158 



1. MALONATE 



Eggleston (1948) then demonstrated a differential effect of malonate on 

 the formation of urea depending on whether glutamate or aspartate is 

 used as the amino donor, the inhibition being less in the latter case. An 

 elucidation of the true mechanism of the inhibition was presented by 

 Ratner and Pappas (1949), who showed a very definite differential effect 

 of malonate when glutamate and aspartate are used (see tabulation). The 



transamination forming aspartate from glutamate is not inhibited by mal- 

 onate so the mechanism must be sought elsewhere. It was proposed that 

 malonate prevents the formation of oxalacetate and thus indirectly blocks 

 the formation of aspartate; fumarate would, of course, overcome this block. 

 They opposed the idea that ATP depletion is important and felt that the 

 ATP derived from a-ketoglutarate oxidation would be sufficient. However, 

 they did not by any means disprove the ATP depletion hypothesis and it is 

 quite possible that it also plays a role in assigning an over all mechanism 

 for the inhibition. Miiller and Leuthardt (1950) extended these observations 

 by showing chromatographically that malonate inhibits the formation of as- 

 partate by reducing the formation of oxalacetate from a-ketoglutarate, and 

 also demonstrated conclusively that the transamination reaction itself is 

 not sensitive to malonate. It should be noted that in the reactions written 

 above, oxalacetate appears to be regenerated in the arginosuccinase reac- 

 tion followed by the hydration and oxidation of fumarate. but this is appar- 

 ently not sufficient to maintain the cycle, probably because much of the 

 oxalacetate disappears in other reactions. This is why an external source 

 of oxalacetate is necessary. 



EFFECTS OF MALONATE ON PORPHYRIN SYNTHESIS 



The pathway for the synthesis of porphyrins in both animals and plants 

 originates in the cycle in the condensation of succinyl-CoA with glycine 

 (Fig. 1-16). The succinyl-CoA can be formed either from a-ketoglutarate 



