Kinetic interaction of 5-AZA-2'-deoxycytidine-5'-monophosphate and its 5'-triphosphate with deoxycytidylate deaminase

RL Momparler, M Rossi, J Bouchard, C Vaccaro, LF Momparler and S Bartolucci

5-AZA-2'-deoxycytidine-5'-monophosphate (5-AZA-dCMP) was tested as a substrate, and 5-aza-2'-deoxycytidine-5'-triphosphate (5-AZA-dCTP) was tested as an allosteric effector of purified spleen dCMP deaminase. Graphic analysis of the velocity of deamination of 5-AZA-dCMP versus its concentration gave a hyperbolic curve in which the estimated apparent Km was 0.1 mM. Since this curve was not sigmoidal and 5-AZA- dCMP at low concentrations stimulated the rate of deamination of the natural substrate, dCMP, it was proposed that the binding of 5-AZA-dCMP to the allosteric enzyme dCMP deaminase induced the R form. At substrate saturation, the rate of deamination of dCMP was 100-fold greater than that of 5-AZA-dCMP. dTTP inhibited the deamination of 5- AZA-dCMP with first-order kinetics. This inhibition was reversed by either 5-AZA-dCTP or dCTP. However, dCTP alone produced only a weak activation of the deamination of 5-AZA-dCMP in comparison to the potent activation when dCMP was the substrate. 5-AZA-dCTP was just as effective as dCTP for the allosteric activation of the deamination of dCMP. These results indicate that dCMP deaminase can play an important role in the metabolism 5-aza-2'-deoxycytidine nucleotides and may possibly modulate some of the pharmacological activity of this antimetabolite.

Volume 25, Issue 3, pp. 436-440, 05/01/1984
Copyright © 1984 by American Society for Pharmacology and Experimental Therapeutics

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