EFFECTS OF MALONATE ON LIPID METABOLISM 



139 



recently more emphasis has been placed on the diversion of carbohydrate 

 and fatty acid metabolism to acetoacetate by malonate. We may summarize 

 some of the major pathways of acetoacetate before discussing the mecha- 

 nisms for the action of malonate (Ac-CoA = acetyl-CoA, and AcAc-CoA = 

 acetoacetyl-CoA). Reaction (1) for the formation of Ac Ac-Co A from aceto- 



Fatty acids ( 

 Pyruvate ij 



Butyrate 



-»- Ac -Co A 



AcAc — CoA 



-»- Ac Ac — CoA 



Even-numbered 

 fatty acids 



•-Butyryl —CoA *- Ac Ac — CoA 



Succinate + Ac Ac— CoA 



/3-Hydroxybutyrate 



Amino acids (phenylalanine, 

 tyrosine, leucine, and 

 isoleucine) 



Acetone + COj 

 .AcAc-CoA (1) 



I acetoacetate I ' *-AcAc— CoA (2) 



Sterols 

 /3-Hydroxybutyrate 



acetate is catalyzed by an activating enzyme in the presence of CoA and 

 ATP, while reaction (2) is catalyzed by a CoA transferase in the presence 

 of succinyl-CoA. All of these reactions do not occur in a single tissue and 

 the response to malonate depends in part on which reactions are possible 

 in any case. 



A block of the cycle restricts the entrance of acetyl-CoA, derived from 

 pyruvate and fatty acids, into the cycle, unless there is an adequate synthe- 

 sis of oxalacetate from a noncycle source, which is seldom the case. If the 

 acetyl-CoA accumulates, coenzyme A soon becomes tied up and the oxida- 

 tion of pyruvate and fatty acids would cease. However, in most tissues 2 

 molecules of acetyl-CoA condense to form acetoacetate and coenzyme A is 

 regenerated; in other situations, hydrolysis to acetate may occur. Malonate 

 may thus divert acetyl-CoA from the cycle to acetoacetate. Quantitative 

 conversion to acetoacetate has been observed (Recknagel and Potter, 1951). 

 Another reaction possibly favoring acetoacetate formation during malonate 

 inhibition results from the accumulation of succinate, which can now react 

 more readily with acetoacetyl-CoA in a transfer of coenzyme A. The effec- 

 tiveness of such a mechanism depends on the continued formation of suc- 

 cinate and, hence, usually on a noncycle source of oxalacetate. Acetoacetyl- 

 CoA is also formed as the terminal product of the helical oxidation of even- 

 numbered fatty acids. These relationships are illustrated in Fig. 1-15 

 where a block of succinate oxidation induces accumulation of acetoacetate 

 by accelerating its formation through two mechanisms. The other pathways 

 for the formation of acetoacetate are probably less important in most tis- 

 sues and would not be accelerated by malonate. Accumulation of aceto- 

 acetate implies that its utilization must not be too rapid. Liver is notable in 

 this respect because it lacks enzymes to metabolize acetoacetate rapidly, 



