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

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