Several chronic ailments stem from the body?s inability to catabolize or excrete excess oxalic acid, including kidney stones and potentially fatal primary hyperoxaluria. Future treatment methods could include the use of enzymes from other organisms to digest oxalate into molecules that are more easily metabolized and excreted. Two such enzymes are an oxalate decarboxylase that transmutes oxalate into formate and carbon dioxide, and oxalate oxidase that produces carbon dioxide and hydrogen peroxide from oxalate and oxygen. Both enzymes contain manganese, and the decarboxylases appear to be a genetic duplication of the oxidases. How duplication leads to a change in overall reaction is currently mysterious. This project seeks to establish procedures by which the catalytic and structural properties of these oxalate-degrading enzymes may be calculated from first principles. Density functional, semi-empirical, and free energy perturbation-molecular dynamics methods will be used to calculate geometries, EPR hyperfine coupling parameters, ultraviolet-visible spectra, and reduction potentials of a variety of Mn (II/III) complexes with oxygen and/or nitrogen ligation. The method will be tested on the active site of superoxide dismutase, an enzyme with extensive experimental data available and identical ligands to those of oxalate oxidase. Methods developed for the dismutase active site will be valuable once the decarboxylase structure becomes known.
| Chang, Christopher H; Boone, Amy J; Bartlett, Rodney J et al. (2004) Toward a computational description of nitrile hydratase: studies of the ground state bonding and spin-dependent energetics of mononuclear, non-heme Fe(III) complexes. Inorg Chem 43:458-72 |
| Chang, Christopher H; Svedruzic, Drazenka; Ozarowski, Andrzej et al. (2004) EPR spectroscopic characterization of the manganese center and a free radical in the oxalate decarboxylase reaction: identification of a tyrosyl radical during turnover. J Biol Chem 279:52840-9 |
| Reinhardt, Laurie A; Svedruzic, Drazenka; Chang, Christopher H et al. (2003) Heavy atom isotope effects on the reaction catalyzed by the oxalate decarboxylase from Bacillus subtilis. J Am Chem Soc 125:1244-52 |
