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We report the macrocyclic ring size-electronic structure-electrophilic reactivity correlation of mononuclear nonheme iron(III)-peroxo complexes bearing N -tetramethylated cyclam analogues ( n -TMC), [Fe III (O 2 )(12-TMC)] + ( 1 ), [Fe III (O 2 )(13-TMC)] + ( 2 ), and [Fe III (O 2 )(14-TMC)] + ( 3 ), as a model study of Rieske oxygenases. The Fe(III)-peroxo complexes show the same δ and pseudo-σ bonds between iron and the peroxo ligand. However, the strength of these interactions varies depending on the ring size of the n -TMC ligands; the overall Fe-O bond strength and the strength of the Fe-O 2 δ bond increase gradually as the ring size of the n -TMC ligands becomes smaller, such as from 14-TMC to 13-TMC to 12-TMC. MCD spectroscopy plays a key role in assigning the characteristic low-energy δ → δ* LMCT band, which provides direct insight into the strength of the Fe-O 2 δ bond and which, in turn, is correlated with the superoxo character of the iron-peroxo group. In oxidation reactions, reactivities of 1 - 3 toward hydrocarbon C-H bond activation are compared, revealing the reactivity order of 1 > 2 > 3 ; the [Fe III (O 2 )( n -TMC)] + complex with a smaller n -TMC ring size, 12-TMC, is much more reactive than that with a larger n -TMC ring size, 14-TMC. DFT analysis shows that the Fe(III)-peroxo complex is not reactive toward C-H bonds, but it is the end-on Fe(II)-superoxo valence tautomer that is responsible for the observed reactivity. The hydrogen atom abstraction (HAA) reactivity of these intermediates is correlated with the overall donicity of the n -TMC ligand, which modulates the energy of the singly occupied π* superoxo frontier orbital that serves as the electron acceptor in the HAA reaction. The implications of these results for the mechanism of Rieske oxygenases are further discussed.

Mononuclear nonheme iron enzymes catalyze a large variety of oxidative transformations responsible for various biosynthesis and metabolism processes. Unlike their P450 counterparts, non-heme enzymes generally possess flexible and variable coordination architecture, which can endow rich reactivity for non-heme enzymes. This Concept highlights that the coordination dynamics of iron can be a key player in controlling the activity and selectivity of non-heme enzymes. In ergothioneine synthase EgtB, the coordination switch of the sulfoxide radical species enables the efficient and selective C-S coupling reaction. In iron(II)- and 2-oxoglutarate-dependent (Fe/2OG) oxygenases, the conformational flip of ferryl-oxo intermediate can be extensively involved in selective oxidation reactions. Especially, the five-coordinate ferryl-oxo species may allow the substrate coordination via O or N atom, which may facilitate the C-O or C-N coupling reactions via stabilizing the transition states and inhibiting the unwanted hydroxylation reactions., (© 2023 Wiley-VCH GmbH.)

Methanobactins (Mbns) are a family of copper-binding peptides involved in copper uptake by methanotrophs, and are potential therapeutic agents for treating diseases characterized by disordered copper accumulation. Mbns are produced via modification of MbnA precursor peptides at cysteine residues catalyzed by the core biosynthetic machinery containing MbnB, an iron-dependent enzyme, and MbnC. However, mechanistic details underlying the catalysis of the MbnBC holoenzyme remain unclear. Here, we present crystal structures of MbnABC complexes from two distinct species, revealing that the leader peptide of the substrate MbnA binds MbnC for recruitment of the MbnBC holoenzyme, while the core peptide of MbnA resides in the catalytic cavity created by the MbnB-MbnC interaction which harbors a unique tri-iron cluster. Ligation of the substrate sulfhydryl group to the tri-iron center achieves a dioxygen-dependent reaction for oxazolone-thioamide installation. Structural analysis of the MbnABC complexes together with functional investigation of MbnB variants identified a conserved catalytic aspartate residue as a general base required for MbnBC-mediated MbnA modification. Together, our study reveals the similar architecture and function of MbnBC complexes from different species, demonstrating an evolutionarily conserved catalytic mechanism of the MbnBC holoenzymes., (© 2022. The Author(s).)

