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THE HISTORY OF THE TRICARBOXYLIC ACID CYCLE* H. A. KREBS] I have often been asked how the work on the tricarboxylic acid cycle arose and developed. Was the concept perhaps due to a sudden inspiration and vision? It was ofcourse nothing ofthe kind, but a very slow evolutionary process, extending over some five years beginning (as far as I am involved) in 1932. At that time the problem of the intermediary stages ofthe pathways ofanaerobic energy metabolism—glycolysis and alcohol fermentation—had been established in outline by 1932, but knowledge of the pathways ofoxidation was very fragmentary. What was known can easily be summarized. There was the principle (though not the enzymic mechanism) of the ^-oxidation of fatty acids. There was the concept of oxidative deamination of amino acids and of the decarboxylation of the resulting a-ketonic acids. A survey oftheknowledge ofintermediary pathways ofoxidation in the early 1930s is to be found in Oppenheimer [1]. The only hypothesis outlining a pathway of the intermediary stages of carbohydrate oxidation was that put forward by Thunberg [2] and supported by Knoop [3] and Wieland [4]. It assumed that two molecules of acetate—formed from lactate via pyruvate or by /3-oxidation of fatty acids—condensed to form succinate which was taken to undergo oxidation via fùmarate, malate, oxaloacetate and pyruvate to form one molecule of acetate: coocoo -coo-cooCH -2H CH2 -2H CH +H2O CHOH + —»- ? —>- Il—>- I CH3 CH2CHCH2 coo-coo-coocoo 2 acetatesuccinatefumaratemalate * The second Verne R. Mason Memorial Lecture, University ofMiami, January ???a. Permission to publish has been granted by the Howard Hughes Medical Institute. Publication costs were kindly contributed to Perspectives by Miles Laboratories, inc. t Metabolic Research Laboratory, Nuffield Department ofClinical Medicine, RadcliffeInfirmary, Oxford, England. I54 H. A. Krebs · Tricarboxylic Acid Cycle Perspectives in Biology and Medicine · Autumn 1970 COO-COO-CO2 -2H COCO+H2O - 2H + ---------y ? ---------»- ? ------------------------->CH2CH3COO COO -+CO2CH3 oxaloacetatepyruvateacetate This scheme was based on the oxidizability ofsome ofthe postulated intermediates , but there was no evidence supporting the key condensation reaction which, as we now know, does not occur in living cells. This weakness, and the general ignorance ofthe pathway ofoxidation offoodstuffs , were fully recognized. In 1932, whilst working as an assistant physician in the Department of Internal Medicine at Freiburg University, I carried out many experiments, mainly on kidney and liver slices, on the oxidizability ofsubstances which might be expected to be intermediates. The idea behind this work was that intermediates mustbe identifiable on account oftheir ready oxidation. There seemed to be no metabolic links between the oxidizability of the dicarboxylic acids and the oxidation offoodstuffs—especially ofcarbohydrate and fat. Therefore we tested a large number of other substances which paper chemistry suggested as intermediates. Some ofthese experiments were done in collaboration with Dr. P. Ostern, a visitor from the laboratory ofJ. Parnas in Lwow, and the only published paper from this work is a manometric method for the determination of oxaloacetic acid by Ostern [5], a method widely used until it was superseded by more sensitive and more specific spectrophotometric methods. The striking impression which these experiments left in my mind was the fact that citrate, succinate, fumarate, malate, and acetate were very readily oxidized invarious tissues, with the formation ofbicarbonate and CO2 (see table i1), and that the rates of oxidation ofthese substances were compatible with the view that they played a major part in tissue respiration; but this had already been shown much earlier—in 1911—by Batelli and Stern [6]. 1 This unpublished experiment, carried out in 1933, illustrates the increased oxygen consumption and the formation ofbicarbonate in kidney cortex after addition ofthe salts ofvarious organic acids. Bicarbonate formation indicates complete combustion. Less bicarbonate was formed than was expected from the O3 uptake required for complete oxidation because intermediates accumulated, e.g., fumarate and malatewhen succinate was the substrate. Slices were incubated in Warburg manometers in a saline medium containing initially 2 raM bicarbonate. After 60 minutes' incubation, the slices were removed and the bicarbonate content ofthe medium was measured manometrically. I55 After my enforced emigration from Germany I continued experiments in this field in Cambridge between 1933 and 1935, though my main research during that time was on other...