39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 495 



The situation is unclear concerning the mechanism of action of diamino- 

 purine as an inhibitor of growth. Although the reversal studies and the 

 specificity of formation of the ribonucleotide suggest that this compound is 

 an adenine antagonist, studies with a mutant of A. aerogenes, 301 in which 

 diaminopurine can substitute for guanine and appear as guanine in the 

 nucleic acids, as well as its deamination to guanosine derivatives, 313 would 

 assign it a role in guanine metabolism. However, resistance to diamino- 

 purine generally is associated with resistance to other antimetabolites of 

 adenine, such as 8-azaadenine, 319, 320 and, in one case at least, such resist- 

 ance results in a reduced capacity to form ribonucleotides of this analog. 318 

 Hence, several reports 298, 318 ' 319 have suggested that it may exert its anti- 

 metabolite function either by competing with adenine or by forming a 

 2-aminoadenine ribonucleotide derivative which blocks the formation or 

 function of one of the critical adenine-containing coenzymes. Although di- 

 aminopurine inhibits the incorporation of formate, 4, 278, 2 " glycine, 3 and 

 aminoimidazolecarboxamide, 321 the utilization of this analog in the synthesis 

 of purine nucleotides makes it difficult to distinguish between true inhibition 

 and dilution of the purine pools by diaminopurine. Furthermore, in at least 

 one instance in which formate and phosphate uptake was measured, even 

 phospholipid metabolism was strongly inhibited, 322 - 323 a circumstance which 

 suggests a general depression of a number if not most parameters of cellu- 

 lar function. The prevention by diaminopurine or its riboside of inhibition 

 of E. coli by urethane or A^-methylformamide, and the nullification of these 

 effects by the simultaneous addition of adenine, confuse the issue even 

 more. 324, 325 In summary, then, although its metabolism has been consider- 

 ably explored, the mechanism of action of diaminopurine is still undefined. 



5. Miscellaneous Purines 



A great variety of naturally occurring or chemically prepared compounds which 

 resemble the purines or their derivatives possess biological activity. Since their pre- 

 cise relationship to nucleic acid metabolism is impossible to define at this point, space 

 limitations permit only brief mention of their properties. Isomers of the natural pu- 

 rines in which the nitrogen and carbon in position 7 and 8 have been interchanged to 



319 G. B. Elion, H. Vander Werff, G. H. Hitchings, M. E. Balis, D. H. Levin, and G. 

 B. Brown, J. Biol. Chem. 200, 7 (1953). 



320 G. B. Elion, S. Singer, G. H. Hitchings, M. E. Balis, and G. B. Brown, J. Biol. 

 Chem. 202, 647 (1953). 



321 Z. Miller and L. Warren, J. Biol. Chem. 205, 331 (1953). 



322 \y q Werkheiser, R. J. Winzler, and D. W. Visser, Cancer Research 15, 641 

 (1955). 



323 W. C. Werkheiser and D. W. Visser, Cancer Research 15, 644 (1955). 



324 H. E. Skipper and F. M. Schabel, Jr., Arch. Biochem. Biophys. 40, 476 (1952). 



325 H. E. Skipper, F. M. Schabel, Jr., V. Binns, J. R. Thomson, and G. P. Wheeler, 

 Cancer Research 15, 143 (1955). 



