INTERMEDIARY METABOLISM 



The view that fatty acids arc metaboHzed by oxidation at their 

 j3-carbon atoms with consequent removal of two-carbon units has 

 been held ever since the classical experiments with phenyl substituted 

 fatty acids were carried out by Knoop. The experiments of Dakin 

 with the ammonium salts of fatty acids brought evidence for the chemi- 

 cal susceptibility of the beta positions to mild oxidizing agents in the 

 test tube. The facts that (1) the component fatty acids of animal 

 tissues contain, without exception, an even number of carbon atoms, 

 and (2) that acetoacetic acid is excreted under conditions of deficient 

 or impaired carbohydrate oxidation, have provided additional though 

 indirect support for the principle of beta oxidation. To this theory, 

 the objection has been raised that none of the postulated intermediary 

 keto acids nor any of the fatty acids below Cio, including the main 

 breakdown product, acetic acid, has been demonstrated in animal 

 tissues. In view of recent experience, the practical absence of such 

 intermediates is not surprising, since the failure to accumulate is 

 characteristic of the breakdown products of the major food constitu- 

 ents and must be attributed to their rapid rate of removal. 



A finding apparently at variance with the beta oxidation theory 

 was the observation that, in isolated tissues, the uptake of oxygen and 

 the formation of ketone bodies are greater with the higher fatty acids 

 than with butyric acid (9), whereas Knoop's theory provided for only 

 one mole of acetoacetate per mole of fatty acid. An attempt to over- 

 come this inconsistency led to the concept of multiple alternate oxida- 

 tion (8) which visualizes simultaneous oxidation of the fatty acid chain 

 at alternate carbon atoms. In this manner palmitic acid could break 

 down to yield four molecules of acetoacetate. It is noteworthy that, 

 for years, little attention had been paid to the observation of Loeb (12) 

 that ketone bodies were formed on perfusion of liver with acetic acid. 

 If acetoacetate could arise synthetically from smaller units as well as 

 by primary breakdown, then the formation of more than one mole of 

 ketone bodies per molecule of fatty acid would no longer be incom- 

 patible with the theory of beta oxidation. 



Another fact which could not be fitted into existing theories 

 was the finding that w-valeric acid is a ketogenic substance (9,13). 

 Neither Knoop's theory nor that of multiple alternate oxidation 

 could satisfactorily explain this observation unless it was supposed 

 that oxidation of odd-numbered fatty acids could be initiated at the 



