Jump to main content
Jump to site search
PLANNED MAINTENANCE Close the message box

Scheduled maintenance upgrade on Thursday 4th of May 2017 from 8.00am to 9.00am (BST).

During this time our websites will be offline temporarily. If you have any questions please use the feedback button on this page. We apologise for any inconvenience this might cause and thank you for your patience.


Issue 13, 2009
Previous Article Next Article

Density-functional theory models of xanthine oxidoreductase activity: comparison of substrate tautomerization and protonation

Author affiliations

Abstract

The hydroxylation mechanism of the molybdoprotein xanthine oxidoreductase (XOR) has been modelled using density-functional theory. High activation barriers are often obtained for models of this enzyme due to the absence of factors that stabilize the accumulation of charge on the substrate at the transition state. Xanthine provides much lower barriers than small model substrates such as formamide or imidazole due to charge delocalization to centers which appear to interact with key residues in the protein. Of the two mechanisms of stabilization discussed in the literature—tautomerization and protonation of xanthine—density-functional theory calculations suggest that proton transfer from Glu1261 to N9 reduces the activation barrier by ∼30 kcal mol−1 and leads to an intuitive product complex. Further, similar values for the activation barriers of methyl xanthine isomers lead to the conclusion that the wide variation in rates for substituted purines is due to interactions with key residues in the active site. In addition, the transition state for oxidation of xanthine can be superimposed over the X-ray structure of inhibitor-bound XO with high correlation suggesting that the enzyme active site orients the substrate into the ideal position for reaction. The activation barriers for models of a hypothetical tungsten-substituted XO are predicted to be ∼10 kcal mol−1 higher in energy due to the higher reduction potential of the metal and unfavourable electrostatic interactions for the hydride transfer.

Graphical abstract: Density-functional theory models of xanthine oxidoreductase activity: comparison of substrate tautomerization and protonation

Back to tab navigation
Please wait while Download options loads

Supplementary files

Publication details

The article was received on 12 Dec 2008, accepted on 29 Jan 2009 and first published on 26 Feb 2009


Article type: Paper
DOI: 10.1039/B821878A
Citation: Dalton Trans., 2009, 2306-2314
  •   Request permissions

    Density-functional theory models of xanthine oxidoreductase activity: comparison of substrate tautomerization and protonation

    C. A. Bayse, Dalton Trans., 2009, 2306
    DOI: 10.1039/B821878A

Search articles by author