EFFECTS OF MALONATE ON PORPHYRIN SYNTHESIS 159 



or from succinate; the latter reaction requires ATP and is catalyzed by 

 succinyl-CoA synthetase (P-enzyme). A total of 8 molecules of succinate and 

 8 molecules of glycine is required for the synthesis of a molecule of proto- 

 porphyrin. The close connection between this pathway and the succinate 

 steps of the cycle, and the great iniportance of porphyrin synthesis in all 

 tissues, make the study of the action of malonate on this system interesting. 

 We may speculate on the various ways in which malonate could modify 

 porphyrin synthesis. (1) If the succinyl-CoA is formed in the cycle through 

 a-ketoglutarate, malonate could restrict its formation by blocking the cycle 



Acetyl -Co A 



Fumarote 



(Malonate) 



I 



a-Ketoglutarote Succmote 



-Succinyl -Co A 



^^ Glycine 



a -Ammo- /9 - ketoadipote 

 S - Aminolevulinote 



I 



Porphobilinogen 



Protoporphyrin 



Fig. 1-16. The pathways involved in 

 porphyrin biosynthesis. 



and reducing the rate of acetyl-CoA entry, especially if no noncycle source 

 of oxalacetate is available. (2) If succinyl-CoA can be formed through the 

 cycle readily in spite of a malonate block, malonate might divert more suc- 

 cinate into the synthesis of porphyrin by inhibiting succinate oxidation. 

 (3) If the succinyl-CoA arises from succinate, this requires ATP and mal- 

 onate could deplete the system of ATP. (4) Malonate might deplete the 

 system of coenzyme A by the formation of malonyl-CoA. (5) It is possible 

 in some way that malonate might inhibit the formation of glycine, although 

 this is rather unlikely because there are usually several pathways avail- 

 able for glycine synthesis. The effects of malonate will thus depend on the 

 type of preparation used and the conditions of the experiment. 



Duck erythrocytes (intact or hemolyzed) incubated with succinate and 

 glycine form porphyrin. Succinyl-CoA could be formed from succinate either 

 directly or through the cycle and the relative importance of these pathways 

 may be demonstrated by the use of succinate-C^'* with subsequent deter- 



