A density functional investigation of the extradiol cleavage mechanism in non-heme iron catechol dioxygenases

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Abstract
The mechanism for extradiol cleavage in non-heme iron catechol dioxygenase was modelled theoretically via density functional theory. Based on the FeII-His,His,Glu motif observed in enzymes, an active site model complex, [Fe(acetate)(imidazole)2(catecholate)(O2)]−, was optimized for states with six, four and two unpaired electrons (U6, U4 and U2, respectively). The transfer of the terminal atom of the coordinated dioxygen leading to "ferryl" Fe=O intermediates spontaneously generates an extradiol epoxide. The computed barriers range from 19 kcal mol−1 on the U6 surface to ~25 kcal mol−1 on the U4 surface, with overall reaction energies of +11.6, 6.3 and 7.1 kcal mol−1 for U6, U4 and U2, respectively. The calculations for a protonated process reveal the terminal oxygen of O2 to be the thermodynamically favoured site but subsequent oxygen transfer to the catechol has a barrier of ~30–40 kcal mol−1, depending on the spin state. Instead, protonating the acetate group gives a slightly higher energy species but a subsequent barrier on the U4 surface of only 7 kcal mol−1 relative to the hydroperoxide complex. The overall exoergicity increases to 13 kcal mol−1. The favoured proton-assisted pathway does not involve significant radical character and has features reminiscent of a Criegee rearrangement which involves the participation of the aromatic ring π-orbitals in the formation of the new carbon-oxygen bond. The subsequent collapse of the epoxide, attack by the coordinated hydroxide and final product formation proceeds with an overall exoergicity of ~75 kcal mol−1 on the U4 surface.

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