CELLULAR METABOLISM II9 



tions, citrate formation, fatty acid synthesis), it will not be detected 

 unless some of these reactions are inhibited. Experiments where the 

 metabolism of pyruvate was studied in the presence of fluoroacetate in 

 kidney, liver, and muscle showed accumulation of acetate and inhibition 

 of pyruvate utilization due to accumulation of its oxidation product, 

 acetate. The other pathways of pyruvate metabolism (amination to 

 alanine, reduction to lactate, and dismutation to lactate and acetate) 

 were not affected. Furthermore none of the oxidative steps of the tri- 

 carboxylic acid cycle — oxidation of isocitric, a-ketogiutaric, succinic, 

 and malic acid — were affected by fluoroacetate. The experiments with 

 fatty acids showed an inhibition in the oxidation and utilization of these 

 substances with an inhibition of acetoacetate formation in liver slices, 

 but with acetate as substrate there was accumulation of acetoacetate. 

 This inhibition of acetoacetate formation in the presence of fluoroacetate 

 supports the view, now generally accepted, that the oxidation of fatty 

 acids occurs by steps until the formation of acetate. In the metabolism 

 of acetate there are then two pathways : oxidation inhibited by fluoro- 

 acetate, and condensation to acetoacetate not affected by it. Since acetate 

 accumulates in the presence of fluoroacetate, it is plausible to postulate 

 that acetate is the end product in the oxidation of fats and carbohydrates. 

 Furthermore the high toxicity of fluoroacetate is indication of the es- 

 sential role of acetate metabolism in higher animals and in some plants. 



The oxidative pathway, however, is not the only avenue of utilization 

 of pyruvate. Pyruvate, the most highly reactive molecule among the 

 intermediates found during the breakdown of foodstuffs, is in fact 

 utilized in a variety of ways in the different cells, and even in the same 

 cell the utilization of pyruvic acid will depend on the oxygen tension, 

 thiamin concentration, glutathione concentration, etc. The multiple 

 pathway of pyruvate metabolism postulated in this laboratory for several 

 years may thus be summarized as follows, all these reactions being 

 reversible (see chart). 



How much of the oxidative removal is performed via acetate and 

 how much via carboxylation to oxaloacetate has not been determined 

 in all tissues. In the experiments of Bartlett and Barron (14) with 

 kidney slices, at least 45 per cent of the pyruvate utilized could be ac- 

 counted for as due to direct oxidation. 



It can be seen from this chart that the only difference between this 

 scheme and Krebs' tricarboxylic acid cycle is that here pyruvate is di- 

 rectly oxidized to acetate. The synthesis of citric acid from acetate was 

 demonstrated in yeast by Sonderhoff and Thomas (79). The oxidation 



