DISCUSSION ON ANIMAL TISSUE RESPIRATION 281 



pyruvate is converted to citrate in the course of its oxidation. The 

 cycle imphes that either citrate should be oxidized as rapidly as 

 pyruvate, or that if citrate is not oxidized as rapidly as pyruvate, but 

 still is a stage in the removal of pyruvate, it should accumulate in 

 quantities suflBcient to account for the difference in the rates of 

 utihzation of the two compounds. We found that pyruvate is oxidized 

 at a far greater rate than citrate, and that citrate does not accumu- 

 late. 



Our experimental observations favor a cycle involving a conver- 

 sion of pyruvic acid to alpha-ketoglutaric acid, without citrate as an 

 intermediary, followed by the Szent-Gyorgyi series of conversions 

 of the dicarboxylic acids to oxalacetate. The occasional catalysis of 

 respiration observed when citrate is added to muscle is probably 

 not due to citrate itself but rather to alpha-ketoglutarate and the 

 four-carbon acids which may be formed from it. Citrate may serve 

 as a "stockroom" for the essential catalysts, exerting an effect on 

 respiration only when they are low. Its synthesis from pyruvate may 

 represent an unusual side reaction which under normal conditions 

 is of little significance. However, under specific experimental condi- 

 tions in vitro, such as large amounts of pyruvate, the rate of their 

 reaction may be accelerated. A similar condition, with a high level 

 of pyruvate, appears to exist in vivo. Thus Sober, Lipton, and Elve- 

 hjem found that in the recovery from acute thiamine deficiency large 

 amounts of citrate are excreted. 



In concluding these remarks, may I emphasize that these criti- 

 cisms of the citric acid cycle are directed against a citric acid cycle 

 which contains citric acid; they do not apply to a citric acid 

 cycle which contains no citric acid. Proponents of the citric acid cycle 

 quite properly spend most of their energy proving that some sort 

 of a cycle exists rather than attempting to answer the question 

 whether citric acid is, or is not, a member of it. 



