KONRAD BLOCH 



providins; information on reaction mechanisms. For instance, l)utyric 

 acid labeled with deuterium at either the a- or tlie 7-position will 

 yield deuterioacetyl groups, indicating fission of the molecule int(} two 

 C2 fragments. Since a-deuteriobutyrate yields an acetyl group of much 

 lower isotope concentration than does 7-deuteriobutyrate, it can be 

 inferred that the intermediate must be of a nature to permit loss of 

 deuterium at the a-carbon atom. In view of the known in vitro labil- 

 ity of the a-hydrogen atoms in /3-keto acids, acetoacetic acid appears 

 to be the most probable intermediate in the butyrate-acetyl con- 

 version. 



Formation of Ketone Bodies 



Theories of fat oxidation have been based, at least in part, on 

 the ketogenic action of certain substances and the ability of others to 

 suppress ketosis. The mechanism of ketone body formation long 

 remained controversial because of the "extra" ketone body formation 

 from even-numbered fatty acids which contain more than four carbon 

 atoms. On administering to fasting rats acetic acid which contained 

 a carboxyl group labeled with heavy carbon, Swendseid et al. (25) 

 observed the presence of C^^ in the excreted ketone bodies. Their 

 data provide unequivocal proof for the early contention of Loeb that 

 acetoacetic acid could be synthesized from smaller molecules. It 

 still remained to be decided whether this process involved a Claisen 

 type of condensation of acetic acid or a coupling with one molecule 

 of pyruvic acid to acetopyruvic acid with subsequent decarboxylation 

 (10). Conclusive evidence pertaining to the mechanism is supplied 

 by recent experiments of Weinhouse et al. (27). Octanoic acid labeled 

 with C^^ in the carboxyl group was incubated with liver slices. Isotope 

 analysis of the resulting acetoacetate revealed the presence of heavy 

 carbon in equal concentrations in the carboxyl and carbonyl groups, 

 a finding which must be ascribed to random condensation of the acetic 

 acid units arising from the oxidation of octanoic acid. The isotope 

 distribution observed can be reconciled neither with the classical view 

 that only the four terminal carbon atoms of a fatty acid are a source of 

 ketone bodies nor with the hypothesis of multiple oxidation at alternate 

 carbon atoms. Consequently, any metabolite capable of forming 



300 



