Theoretical Approximation to the Reaction Mechanism of Adenosine Deaminase

Abstract

AbstractA quantum chemistry‐based strategy has been used for obtaining correlations between electronic parameters and the relative activity of some adenosine analogues that are substrates of adenosine deaminase. A semi‐empirical method (MOPAC program using AM1 hamiltonian) has been used for designing a molecule, alternative to adenosine, and less expensive from a computational point of view. It has been demonstrated that 9‐hydroxymethyl‐adenine effectively mimics adenosine behaviour in terms of electronic characteristics of purine ring. The parameters studied were net charge on N1 and C6, global (∑Q) charge over pyrimidine and purine rings and orbital frontier parameters over C6 and N1. For analogues of adenosine and formycin in which ribose were substituted by a hydroxymethyl group, correlations between these parameters and the log Vm of reaction (collected from experimental data) with adenosine deaminase have been studied. The results indicate that there is an increase in the maximum rate of deamination Vm when the negative net charge over the pyrimidine and purine rings also increases. In view of the results obtained with different forms (neutral, protonated at N1 and hydroxylated at C6) of adenosine and formycin analogues it is suggested that the protonation at N1 is the rate limiting step of the reaction catalyzed by adenosine deaminase.