Dioxygen activation at mononuclear nonheme iron active sites: enzymes, models, and intermediates.

In this review, primary attention is given to the antioxidant (and prooxidant) activity of polyphenols arising from their interactions with iron both in vitro and in vivo. In addition, an overview of oxidative stress and the Fenton reaction is provided, as well as a discussion of the chemistry of iron binding by catecholate, gallate, and semiquinone ligands along with their stability constants, UV–vis spectra, stoichiometries in solution as a function of pH, rates of iron oxidation by O2 upon polyphenol binding, and the published crystal structures for iron–polyphenol complexes. Radical scavenging mechanisms of polyphenols unrelated to iron binding, their interactions with copper, and the prooxidant activity of iron–polyphenol complexes are briefly discussed.

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A Review of the Antioxidant Mechanisms of Polyphenol Compounds Related to Iron Binding

FeII/alpha-ketoglutarate (alphaKG)-dependent hydroxylases catalyze an amazing diversity of reactions that result in protein side-chain modifications, repair of alkylated DNA/RNA, biosynthesis of antibiotics and plant products, metabolism related to lipids, and biodegradation of a variety of compounds. These enzymes possess a beta-strand "jellyroll" structural fold that contains three metal-binding ligands found in a His1-X-Asp/Glu-Xn-His2 motif. The cosubstrate, alphaKG, chelates FeII using its C-2 keto group (binding opposite the Asp/Glu residue) and C-1 carboxylate (coordinating opposite either His1 or His2). Oxidative decomposition of alphaKG forms CO2 plus succinate and leads to the generation of an FeIV-oxo or other activated oxygen species that hydroxylate the primary substrate. The reactive oxygen species displays alternate reactivity in related enzymes that catalyze desaturations, ring expansions, or ring closures. Other enzymes resemble the FeII/alphaKG-dependent hydroxylases in terms of protein structure or chemical mechanism but do not utilize alphaKG as a substrate. This review describes the reactions catalyzed by this superfamily of enzymes, highlights key active site features revealed by structural studies, and summarizes results from spectroscopic and other approaches that provide insights into the chemical mechanisms.

FeII/alpha-ketoglutarate-dependent hydroxylases and related enzymes.

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.

Although quite a familiar feature in high-valent manganese chemistry, the M(2)(mu-O)(2) diamond core motif has only recently been found in synthetic complexes for M=Cu or Fe. Structural and spectroscopic characterization of these more reactive Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) compounds has been possible through use of appropriately designed supporting ligands, low-temperature handling methods, and techniques such as electrospray ionization mass spectrometry and X-ray crystallography with area detector instrumentation for rapid data collection. Despite differences in electronic structures that have been revealed through experimental and theoretical studies, Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) cores exhibit analogously covalent metal-oxo bonding, remarkably congruent Raman and extended X-ray absorption fine structure (EXAFS) signatures, and similar tendencies to abstract hydrogen atoms from substrates. Core isomerization is another common reaction attribute, although different pathways are traversed; for Fe, bridge-to-terminal oxo migration has been discovered, while for Cu, reversible formation of an O-O bond to yield a peroxo isomer has been identified. Our understanding of biocatalysis has been enhanced significantly through the isolation and comprehensive characterization of the Cu(2)(mu-O)(2) and Fe(2)(mu-O)(2) complexes. In particular, it has led to the development of new mechanistic notions about how non-heme multimetal enzymes, such as methane monooxygenases, fatty acid desaturase, and tyrosinase, may function in the activation of dioxygen to catalyze a diverse array of organic transformations.

