39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 483 



derivatives. This assumes that a major part of purine synthesis de novo 

 passes through this common intermediate. An additional site of action 

 which has been proposed for microbial systems is in the formation of a 

 purine precursor prior to the ribonucleotide of aminoimidazolecarboxamide. 

 The accumulation of aminoimidazolecarboxamide by suspensions of a 

 purine-requiring mutant of E. coli was suppressed not only by the presence 

 of natural purines in the medium, but also by mercaptopurine 195 ; this re- 

 sult was interpreted as a possible negative feedback control of the pathways 

 of purine synthesis by the analog. 



Numerous other effects of mercaptopurine in systems in vivo have been reported, 

 but these may be referable to reduced production of purine ribonucleotides and co- 

 enzymes. Thus, not only the increase in the level of DPN in the liver caused by the 

 injection of nicotinamide, but also the rate of the subsequent diminution of the DPN- 

 level, were reduced by mercaptopurine. 196 The adaptive formation of /3-galactosidase 

 by Mycobacterium tuberculosis was inhibited by this analog. 197 Mercaptopurine also 

 appears to reduce or eliminate the formation of antibodies in rabbits 198 and to inhibit 

 the acetylation of sulfanilamide. 199 



The possible relationship of this latter finding to reversal by coenzyme A 200 ' 201 of 

 the inhibition of mitosis of sarcoma-180 and of lipogenesis in mouse fibroblasts in 

 cell culture by mercaptopurine will be apparent. In a detailed study of the effects 

 of this antimetabolite on a number of biosynthetic systems in growing cultures of 

 E. coli B, 202 temporary inhibition of growth was seen at levels of the analog which 

 had demonstrated no effect on other aspects of cellular chemistry. Other parameters 

 of cell function were affected in the following order of decreasing sensitivity: acetate 

 utilization for lipid and protein synthesis, formate incorporation, and nucleic acid 

 synthesis. Effects of mercaptopurine on glycolysis, presumably indirect, have been 

 noted at high levels of the agent. 203 " 206 However, as pointed out by many of the 

 workers quoted above, the subtle effects of purine nucleotide or coenzyme depriva- 

 tion on cell growth by the mechanisms discussed may be difficult to detect when 

 growth phenomena are studied in the living cell. 



Of the many derivatives of mercaptopurine, certain S-glycosyl compounds 207-209 



195 J. S. Gots and E. G. Gollub, Proc. Am. Assoc. Cancer Research 2, 207 (1957). 



196 N. 0. Kaplan, A. Goldin, S. R. Humphreys, M. M. Ciotti, and F. E. Stolzenbach, 

 J. Biol. Chem. 219, 287 (1956). 



197 L. Ottey, /. Pharmacol. Exptl. Therap. 115, 339 (1955). 



198 R. Schwartz, A. Eisner, and W. Dameshek, Clin. Research 7, 39 (1959). 



199 S. Garattini and R. Paoletti, Giorn. Hal. chemioterap. 3, 55 (1956); Chem. Abstr. 

 51, 4452 (1957). 



200 J. J. Biesele, Ann. N. Y. Acad. Sci. 71, 1054 (1958). 



201 J. J. Biesele, Ann. N. Y. Acad. Sci. 60, 228 (1954). 



202 E. T. Bolton and H. G. Mandel, J. Biol. Chem. 227, 833 (1957). 



203 P. Hochstein, Proc. Am. Assoc. Cancer Research 2, 214 (1957). 



204 I). Burk, J. Laszlo, J. Stengle, and K. Wight, Federation Proc. 16, 160 (1957). 



205 J. Laszlo, J. Stengle, K. Wight, and D. Burk, Proc. Am. Assoc. Cancer Research 

 2, 224 (1957). 



206 D. Burk, Klin. Wochschr. 35, 1102 (1957;. 



207 I. Goodman, G. B. Elion, and G. H. Hitchings, Federation Proc. 14, 219 (1955). 



208 I. Goodman, J. R. Fouts, and G. H. Hitchings, Federation Proc. 17, 232 (1958). 



