Effects of a folic acid antagonist on nucleic acid metabolism.

Microbiological evidence (1) first implicated folic acid in nucleic acid synthesis, and several lines of investigation suggest that citrovorum factor, or another derivative of folic acid, may function in some manner as a coenzyme in the metabolism of a l-carbon moiety. The function of the formy1 group in rhizopterin (2) and citrovorum factor (3) has not been clarified. The incorporation of formate into carbon atoms 2 and 8 of purines (4) and the production by bacteria of an incomplete purine skeleton (4-amino-5imidazolecarboxamide (5)) in the presence of a sulfonamide (6) or a folic acid antagonist (7) led to the demonstration in vitro that citrovorum factor was necessary for the production of the purine ring from formate and the carboxamide ribotide (8). This was substantiat,ed by the requirement of citrovorum factor in a system in vitro in which the purine skeleton could be synthesized from small fragments (9). Experiments in vivo have shown a decrease in formate incorporation into the purines of folic acid-deficient bacteria (10) and into the serine of folic acid-deficient rats (II), while the conversion of serine to glycine in the deficient rat was also depressed (12). In mice treated with a folic acid antagonist, the incorporation of formate into the nucleic acids was decreased (13). It was also demonstrated that nitrogen mustards, urethane, cortisone, and x-rays produce a decrease in formate incorporation into nucleic acids (14). However, because the folic acid antagonist produced a more marked decrease in formate incorporation than that observed when bicarbonate was employed as a precursor, it was concluded that the folic acid antagonist had a specific effect on formate incorporation. The experiments described here involved the simultaneous administration of C4-formate and N15-adenine as precursors of nucleic acid. It was demonstrated that the ratio of incorporation of formate to that of adenine was decreased when aminopterin was also given. The degree of formate