Krebs and the citric acid cycle

Biochemists of the 1930s knew many single reactions by which cells burn food, and could not connect them. Between 1906 and 1920 Thunberg tested more than 60 organic substances, mostly in muscle, and found that salts of lactate, succinate, fumarate, malate, citrate and glutamate were oxidized fast. In 1935 Albert Szent-Györgyi in Szeged found that minced pigeon breast, the bird's main flight muscle, kept its oxidizing power well, and that succinate, fumarate, malate and oxaloacetate acted partly as catalysts of its respiration. In December 1936 Stare and Baumann proved the catalytic effect: very small amounts raised respiration far beyond what their own oxidation needed. Nobody could explain it.

Hans Krebs, a German physician trained under Otto Warburg, had been dismissed by the National Socialist government in June 1933 and went to Cambridge at the invitation of Frederick Gowland Hopkins. In 1935 he moved to Sheffield as a lecturer in pharmacology. He had already studied how the liver makes urea. Early in 1937 his laboratory found that citrate acted as a catalyst of respiration just as succinate did, and in March Martius and Knoop worked out the first steps of citrate breakdown.

Between March and June 1937 Krebs and W. A. Johnson supplied the rest. Citrate broke down quickly in muscle. With malonate added to block the oxidation of succinate, succinate built up from citrate. Most telling, muscle made citrate when given oxaloacetate, as if oxaloacetate combined with a fragment of pyruvate or acetate. The loop closed: that fragment joins oxaloacetate to form citrate, which passes through cis-aconitate, isocitrate, alpha-ketoglutarate, succinate, fumarate and malate back to oxaloacetate, oxidizing one acetic acid equivalent each turn. They named it the citric acid cycle.

Krebs sent a letter on the cycle to Nature, which rejected it five days later. The paper appeared in the Dutch journal Enzymologia. Later workers added three intermediates, among them oxalosuccinate, established in 1948 by Severo Ochoa and independently by Feodor Lynen, and acetyl coenzyme A, the two-carbon compound that enters the cycle, which followed from Fritz Lipmann's work on coenzyme A. Amino acids such as glutamic acid, aspartic acid and alanine also feed the cycle, so protein is burned through it as well as carbohydrate.

Krebs and Lipmann shared the 1953 Nobel Prize in Physiology or Medicine. In 1954 Krebs moved to Oxford as Whitley Professor of Biochemistry, bringing his Medical Research Council unit with him.