SYNTHESIS OF THE PORPHYRIN NUCLEUS 637 



found. At that time, however, Fischer's evidence for th^ occurrence 

 of a protoporphyrin of type II had not yet been withdrawn. 



8.2. Attempts at a New Theory of Porphyrinogenesis 



8.2.1. Precursors and Mechanism. Before a new theory of por- 

 phyrinogenesis is attempted we sum up once more the most important 

 experimental results. The studies on porphyrin formation in yeast 

 (c/. Section 7.3.2.) as well as the investigation on the porphyrin of 

 the Harderian gland of the rat by Thomas (2798) indicate a close 

 relationship between carbohydrate metabolism and porphyrin forma- 

 tion. They show that the precursors must be sought among com- 

 pounds which occur as metabolites in carbohydrate metabolism and 

 simple nitrogen compounds, either ammonia or compounds easily 

 formed from ammonia in the animal body or the yeast cells, such as 

 glutamic acid or glycine. Schoenheimer, Rittenberg, and co-workers 

 {290,2276,2277 ,2Jf53,25Jf3) have attempted to solve the problem by 

 making use of nitrogen compounds containing an excess of N^*. 

 They found that the N'* of ammonia, leucine, and particularly of 

 glycine was incorporated in the hematin of rat erythrocytes in the 

 course of a few (9-18) days and was found in hemin crystals prepared 

 from them. Similarly the carbon-bound deuterium of deuterio- 

 acetate was found in the hemin crystals. After feeding N'^-labeled 

 glycine, the N^^ content of hemin was so high that only glycine 

 itself could be considered to be the precursor. While there is no 

 proof that acetic acid is used directly for porphyrin synthesis, the 

 actual precursor must be a metabolic product readily formed from 

 acetic acid, such as succinic, a-ketoglutarie or glutamic acid.* 



Secondly we have seen {cf. Chapter XII, Section 3.2.3.) that there 

 is no reliable evidence for conversion of protoporphyrin into copro- 

 porphyrin by ascending carboxylation. There is no evidence whatso- 

 ever for ascending carboxylation of coproporphyrin to uroporphyrin, 

 which is not a reaction likely to occur in the animal body (transforma- 

 tion of methyl to acetic acid side chains). Fischer's assumption that 

 the occurrence of uroporphyrin in porphyria is due to a detoxication 

 reaction taking place in the kidney to aid excretion {782) is disproved 

 by the facts that, in chronic porphyria, uroporphyrin is deposited in 



* According to Orten and Keller (W88a), young rats on a protein-deficient diet 

 excrete far less protoporphyrin than on a normal diet. Compounds such as glutamic 

 acid and a-ketoglutaric acid are of importance in protein as well as in carbohydrate 

 metabolism. 



