162 



1. MALONATE 



mation of protoporphyrin. from S-aminolevulinate is not inhibited by mal- 

 onate so that an action on this part of the pathway is excluded. Granick 

 suggested that malonate reacts with coenzyme A and thus depletes the 

 system so that succinyl-CoA cannot be so readily formed. These effects 

 were confirmed in lysed chicken erythrocytes by Brown (1958). Porphyrins 

 are not formed in these preparations but (5-aminolevulinate is formed from 

 glycine and succinyl-CoA derived from a variety of cycle substrates. Mal- 

 onate at 10 mM inhibits this reaction 30% when the incubation is with 

 glycine and citrate, substantiating the action on this region of the pathway. 





1 50 





2 I 



A Arsenite 



B DNP 



C Fluoroacetote 



D Malonate 



pi ► 



Fig. 1-17. Effects of four inhibitors on the sjti thesis 



of protoporphyrin in chicken erythrocytes with the 



substrates as indicated. (From Granick, 1958.) 



It is interesting that the addition of succinate to glycine and citrate in the 

 incubation medium leads to an inhibition of (5-aminolevulinate synthesis. 

 This was shown to be due to the formation of oxalacetate, which inhibits 

 a-ketoglutarate oxidase. Malonate is able to overcome this inhibition by 

 succinate through the prevention of oxalacetate formation. This indicates 

 another minor mechanism for the effect of malonate on porphyrin synthesis, 

 namely, the reduction in oxalacetate concentration and a consequent release 

 from any inhibition on the oxidation of a-ketoglutarate. Finally, we may 

 note that coproporphyrin synthesis from glycine and a-ketoglutarate in 



