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A Kinetic Comparison on the Inhibition of Adenosine Deaminase by Purine Drugs

The effects of allopurinol, acyclovir and theophylline on the activity of adenosine deaminase (ADA) were studied in 50 mM sodium phosphate buffer pH 7.5 at 27 °C, using a UV– Vis spectrophotometer. Adenosine deaminase is inhibited by these ligands, via different types of inhibition. Allopurinol, as a transition state analog of xanthine oxidase, and acyclovir competitively inhibit the catalytic activity of ADA. Inhibition constant values are 285 and 231 µM for allopurinol and acyclovir, respectively. Theophylline acts as a non-competitive inhibitor for ADA, which shows different affinity binding sites at various drug concentrations. There were two different types of inhibition constant, one of them due to a low concentration of the drug (K i = 56 μM) and the other appearing at higher concentrations of theophylline (K i = 201 μM). Thermodynamic parameters also show that ADA has two binding sites for theophylline. The comparison of inhibition constant for inosine (K i = 143 μM) and acyclovir (K i = 231 μM) elucidates the critical role of the ribose ring within the inosine structure, relative to the open ring of acyclovir. Comparison of the inhibition constant of theobromine (K i = 311 μM) with inosine (K i = 143 μM) shows the critical binding role of N 7 position within the purine ring. Interestingly, the N 7 position in allopurinol is replaced by a CH 2 group, which demonstrates the lower inhibiting potency of allopurinol (K i = 285 μM) relative to inosine (K i = 143 μM). In a structural sense, a comparison made between the structure of theophylline and theobromine besides a comparison between the inhibition constant of theophylline (K i = 56 μM at low and 201 μM at higher concentrations) and caffeine (K i = 342 μM) indicate that substitution of a bulky group in N 1 and N 7 positions of purine has a critical role in the binding affinity of the above- mentioned inhibitors to the enzyme.