided Martius and Knoop in 1937: Oxalacetate and pyruvate can be converted to citrate in the presence of hydrogen peroxide. Pyruvate as a product of glucose metabolism was detected by Krebs as the missing link. For he was familiar with the principle of a catalytic cyclic reaction sequence (in 1932 he investigated the urea cycle together with Kurt Henseleit), Krebs transformed the linear reaction sequence to a cyclic system. In the same year he and WA Johnson could suggest the citric acid cycle as an explanation for previously clarified observations. The fact that not pyruvate, but acetyl-CoA reacts with oxalacetate into citrate, was discarded in 1951.

For the discovery of the citric acid cycle Hans Adolf Krebs awarded jointly with Fritz Albert Lipmann the Nobel Prize in Physiology in 1953.