EFFECTS OF MALONATE ON LIPID METABOLISM 145 



The over-all reaction is the carboxylation of propionate to succinate. Other 

 pathways occur in bacteria, e.g. 



Propionate -> propionyl-CoA -> acrylyl-CoA -> lactyl-CoA ->■ pyruvate -> COg + H2O 



Such a sequence may also operate in animal tissues, since lactate was iden- 

 tified chromatographically after incubation of mouse liver slices with pro- 

 pionate (Daus et al., 1952). If the principal pathway of propionate is via 

 succinate, malonate would be expected to inhibit its oxidation readily but, 

 if acetyl-CoA is formed, the inhibition will vary with the conditions as 

 discussed for the effects of malonate on pyruvate oxidation. 



Malonate has been shown to inhibit strongly the C^^Oo formation from 

 labeled propionate in mouse liver slices (Daus et al., 1952), rat liver slices 

 (Katz and Chaikoflf, 1955), suspensions of rabbit liver particles (Wolfe, 

 1955), and peanut mitochondria (Giovanelli and Stumpf, 1958), as anticipat- 

 ed. In the rabbit liver particulate preparation, 10 mM malonate suppresses 

 the formation of C^^O, from both propionate-l-C^* and propionate-2-C^^ 

 almost completely, and at the same time leads to the accumulation of suc- 

 cinate, and in rat liver slices malonate also causes succinate accumulation. 

 From these data alone it is impossible to say whether the succinate arises 

 directly from propionate or is formed via the cycle, but the marked inhibi- 

 tion of C^^O, formation would indicate the former. This is substantiated 

 by the demonstration of labeled methylmalonate in the rat liver slices. 

 Another possible site for malonate inhibition is suggested by the work of 

 Flavin et al. (1955) on rat tissues. The intercon version of methylmalonate 

 and succinate was shown to be inhibited completely by 5 mM malonate and 

 thus malonate leads to the accumulation of methylmalonate during propion- 

 ate metabolism. However, it is not known if malonate can inhibit the 

 methylmalonyl-CoA isomerase, which catah^zes the interconversion in the 

 normal pathway, or if malonate only inhibits the formation of methyl- 

 malonyl-CoA from methylmalonate. The latter is reasonable because mal- 

 onate could compete with methylmalonate for the active site on the enzyme. 



In peanut mitochondria the situation may well be different. Malonate at 

 6 mM inhibits the formation of C^^Oa from propionate- 1-C^* 41% (Giovanelli 

 and Stumpf, 1958). It was felt that this inhibition is not as much as would 

 be expected if the pathway from propionate leads to succinate. Further- 

 more, fluoride, which inhibits the carboxylation of propionyl-CoA, does 

 not depress the C^^Oa significantly. The pathway through methylmalonyl- 

 CoA to succinate may not be operative here, and the following pathway was 

 proposed: 



Propionate ->• propionyl-CoA -> acrylyl-CoA -> ^-hydroxypropionyl-CoA ->• 

 /?-hydroxypropionate -> malonic semialdehyde -> malonyl-CoA -> acetyl-CoA 



The COo formed in the last step derives from the carboxyl group of propion- 



