Heme-iron oxidoreductases operating through the
high-valent Fe<sup>IV</sup>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 (<b><i>F<sub>z</sub></i></b>). The Cys-ligated P450
oxygenases have the highest average <b><i>F<sub>z</sub></i></b> of
28.5 MV cm<sup>-1</sup>, 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 <b><i>F<sub>z</sub></i></b> is
only 3.0 MV cm<sup>-1</sup>, apparently suppressing single-electron
off-pathway oxidations, and in His-ligated proteins, <b><i>F<sub>z</sub></i></b> is
–8.7 MV cm<sup>-1</sup>. The operational field range is given by the trade-off
between the low reactivity of the Fe<sup>IV</sup>O Compound I at the more
negative <b><i>F<sub>z</sub></i></b>, and the low selectivity at the more
positive <b><i>F<sub>z</sub></i></b>. 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.
Local Electric Fields As a Natural Switch of Heme-Iron Protein Reactivity
