288 2. ANALOGS OF ENZYME REACTION COMPONENTS 



0.1 niM, and hence the true potency of the inhibition has been somewhat 

 obscured. Pterin-6-aldehyde is actually oxidized very slowly by xanthine 

 oxidase and reversal of the inhibition develops gradually. The oxidations 

 of aldehydes (Kalckar et al., 1950) and sulfite (Fridovich and Handler, 

 1957) by xanthine oxidase are also inhibited by pterin-6-aldehyde, but the 

 oxidation of NADH is not affected (Lowry et al., 1949 b). 



Although it has generally been stated that the inhibition by pterin-6- 

 aldehyde is competitive, the Ijv — 1/(S) plots are not linear (Bradshaw 

 and Barker, 1960), and others (Hofstee, 1949) have presented only quali- 

 tative evidence for competition. Deviations from the classic kinetics might 

 be expected because of the mutual depletion of free enzyme and inhibitor 

 concentrations, the difficulty in achieving true equilibrium, and the oxida- 

 tive removal of the inhibitor. There is no evidence against a competitive 

 mechanism, however, and competition has been more clearly demonstrated 

 for some other pteridines. 



The inhibition by pterin-6-aldehyde is quite specific although it must 

 be admitted that not many enzymes have been tested. Uricase, glucose 

 oxidase, and 3-phosphoglyceraldehyde dehydrogenase are not affected, but 

 the quinine oxidase of liver is inhibited (Kalckar et al. 1950; Villela, 1963). 

 Mouse liver guanase, using 8-azaguanine as a substrate, is inhibited but 

 not potently when the substrate is 11 mM and 30-min preincubation is 

 allowed (see accompanying tabulation) (Shapiro et al., 1952). In fact, 



Pterin-b-aldehyde n, n ■ i i x- 



/n Guanase inhibition 

 (mi/) 



1 32 



6 62 



11 80 



16 88 



xanthopterin is a more potent and more rapidly acting inhibitor (Dietrich 

 and Shapiro, 1953 b). Pterin-6-aldehyde is not carcinostatic itself, but 

 potentiates the action of 8-azaguanine and a suppression of 8-azaguanine 

 destruction was claimed as the mechanism, although the relatively low 

 inhibitory potency coupled with the low doses (20 mg/kg) necessary makes 

 it difficult to accept this explanation. Byers (1952) investigated the effects 

 of pterin-6-aldehyde injections in rats (200 mg/kg intraperitoneally) on 

 the tissue urate levels and found no significant changes, which might in- 

 dicate a rapid destruction of the inhibitor in the animal. Daily injections 

 of 30 //g pterin-6-aldehyde in chicks also does not alter liver xanthine oxi- 

 dase activity despite the potent inhibition in vitro (Dietrich et al., 1952). 

 Other pteridines, although less potent than pterin-6-aldehyde, are nev- 



