The Specificity of Purine Derivatives towards Xanthine Oxidase Enzyme and the Factors Affecting the Enzyme Catalyzed Reaction

Resumen

Xanthine oxidase (XO) is a molybdenum-containing enzyme catalyzing the hydroxylation of a sp2-hybridized carbon in a broad range of aromatic heterocycles and aldehydes. Further, it is a key enzyme in the last two steps of purine metabolism. Thus, the need for an understanding and developing unified reaction mechanism to minimize the amount of accumulated uric acid inside human body has led us to the present detailed study of the reaction of XO with purine derivatives. In addition to its obscure mechanism of action that has been studied experimentally with purines and related analogues substrates, it is not also yet investigated computationally with these substrates. During catalytic transformation of substrates to their products, many factors are simulated to affect the mechanism of action that pass through different intermediates in the catalytic cycle. Accordingly, the study was particularly intended to identify the factors affecting the binding stage of catalysis and look forward to the role of active binding pocket amino acids in providing proper orientation to the substrates for nucleophilic reaction to take place. Gaussian 03W (version 6.0) program software package using density functional theory (DFT) method of the B3LYP correlation functional formalism was used. The calculated results of Mulliken atomic charge and total energy has been provided link to the factors regarding the orientation of substrates, role of binding pocket amino acid residues, polarity effect and selectivity of the interaction sites. In light of this, there was no clear cut relation between the charge distribution and reactivity of substrates. On top of this, the role of amino acids on proper orientation of substrates is deduced as the primary factor on selectivity and reactivity of heterocyclic substrates in XO enzyme family. On the other side, energy barrier was related to the reactivity of the substrates. This research is applicable in analysis of substrate specificities which is aimed at providing the role of bringing pocket amino acid residues in recognition of heterocyclic substrate for proper orientation in a nucleophilic hydroxylation reaction that simulated to give insights into the potential physiological roles of these enzymes.  Keywords: purine derivatives, xanthine oxidase (XO), xanthine oxidoreductase (XOR)Cite this Article Gereziher G, Gebremeskel G, Berhane A. The Specificity of Purine Derivatives towards Xanthine Oxidase Enzyme and the Factors Affecting the Enzyme Catalyzed Reaction. Research & Reviews: A Journal of Life Sciences. 2016; 6(2): 28–44p.