Mononuclear nonheme iron(II) enzymes abstract hydrogen (H●) from unactivated aliphatic carbon centers to initiate hydroxylation, halogenation, desaturation, cyclization, endoperoxidation, epimerization, ring-expansion, and C–C-coupling/fragmentation reactions (some examples are shown in the Scheme). Available evidence suggests that a largely conserved intermediate, containing a variably coordinated Fe(III) cofactor and substrate carbon radical (C●), decays by multiple divergent pathways, involving: radical coupling of the C● with an Fe(III) ligand (OH or L) to form a new C–O/L bond; transfer of a second H● from an adjacent carbon to form an olefin; anchimerically assisted electron transfer to produce a formal carbocation that reacts as an acid or electrophile, leading to desaturation or heterocyclization; transfer of H● to the C●, but on the opposite face of the original C–H bond; addition of O2 to the radical to form a reactive peroxyl radical; or addition of the C● to an olefin to produce a new C–C bond and migrate the radical (which then reacts via one of the other possible steps). By (i) mapping these reaction pathways, (ii) solving and comparing structures of “resting” states, stable mimics of intermediate states, and the reactive intermediates themselves, and (iii) altering sequences/structures (both rationally and randomly) to alter outcomes, we aim to define the structural and dynamical bases for selection of a particular pathway by individual members of this large enzyme family. I will present our most recent analysis of one or more of the less well-studied reactions catalyzed by these versatile enzymes.

Award Address (Nobel Laureate Signature Award for Graduate Education in Chemistry sponsored by Avantor). Mechanistic and structural analysis of how nonheme-iron enzymes direct different oxidation reactions

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