DFT and ONIOM(DFT:MM) computational studies of myo-inositol oxygenase: Insights into the (superoxo)diiron(III/III) intermediate and reaction mechanism

COMP 20

Hajime Hirao, hirao@euch4e.chem.emory.edu and Keiji Morokuma, morokuma@fukui.kyoto-u.ac.jp. Fukui Institute for Fundamental Chemistry, Kyoto University, 34-4 Takano Nishihiraki-cho, Sakyo-ku, 606-8103 Kyoto, Japan
Accumulated evidence indicates that depletion of the intracellular level of myo-inositol is associated with various diabetic complications such as nephropathy, retinopathy, neuropathy, and cataract. A nonheme diiron enzyme myo-inositol oxygenase (MIOX) catalyzes the oxidative conversion of myo-inositol to D-glucuronate, which is the first committed step in myo-inositol catabolism. MIOX has thus been implicated to play a critical role in the pathogenesis of those diabetic diseases. Recently, significant progress has been made experimentally in understanding the mechanistic, electronic, and structural details of MIOX. However, many fundamental aspects of the enzyme, particularly those which are not readily tractable by experimental means, still remain unclear. We therefore performed computational studies using density functional theory and hybrid ONIOM(DFT:MM) methods. Our calculations provided new insights into the (superoxo)diiron(III/III) intermediate formation and subsequent substrate oxidation reaction. The effect of protein environment on these events was found to be important.