This article addresses the intriguing hydrogen-abstraction (H-abstraction) and oxygen-transfer (O-transfer) reactivity of a series of nonheme [Fe(IV)(O)(TMC)(Lax)](z+) complexes, with a tetramethyl cyclam ligand and a variable axial ligand (Lax), toward three substrates: 1,4-cyclohexadiene, 9,10-dihydroanthracene, and triphenyl phosphine. Experimentally, O-transfer-reactivity follows the relative electrophilicity of the complexes, whereas the corresponding H-abstraction-reactivity generally increases as the axial ligand becomes a better electron donor, hence exhibiting an antielectrophilic trend. Our theoretical results show that the antielectrophilic trend in H-abstraction is affected by tunneling contributions. Room-temperature tunneling increases with increase of the electron donation power of the axial-ligand, and this reverses the natural electrophilic trend, as revealed through calculations without tunneling, and leads to the observed antielectrophilic trend. By contrast, O-transfer-reactivity, not being subject to tunneling, retains an electrophilic-dependent reactivity trend, as revealed experimentally and computationally. Tunneling-corrected kinetic-isotope effect (KIE) calculations matched the experimental KIE values only if all of the H-abstraction reactions proceeded on the quintet state (S = 2) surface. As such, the present results corroborate the initially predicted two-state reactivity (TSR) scenario for these reactions. The increase of tunneling with the electron-releasing power of the axial ligand, and the reversal of the "natural" reactivity pattern, support the "tunneling control" hypothesis (Schreiner et al., ref 19). Should these predictions be corroborated, the entire field of C-H bond activation in bioinorganic chemistry would lay open to reinvestigation.

The high‐resolution X‐ray crystal structure of the ternary complex FtmOx1 ⋅ 2OG ⋅ fumitremorgin B and the catalytic mechanism were recently reported by us (DOI 10.1002/anie.202112063). In their Correspondence, Zhang, Costello, Liu et al. criticize our work in several aspects. Herein, we address these questions one by one. These structural clarifications and new computational results further support the CarC‐like mechanistic model. [ABSTRACT FROM AUTHOR]

The non‐heme iron ergothioneine synthase (EgtB) is a sulfoxide synthase that catalyzes oxidative C−S bond formation in the synthesis of ergothioneine, which plays roles against oxidative stress in cells. Despite extensive experimental and computational studies of the catalytic mechanisms of EgtB, the root causes for the selective C−S bond formation remain elusive. Using quantum mechanics/molecular mechanics (QM/MM) calculations, we show herein that a coordination switch of the sulfoxide intermediate is involved in the catalysis of the non‐heme iron EgtB. This coordination switch from the S to the O atom is driven by the S/π electrostatic interactions, which efficiently promotes the observed stereoselective C−S bond formation while bypassing cysteine dioxygenation. The present mechanism is in agreement with all available experimental data, including regioselectivity, stereoselectivity and KIE results. This match underscores the critical role of coordination switching in the catalysis of non‐heme enzymes. [ABSTRACT FROM AUTHOR]

QM/MM and MM MD simulations are used to explore the biodegradation mechanism of 2-oxoadiapte (2OA) to D-2-hydroxyglutarate (D-2HG) by hydroxyglutarate synthase (HglS), which is the last step of lysine catabolism. The coordination dynamics of iron center and the secondary sphere residues are play key roles in this process. [Display omitted] • QM/MM study revealed two coordination modes of the Fe(IV)-oxo species during the reactions of HglS. • The conformational switch of the "distal" Fe(IV)-oxo species to the "proximal" Fe(IV)-oxo conformation was found to be essential for the C–H bond activation by HgIS. • The study provides a novel mechanistic picture for the C–H bond activation by the non-heme family. Hydroxyglutarate synthase (HglS) from Pseudomonas putida is an iron (II) dependent non-heme oxygenase, which is responsible for the biodegradation of 2-oxoadipate (2OA) to D-2-hydroxyglutarate (D-2HG) in plant lysine catabolism. Here detailed mechanisms for the chemical steps involved in decarboxylation and hydroxylation in the biodegradation of 2OA have been explored by extensive MD simulations and QM/MM calculations. Our study revealed the existence of two coordination modes of the Fe(IV)-oxo species during the reactions of HglS, and the "proximal" one is responsible for the C–H bond activation. The reaction initiates with the attack of Fe(III)-superoxo species on 2OA, resulting in the FeII-O-O-2OA species. After the release of CO 2 and the subsequent O-O cleavage, the reactions lead to the "distal" Fe(IV)-oxo species. This species can undergo a coordination switch to evolve into the "proximal" conformation of Fe(IV)-oxo, which is the rate-limiting step with an energy barrier of 20.6 kcal/mol. Moreover, residues in the second coordination sphere, including Arg74, Gln266, Val402, and Ser403, not only strengthen the substrate binding but also facilitate the ferryl-flip, leading to the "proximal" Fe(IV)-oxo conformation that is ideal for the C–H bond activation. These findings may expand our understanding of the coordination dynamics of the iron center in HglS enzyme, which has general implications for other non-heme oxygenases. [ABSTRACT FROM AUTHOR]