284 2. ANALOGS OF ENZYME REACTION COMPONENTS 



studied by Mahler et at. (1956) (see tabulation) and the results give some 

 information on the nature of the binding to the active site. Three binding 

 sites were recognized: (1) a cationic group binding the 2-substituent, 



(2) a neutral group binding the 8-substituent, and (3) the copper which 

 chelates with the 6- substituent and the 7-N atom. It is difficult to under- 

 stand on this basis the high affinity of the trichlorourate for the enzyme, 

 since one would predict that substitution of chlorine in the 2-position would 

 reduce binding to the cationic group and substitution in the 6-position would 

 interfere with the chelation. The increased binding produced by chlorine 

 substitution might be in part the result of a stabilization of conjugative 

 resonance and an increased hydrogen bonding (and perhaps an increased 

 chelation of two N atoms with the copper). Also resonance with structures 

 in which one or more of the chlorine atoms are in the form 



C1+ 



— N-— C— 



would produce strong dipoles. The most potent inhibitor apparently is 

 6-chloro-2,8-dihydroxy purine (usually misnamed 6-chlorourate), which is 



