Abstract
Xanthine oxidase (XO) is an important molybdenum-containing enzyme catalyzing the hydroxylation of hypoxanthine to xanthine and xanthine to uricacid. The mechanistic action by which xanthine oxidase oxidizes purine derivatives is not well understood. A better understanding of the overall mechanism is supposed to enhance our ability to control the metabolic properties of potential drug molecules metabolized by this enzyme. In this work a model substrate, 2-Amino Xanthine has been used to study the mechanistic action of the enzyme. For this reason, the present theoretical work was intended to probe a unified mechanism for the oxidation of 2-Amino Xanthine by xanthine oxidase. Parameters like total electronic energy, Mulliken atomic charges, wave functions, and percent contribution of chemical fragments were generated using a DFT method employing B3LYP level of theory with 6-31G(d',p') basis set for nonmetals and LanL2DZ basis set for molybdenum. AOmix software package that employs single point energy output as an input file was employed for wave function and percent fragment analysis. From these result new reaction intermediates and plausible reaction mechanism root has been reported for reductive and oxidative half reaction using 2-Amino Xanthine as model substrate. In this work it can be concluded that a stepwise mechanistic route with hydrogen bonding reaction complex and active site resemble very rapid Mo (V) intermediate is most plausible.    Â
Highlights
Xanthine oxidase (XO) is a form of Xanthine oxidoreductase (XOR) enzyme which is a kind of molybdoflavoenzyme that catalyzes the oxidation of hypoxanthine to xanthine or xanthine to uric acid [Okamoto, Kusano and Nishino, (2013), Danijela, Kostić, Danica S
Parameters like total electronic energy, Mulliken atomic charges, wave functions, and percent contribution of chemical fragments were generated using a DFT method employing B3LYP level of theory with 6-31G(d',p') basis set for nonmetals and LanL2DZ basis set for molybdenum
Probing a plausible mechanistic route: The DFT method employing the B3LYP level of theory was applied on the truncated analogue of the reductive half reaction active site of XO bound to 2-Amino Xanthine (2AX)
Summary
Xanthine oxidase (XO) is a form of Xanthine oxidoreductase (XOR) enzyme which is a kind of molybdoflavoenzyme that catalyzes the oxidation of hypoxanthine to xanthine or xanthine to uric acid [Okamoto, Kusano and Nishino, (2013), Danijela, Kostić, Danica S. Understanding the reaction mechanism of xanthine oxidase enzyme is prime important since the enzyme is linked to the metabolism of different drugs [Alfaro, and Jones, (2008)]. Understanding whether the transition state structure resembles the substrate or product is a key indication whether the mechanism for XO mediated catalysis is substrate dependent or not. If this is the case, the reaction mechanism might follow stepwise or concerted paths depending on the substrate. The reaction stoichiometries of these enzymes are unique among other hydroxylation reactions catalyzed by mono-oxygenase enzymes Monoxygenase enzymes hydroxylate their substrates using the oxygen, derived from molecular oxygen (equation 1). Unlike the mono-oxygenase enzymes, the XOR enzymes use oxygen derived from water and generates a pair of reducing equivalents (equation 2) [Hille, Kim, and Hemann, (1993), Hille, (2006) and Choi, Stockert, Leimkuhler, Hille (2004)
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