Bis(μ‐oxo)dimetal “Diamond” Cores in Copper and Iron Complexes Relevant to Biocatalysis

Iron-peroxo Fe(III)O2 and hydroperoxo Fe(III)OOH systems are important intermediates between the initial Fe(II)-dioxygen adduct and the “activated” form of the catalytic site in many mono-iron biomolecules. To the same peroxidic level correspond, in diiron enzymes, bridged peroxo Fe(III)-O-O-Fe(III) intermediates. This review is concerned with the preparation and spectroscopic characterization of such intermediates in non-heme chemical systems, the properties of the natural systems being quoted as references. Although none have been crystallized, it seems very likely that Fe(III)OOH systems present a η 1 - coordination mode for the hydroperoxo group. These Fe(III)OOH units have given clear signatures in UV-vis, resonance Raman and mass spectrometry. By EPR it was found that in Fe(III)OOH, the Fe(III) is low-spin (S = 1/2) and we propose here a simple rationalization of the characteristics of the EPR g-tensor. The electronic properties of the Fe(III)(η1-OOH) known so far, point toward a strong Fe-O bond and a weak O-O bond, in total agreement with the reactivity scheme implying a cleavage of the O-O bond to lead formally to a Fe(V)O unit. Alkylperoxo systems are also included in this review. Fe(III)-peroxo systems Fe(III)O2 have been prepared and described. They contain high-spin Fe(III) and those identified seem to be of the η 2 type. The Fe-O bond is weaker and the O-O one is stronger than in the Fe(III)OOH systems. The implication of these Fe(III)O2 units in catalysis is unclear. “Complementary” systems, such as Fe(III)(η 1-OO) or Fe(III)(η 2-OOH) have been evoked in publications but not identified spectroscopically. These systems certainly deserve to be actively looked for.

Characterization and Properties of Non-Heme Iron Peroxo Complexes

Characterization of a Nonheme Mononuclear Peroxoiron(III) Intermediate by UV/Vis and EPR Spectroscopy and Mass Spectrometry

Complexes of general formula [(TPA)Fe(R-Cat)]X·nS were synthesised with different catecholate derivatives and anions (TPA = tris(2-pyridylmethyl)amine, R-Cat2−
				= 4,5-(NO2)2-Cat2− denoted DNC2−; 3,4,5,6-Cl4-Cat2− denoted TCC2−; 3-OMe-Cat2−; 4-Me-Cat2− and X = BPh4−; NO3−; PF6−; ClO4−; S = solvent molecule). Their magnetic behaviours in the solid state show a general feature along the series, viz., the occurrence of a thermally-induced spin crossover process. The transition curves are continuous with transition temperatures ranging from ca. 84 to 257 K. The crystal structures of [(TPA)Fe(DNC)]X (X = PF6−; BPh4−) and [(TPA)Fe(TCC)]X·nS (X = PF6−; NO3− and n
				= 1, S = H2O; ClO4− and n
				= 1, S = H2O; BPh4− and n
				= 1, S = C3H6O) were solved at 100 (or 123 K) and 293 K. For those two systems, the characteristics of the [FeN4O2] coordination core and those of the dioxolene ligands appear to be consistent with a prevailing FeIII–catecholate formulation. This feature is in contrast with the large quantum mixing between FeIII–catecholate and FeII–semiquinonate forms recently observed with the more electron donating simple catecholate dianion. The thermal spin crossover process is accompanied by significant changes of the molecular structures as shown by the average variation of the metal–ligand bond distances which can be extrapolated for a complete spin conversion from ca. 0.123 to 0.156 A. The different space groups were retained in the low- and high-temperature phases.

Spin crossover of ferric complexes with catecholate derivatives. Single-crystal X-ray structure, magnetic and Mössbauer investigations.

Measurement of magnetic susceptibility with temperature of a powdered iron(III) catecholate complex clearly indicated a two-step spin-crossover process S=(1/2) S=5/2. The picture shows the plot of chi(M)T against temperature.

Ariane Jalila Simaan

Papers

Characterization and Properties of Non-Heme Iron Peroxo Complexes

Characterization of a Nonheme Mononuclear Peroxoiron(III) Intermediate by UV/Vis and EPR Spectroscopy and Mass Spectrometry

Spin crossover of ferric complexes with catecholate derivatives. Single-crystal X-ray structure, magnetic and Mössbauer investigations.

A Two-Step Spin Crossover in