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  1. Abstract

    Ergothioneine (ESH) and ovothiol A (OSHA) are two natural thiol‐histidine derivatives. ESH has been implicated as a longevity vitamin and OSHA inhibits the proliferation of hepatocarcinoma. The key biosynthetic step of ESH and OSHA in the aerobic pathways is the O2‐dependent C−S bond formation catalyzed by non‐heme iron enzymes (e.g., OvoA in ovothiol biosynthesis), but due to the lack of identification of key reactive intermediate the mechanism of this novel reaction is unresolved. In this study, we report the identification and characterization of a kinetically competentS=1 iron(IV) intermediate supported by a four‐histidine ligand environment (three from the protein residues and one from the substrate) in enabling C−S bond formation in OvoA fromMethyloversatilis thermotoleran, which represents the first experimentally observed intermediate spin iron(IV) species in non‐heme iron enzymes. Results reported in this study thus set the stage to further dissect the mechanism of enzymatic oxidative C−S bond formation in the OSHA biosynthesis pathway. They also afford new opportunities to study the structure‐function relationship of high‐valent iron intermediates supported by a histidine rich ligand environment.

     
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  2. Abstract

    Hydrogen bonds (H‐bonds) have been shown to modulate the chemical reactivities of iron centers in iron‐containing dioxygen‐activating enzymes and model complexes. However, few examples are available that investigate how systematic changes in intramolecular H‐bonds within the secondary coordination sphere influence specific properties of iron intermediates, such as iron‐oxido/hydroxido species. Here, we used57Fe nuclear resonance vibrational spectroscopy (NRVS) to probe the Fe‐O/OH vibrations in a series of FeIII‐hydroxido and FeIV/III‐oxido complexes with varying H‐bonding networks but having similar trigonal bipyramidal primary coordination spheres. The data show that even subtle changes in the H‐bonds to the Fe‐O/OH units result in significant changes in their vibrational frequencies, thus demonstrating the utility of NRVS in studying the effect of the secondary coordination sphere to the reactivities of iron complexes.

     
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  3. Abstract

    Oxoiron(IV) units are often implicated as intermediates in the catalytic cycles of non‐heme iron oxygenases and oxidases. The most reactive synthetic analogues of these intermediates are supported by tetradentate tripodal ligands withN‐methylbenzimidazole or quinoline donors, but their instability precludes structural characterization. Herein we report crystal structures of two [FeIV(O)(L)]2+complexes supported by pentadentate ligands incorporating these heterocycles, which show longer average Fe–N distances than the complex with only pyridine donors. These longer distances correlate linearly with log k2′ values for O‐ and H‐atom transfer rates, suggesting that weakening the ligand field increases the electrophilicity of the Fe=O center. The sterically bulkier quinoline donors are also found to tilt the Fe=O unit away from a linear N‐Fe=O arrangement by 10°.

     
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  4. Engineered nonheme iron enzymes perform enantioselective radical azidation on aryl N -fluoroamide substrates. 
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  5. Mononuclear non-heme iron enzymes are a large class of enzymes catalyzing a wide-range of reactions. In this work, we report that a non-heme iron enzyme in Methyloversatilis thermotolerans , OvoA Mtht, has two different activities, as a thiol oxygenase and a sulfoxide synthase. When cysteine is presented as the only substrate, OvoA Mtht is a thiol oxygenase. In the presence of both histidine and cysteine as substrates, OvoA Mtht catalyzes the oxidative coupling between histidine and cysteine (a sulfoxide synthase). Additionally, we demonstrate that both substrates and the active site iron's secondary coordination shell residues exert exquisite control over the dual activities of OvoA Mtht (sulfoxide synthase vs. thiol oxygenase activities). OvoA Mtht is an excellent system for future detailed mechanistic investigation on how metal ligands and secondary coordination shell residues fine-tune the iron-center electronic properties to achieve different reactivities. 
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  6. null (Ed.)
    Mononitrosyl and dinitrosyl iron species, such as {FeNO} 7 , {FeNO} 8 and {Fe(NO) 2 } 9 , have been proposed to play pivotal roles in the nitrosylation processes of nonheme iron centers in biological systems. Despite their importance, it has been difficult to capture and characterize them in the same scaffold of either native enzymes or their synthetic analogs due to the distinct structural requirements of the three species, using redox reagents compatible with biomolecules under physiological conditions. Here, we report the realization of stepwise nitrosylation of a mononuclear nonheme iron site in an engineered azurin under such conditions. Through tuning the number of nitric oxide equivalents and reaction time, controlled formation of {FeNO} 7 and {Fe(NO) 2 } 9 species was achieved, and the elusive {FeNO} 8 species was inferred by EPR spectroscopy and observed by Mössbauer spectroscopy, with complemental evidence for the conversion of {FeNO} 7 to {Fe(NO) 2 } 9 species by UV-Vis, resonance Raman and FT-IR spectroscopies. The entire pathway of the nitrosylation process, Fe( ii ) → {FeNO} 7 → {FeNO} 8 → {Fe(NO) 2 } 9 , has been elucidated within the same protein scaffold based on spectroscopic characterization and DFT calculations. These results not only enhance the understanding of the dinitrosyl iron complex formation process, but also shed light on the physiological roles of nitric oxide signaling mediated by nonheme iron proteins. 
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  7. null (Ed.)