Xanthine Oxidase Reactivity: A Proton-Release-Coupled Rate Acceleration
Peter Ilich, St. John’s College of Liberal Arts and Science, Department of Chemistry
Abstract: The range of reaction rates observed in, and the substrate profiles accepted by, Xanthine Oxidase and Aldehyde Oxidoreductase suggest that the first order chemical effects in the enzyme active site are determined by the intrinsic properties of the Mo-pterin center. The coincidence of the results of molecular modeling of Xanthine Oxidase reactivity, carried out with the enzyme models ranging from the 4-atom enedithiolate [Bray & Deeth, Inorg. Chem., 1996, 35, 5720] to a 36-atom fraction of the molybdopterin cofactor [Amano et al., J. Am. Chem. Soc., 2007, 129, 8138] to a 23357-atom morsel of a salty, wet protein [Merz et al., J. Am. Chem. Soc., 2009, 13, 4628], appears to corroborate this observation. Using a simplest enzyme model we have demonstrated that a consistent set of reaction parameters – the active site geometry and chirality, substrate orientation and coordination, electron density distribution - is obtained only when the Xanthine Oxidase : substrate reductive half reaction is modeled as a synchronous metathetic exchange. We now extend this paradigm by showing, firstly, that a significant rate acceleration of this reaction step can result from a proton-dissociative transition state, and secondly, that the first-order effect in this acceleration is due to the incipient acidity of a Mo-center Brønsted site rather than the pKa landscape of the active site peptide.