39. ANTIMETABOLITES AND NUCLEIC ACID METABOLISM 489 



azaguanine appeared to be a competitive inhibitor of the incorporation of 

 guanine; this was indicated by experiments in which guanine was effective 

 in overcoming the inhibition produced by this analog. However, subse- 

 quent studies have shown that its effects are more complicated and prob- 

 ably are related to the action of the nucleotide derivatives of azaguanine. 

 The noninhibitory nature of 9-ethyl-8-azaguanine, a compound substituted 

 at the normal point of ribose attachment, would tend to support this con- 

 cept. 179 The formation of nucleotides was implied by the discovery of this 

 analog in the nucleic acids of mice treated with azaguanine, 251 ' 252 a finding 

 which has been extended to viruses, 253 " 255 plants, 255 microorganisms, 255 " 258 

 and animal tumors. 252, 257, 259 The extent of incorporation into DNA appears 

 to be very small, 251, 252 while that into RNA is usually less than 5 % of the 

 total guanine (an exception is found in Bacillus cereus, in which up to 40 % 

 of the guanine of the RNA may be replaced by azaguanine under appropri- 

 ate conditions 255 ). That incorporation into RNA was not the result of purine 

 exchange was established by the isolation of azaguanine ribonucleoside 

 from the medium, after additional growth of a culture of B. cereus (previ- 

 ously treated with the analog) in the presence of the reversing agent, 

 guanosine. 260 



The form of the incorporated analog has been clearly verified by the iso- 

 lation and characterization of the mixed 2'- and 3'-phosphates of azaguano- 

 sine following alkaline digestion of the RNA. 253, 257 ' 261 Data obtained by 

 analysis of RNA from B. cereus fractionated by ethanol, dialysis, or en- 



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