612 XIII. HEMOGLOBIN AND PORPHYRIN SYNTHESIS 



cell rather than hemoglobin synthesis; in recovery from pernicious 

 anemia the increase of the erythrocyte count outstrips the increase 

 in hemoglobin, while in relapse the cell is not hypochromic. It has 

 also been suggested that the principle is required for the detoxication 

 of endogenous aromatic (benzene) derivatives. 



The nature of the Hver principle is still unknown. It is formed by the action 

 of an intrinsic factor, probably aminopolypeptidase on an extrinsic food 

 factor. Castle (4^9) excluded all known vitamin B factors, including ribo- 

 flavin and xanthopterin from identity with the extrinsic factor. On the 

 other hand, according to recent investigations of Jacobson and collaborators 

 (l^'Oi, 14-06), the gastric principle contains leucopterin or a similar pterin, 

 perhaps in conjunction with another factor; xanthopterin appears to be less 

 active than leucopterin. The opinion of SubbaRow and Jacobson {2690,2691) 

 that the antipernicious anemia principle is of multiple nature is probably 

 correct.* A polypeptide, L-tyrosine and a purine (pterin.^) substance were 

 found to play a role {14-01), although tyrosine was not found in other prep- 

 arations {cf. below). SubbaRow and co-workers {2692) isolated a "complex 

 pterin" in the form of a crystalline salt of intense blue fluorescence, and 

 Mazza and Penati {1892) found pterins in liver extract. 



It appears likely that certain compounds isolated from the liver by West, 

 Howe, and Dakin {525,526,3039) may also form part of the complex principle. 

 These are a dipeptide of j8-hydroxyglutamic acid with 7-hydroxyproline 

 and a pyrrolidonetricarboxylic acid, the former producing a strong, the 

 latter a much smaller, reticulocytosis in pernicious anemia. The possible 

 connection between these, particularly the latter, and porphyrin synthesis 

 will be discussed in Section 8. The dipeptide may perhaps contribute to the 

 glutamic acid part of folic acid. 



Folic add. Vitamin Be, the lack of which causes macrocytic 

 anemia of the chick {.IfOO, 1304-4570, 17 86, 206^,2 147, 2523), a similar 

 factor required for hemopoiesis in the rat, particularly in rats treated 

 with sulfasuxidine {103,279,285,524,1272,1569,1570,2205), but also 

 without this drug {4-09), and the vitamin M necessary for blood 

 formation in monkeys {5^6,2819) have now all been shown to be 

 closely related to folic acid. The lack of other factors may also 

 contribute to the macrocytic anemia of monkeys. 



The chemical structure of the folic acid of the liver as pteroyl- 

 glutamic acid has been elucidated by Angier and co-workers, who 

 also achieved its synthesis {58). Pteroic acid is pteridyl-p-amino- 

 benzoic acid, pteridines being closely related in structure to pterins. 



The effectiveness of folic acid in curing both pernicious anemia and 

 macrocytic nutritional anemia has recently been demonstrated by 



* Cf., however, the vitamin B12 of Smith {'2575b) and Rickes and co-workers {2248a), 

 a cobalt compound. 



