The Amazing High-Valent Nonheme Iron-Oxo Landscape

Over the past 25 years, a-ketoglutarate (aKG)-dependent enzymes with mononuclear nonheme iron centers that activate dioxygen have emerged as a versatile family of enzymes involved in a variety of important metabolic transformations as well as in the biosynthesis of antibiotics. These enzymes are capable of C–H bond hydroxylation, halogenation, and stereoinversion, C–C bond desaturation, and heterocyclic ring formation. Their active sites, as represented by taurine:aketoglutarate dioxygenase (TauD), generally consist of a 2-His-1-carboxylate facial triad that serves to bind the iron(II) center. In the nonheme iron halogenase enzymes, the carboxylate is replaced by a chloride or a bromide, which is the atom that is incorporated into the C–H bond. Reaction of the reduced enzymes with O2 leads to the generation of highvalent oxoiron intermediates responsible for the critical C– H cleavage step (Scheme 1). Such species have been trapped by Bollinger and Krebs for several enzymes in this family and demonstrated to have a high-spin S = 2 Fe=O unit that is kinetically competent to cleave the C–H bonds of their respective substrates with large nonclassical H/D kinetic isotope effects.