O₂ Activation by Non-Heme Iron Enzymes

Abstract

The non-heme Fe enzymes are ubiquitous in nature and perform a wide range of functions involving O2 activation. These had been difficult to study relative to heme enzymes; however, spectroscopic methods have now been developed that provide significant insight into the correlation of structure with function. This Current Topics article summarizes both the molecular mechanism these enzymes use to control O2 activation in the presence of cosubstrates and the oxygen intermediates these reactions generate. Three types of O2 activation are observed. First, non-heme reactivity is shown to be different from heme chemistry where a low-spin FeIII-OOH non-heme intermediate directly reacts with substrate. Also, two subclasses of non-heme Fe enzymes generate high-spin FeIV=O intermediates that provide both σ and π frontier molecular orbitals that can control selectivity. Finally, for several subclasses of non-heme Fe enzymes, substrate binding to the FeII site leads to the one electron reductive activation of O2 to an FeIII-superoxide capable of H-atom abstraction and electrophilic attack.

NRVS Studies of the Peroxide Shunt Intermediate in a Rieske Dioxygenase and Its Relation to the Native FeII O2 Reaction

“…1–3 The majority of these enzymes use an Fe II site ligated by a facial triad of two His residues and one Glu/Asp carboxylate residue, which remain 6-coordinate (6C) until the substrate and any necessary cofactors are present in the active site. 2,4,5 When these are all present, the active site becomes 5- coordinate (5C) through loss of a water ligand, allowing O 2 to bind to the Fe II site and become activated for reactivity.…”

“…2,4,5 When these are all present, the active site becomes 5- coordinate (5C) through loss of a water ligand, allowing O 2 to bind to the Fe II site and become activated for reactivity. 3 These NHFe II enzymes are divided into subclasses based on the source of the electrons used for the multielectron reduction of O 2 , the nature of the substrate, and whether a cofactor is required. 2 There has been much interest in characterizing the activated O 2 intermediates responsible for reacting with substrate.…”

Spectroscopic and Electronic Structure Study of ETHE1: Elucidating the Factors Influencing Sulfur Oxidation and Oxygenation in Mononuclear Nonheme Iron Enzymes

“…1–6 One subclass of these enzymes activates O 2 utilizing non redox active substrates, 7 and a growing number of these act on sulfur containing substrates including isopenicillin N-synthase (IPNS), cysteine dioxygenase (CDO), persulfide dioxygenase (ETHE1) and sulfoxide synthase (EgtB, OvoA). These enzymes perform different reactions, including sulfur oxidation (IPNS) and sulfur oxygenation (CDO, ETHE1).…”

“…7 We formed the {FeNO} 7 complexes without and with substrate and determined the new spectral features from the bound persulfide. Using DFT we were able to define the orientation of the persulfide bond relative to the other Fe ligands, and we described the persulfide-Fe III bond for comparison to the thiolate-Fe III bond defined for IPNS.…”

Assembly of a mononuclear ferrous site using a bulky aldehyde-imidazole ligand

“…For mononuclear non-heme iron sites, enzymatic functions include a variety of oxygen activating functions [7]. X-ray structures have established examples where mononuclear iron is bound to two, three, or four histidine ligands [2].…”