Transition State Structure Modeling and Mechanistic Study of Purine Derivatives

Abstract

Xanthine oxidase is one of the members of molybdo-enzymes known to catalyze the oxidative hydroxylation of various purine derivatives. The mechanistic transformation of the tetrahedral Michaelis-Menten type complex ((EOX)-[Mo(VI)-Oeq-CCRH]) to the product bound intermediate ((EOX)-[Mo(IV)-Oeq-CCR]) is expected to pass through the tetrahedral transition state complex ((EOX)-[Mo(VI)(-Oeq-CCRH---HRH---)(=SMo)]#). Although several accounts are made regarding the events taking place at the transition state, they have never been fully explored nor quite understood. Similarly, the description of the formation of Oeq-CCRH bond, cleavage of CCRH-HRH bond, migration of HRH to SMo terminal, and reduction of (EOX)-Mo(VI) to (ERED)-Mo(IV) was not well understood. In order to understand the events taking place during catalysis, new computational models have been used to perform an electronic structure calculation. The calculations were performed on the active site model compound bound to purine derivatives, mainly 2-hydroxy-6-methyl purine (HMP) that has never been investigated computationally. The transition state modeling also reveals a reactant like transition state for the reaction of HMP with the active site. Understanding the transition state geometry is a prime importance in developing a plausible reaction mechanism. From the four alternative paths, path one has small energy barrier compare to the three alternative paths. Understanding the mechanism may be used in the drug design process. From our mechanistic study HMP favor concerted mechanism rather than step wise mechanism.