ANTIPERNICIOUS ANEMIA PRINCIPLE AND FOLIC ACID 611 



believe that these amino acids are required for the synthesis of the prosthetic 

 group. In view of the fact that ghitamic acid is a building stone of folic acid 

 and in view of the possible role of a-ketoglutaric acid in porphyrin synthesis 

 (c/. Sections 3.3. and 8.) this observation is of some interest, but Elvejhem 

 and co-workers {2x30) have been unable to confirm it; they ascribe the results 

 of Drabkin and Miller to contamination of the amino acids with copper {683). 



Lack of lysine slows down the development of the hemopoietic system of 

 growing rats, but causes no real anemia (1133). Deaminated casein, in which 

 the €-amino groups of lysine are replaced by hydroxyl, causes anemia in 

 rats {1305), and this may well be another instance of competition by struc- 

 tural analogs. 



Orten, Bourque, and Orten {2088) found that if ox globin, which contains 

 little isoleucine, was the only protein fed to young rats, an anemia developed 

 which could be abolished by feeding small amounts of this amino acid (c/. 

 also 32,33). Rat hemoglobin is probably equally poor in isoleucine, but the 

 isoleucine may be used predominantly for growth. Hemoglobin is also rather 

 poor in methionine. In adult anemic dogs Whipple and co-workers {2292) 

 found increase of hemoglobin synthesis and of plasma protein formation by 

 addition of methionine, but not of isoleucine, to a hemoglobin diet. The 

 difference between the results found with isoleucine is probably due to the 

 fact that in Whipple's experiments the amino acid was required only for 

 maintenance, not for growth. 



In hemoglobin-depleted dogs, Whipple and Robscheit-Robbins {3061) 

 found no large differences between the hemopoietic activity of various amino 

 acids. The unphysiologic D-forms were quite as active as the L forms. Simi- 

 larly none of the ten essential amino acids was found to be a key substance 

 for hemopoiesis in rats anemic from lack of protein (Orten and Orten, 2085). 

 Metcoff, Favour, and Stare {1918), studying the formation of total circulat- 

 ing hemoglobin in rats deficient in protein, found that inadequate hemoglobin 

 synthesis is probably not wholly responsible for the anemia. The diminution 

 of the erythrocyte volume was the predominant factor. Casein (perhaps due 

 to its higher methionine content) was more effective in restoring hemoglobin 

 than was lactalbumin. 



According to Jacobson and Williams {H06) arginine is the only amino 

 acid which may conceivably play a role in the effect of the antipernicious 

 anemia principle. Jacobson and SubbaRow {1401,1402,2691) had claimed 

 that tyrosine and perhaps tryptophane were of importance, but these amino 

 acids were missing in other active preparations studied by Dakin and Karrer. 

 Tyrosine is probably a factor in the reticulocyte-ripening principle {cf. 

 above). 



3.3, Factors Necessary for Hemopoiesis 



3.3.1. Antipernicious Anemia Principle and Folic Acid. The 



principle is necessary for the correct maturation of the erythroblast 

 to the normoblast in the bone marrow and the formation of a stable 

 erythrocyte. It serves the building up of the architecture of the red 



