High-valent non-heme iron–oxo intermediates have been proposed for decades as the key intermediates in numerous biological oxidation reactions. In the past three years, the first direct characterization of such intermediates has been provided by studies of several αKG-dependent oxygenases that catalyze either hydroxylation or halogenation of their substrates. In each case, the Fe(IV)–oxo intermediate is implicated in cleavage of the aliphatic C–H bond to initiate hydroxylation or halogenation. The observation of non-heme Fe(IV)–oxo intermediates and Fe(II)-containing product(s) complexes with almost identical spectroscopic parameters in the reactions of two distantly related αKG-dependent hydroxylases suggests that members of this subfamily follow a conserved mechanism for substrate hydroxylation. In contrast, for the αKG-dependent non-heme iron halogenase, CytC3, two distinct Fe(IV) complexes form and decay together, suggesting that they are in rapid equilibrium. The existence of two distinct conformers ...

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Non-heme Fe(IV)-oxo intermediates.

High-valent iron in chemical and biological oxidations.

Iron-containing enzymes are one of Nature’s main means of effecting key biological transformations. The mononuclear non-heme iron oxygenases and oxidases have received the most attention recently, primarily because of the recent availability of crystal structures of many different enzymes and the stunningly diverse oxidative transformations that these enzymes catalyze. The wealth of available structural data has furthermore established the so-called 2-His-1-carboxylate facial triad as a new common structural motif for the activation of dioxygen. This superfamily of mononuclear iron(II) enzymes catalyzes a wide range of oxidative transformations, ranging from the cis-dihydroxylation of arenes to the biosynthesis of antibiotics such as isopenicillin and fosfomycin. The remarkable scope of oxidative transformations seems to be even broader than that associated with oxidative heme enzymes. Not only are many of these oxidative transformations of key biological importance, many of these selective oxidations are also unprecedented in synthetic organic chemistry. In this critical review, we wish to provide a concise background on the chemistry of the mononuclear non-heme iron enzymes characterized by the 2-His-1-carboxylate facial triad and to discuss the many recent developments in the field. New examples of enzymes with unique reactivities belonging to the superfamily have been reported. Furthermore, key insights into the intricate mechanistic details and reactive intermediates have been obtained from both enzyme and modeling studies. Sections of this review are devoted to each of these subjects, i.e. the enzymes, biomimetic models, and reactive intermediates (225 references).

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Mononuclear non-heme iron enzymes with the 2-His-1-carboxylate facial triad: recent developments in enzymology and modeling studies.

Oxoiron(IV) species are often implicated in the catalytic cycles of oxygen-activating non-heme iron enzymes. The paucity of suitable model complexes stimulated us to fill this void, and our synthetic efforts have afforded a number of oxoiron(IV) complexes. This Account provides a chronological perspective of the observations that contributed to the generation of the first non-heme iron(IV)-oxo complexes in high yield and summarizes their salient properties to date.

The Road to Non-Heme Oxoferryls and Beyond †

High-valent nonheme iron-oxo complexes: Synthesis, structure, and spectroscopy

The iron(II)- and α-ketoglutarate-dependent dioxygenases comprise enzymes that catalyze a variety of important reactions in biology, including steps in the biosynthesis of collagen and antibiotics, the degradation of xenobiotics, the repair of alkylated DNA, and the sensing of oxygen and response to hypoxia. In these reactions, the reductive activation of oxygen is coupled to hydroxylation of the substrate and decarboxylation of the co-substrate, α-ketoglutarate. It is believed that a single, conserved mechanistic pathway for formation of a high-valent iron intermediate that attacks the substrate is operant in all members of this family. Application

Mechanism of Taurine: α-Ketoglutarate Dioxygenase (TauD) from Escherichia coli

The flavin-dependent halogenase RebH catalyzes chlorination at the C7 position of tryptophan as the initial step in the biosynthesis of the chemotherapeutic agent rebeccamycin. The reaction requires reduced FADH2 (provided by a partner flavin reductase), chloride ion, and oxygen as cosubstrates. Given the similarity of its sequence to those of flavoprotein monooxygenases and their common cosubstrate requirements, the reaction of FADH2 and O2 in the halogenase active site was presumed to form the typical FAD(C4a)−OOH intermediate observed in monooxygenase reactions. By using stopped-flow spectroscopy, formation of a FAD(C4a)−OOH intermediate was detected during the RebH reaction. This intermediate decayed to yield a FAD(C4a)−OH intermediate. The order of addition of FADH2 and O2 was critical for accumulation of the FAD(C4a)-OOH intermediate and for subsequent product formation, indicating that conformational dynamics may be important for protection of labile intermediates formed during the reaction. Format...

J. Martin Bollinger

Papers

Mechanism of Taurine: α-Ketoglutarate Dioxygenase (TauD) from Escherichia coli

Flavin redox chemistry precedes substrate chlorination during the reaction of the flavin-dependent halogenase RebH.

Supplementary Materials for Mechanism of the C5 Stereoinversion Reaction in the Biosynthesis of Carbapenem Antibiotics

Mechanism of Taurine: α-Ketoglutarate Dioxygenase (TauD) from Escherichia coli