METABOLIC CYCLES AND DECARBOXYLATION 203 



malate system in the aerobic cycle, this reaction may also explain 

 why citrate does not accumulate to any extent. On the other hand, 

 the only reason we have for including citric acid in the cycle is the 

 rapidity of its formation from oxalacetate and pyruvate as indicated 

 in equation 8 and the fact that its oxidative breakdown will yield 

 alpha-ketoglutarate and succinate at the required rate. It has been 

 suggested, first by Breusch (10) and later by others, that citrate 

 formation represents a side reaction in pyruvate metabolism— a 

 means for disposing of excessive amounts of the dicarboxylic acids. 

 There is, however, no experimental support for this concept at the 

 present time; the simpler hypothesis, in which citric acid is regarded 

 as an intermediate in the cycle, is probably to be preferred as a basis 

 for further experiments. It should be emphasized that succinate is 

 formed in malonate-poisoned muscle at the proper rate only by 

 those compounds listed as intermediates, although a great number 

 of other possible substances have been examined for their ability 

 to do this. It seems improbable, therefore, that the quantitative 

 formation of succinate from citrate in the malonate-poisoned muscle 

 is without significance for the role of citrate in muscle metabolism; 

 Smyth's failure to obtain consistent results with citrate in pig heart 

 muscle may be due to our ignorance of the essential conditions for 

 citrate oxidation, as he suggests. 



With other tissues the evidence for similar mechanisms of pyru- 

 vate oxidation is much less complete. It has been shown in pigeon 

 hver, for example, that the enzyme systems necessary for the reac- 

 tions of the citric acid cycle are present (6). Whetlier or not they 

 play any considerable role in its metabolic function remains a 

 question for further study. We do have evidence that alpha- 

 ketoglutaric acid formation can occur in this tissue independently 

 of the reactions of the citric acid cycle (9, 11, 12). 



Demonstration of the synthesis of alpha-ketoglutaric acid from 

 pyruvic acid in pigeon liver has been followed by efforts to ascer- 

 tain the mechanism involved. The reaction proceeds in the presence 

 of malonic acid and without the addition of any of the four-carbon 

 dicarboxylic acids, presumably by a direct utilization of the three- 

 carbon compound. The scheme of Toeniessen and Brinkmann (13) 

 for succinate synthesis from pyruvate in muscle, involving the inter- 

 mediate formation of diketo-adipic acid, could be disregarded, since 

 pigeon liver is incapable of metabolizing formic acid at a rate neces- 

 sary for this mechanism to operate (6). 



Since pigeon Hver can form citric acid from oxalacetic acid and 



