Local Electric Fields As a Natural Switch of Heme-Iron Protein Reactivity

Heme-iron oxidoreductases operating through the high-valent Fe IV O intermediates perform crucial and complicated transformations, such as oxidations of unreactive saturated hydrocarbons. These enzymes share the same Fe coordination, only differing by the axial ligation, e.g., Cys in P450 oxygenases, Tyr in catalases, and His in peroxidases. By examining ~200 heme-iron proteins, we show that the protein hosts exert highly specific intramolecular electric fields on the active sites, and there is a strong correlation between the direction and magnitude of this field and the protein function. In all heme proteins, the field is preferentially aligned with the Fe-O bond ( F z ). The Cys-ligated P450 oxygenases have the highest average F z of 28.5 MV cm -1 , i.e., most enhancing the oxyl-radical character of the oxo group, and consistent with the ability of these proteins to activate strong C-H bonds. In contrast, in Tyr-ligated proteins, the average F z is only 3.0 MV cm -1 , apparently suppressing single-electron off-pathway oxidations, and in His-ligated proteins, F z is -8.7 MV cm -1 . The operational field range is given by the trade-off between the low reactivity of the Fe IV O Compound I at the more negative F z , and the low selectivity at the more positive F z . Consequently, a heme-iron site placed in the field characteristic of another heme-iron protein class loses its canonical function, and gains an adverse one. Thus, electric fields produced by the protein scaffolds, together with the nature of the axial ligand, control all heme-iron chemistry.