Activation of a Non‐Heme Fe<sup>III</sup>‐OOH by a Second Fe<sup>III</sup> to Hydroxylate Strong C−H Bonds: Possible Implications for Soluble Methane Monooxygenase

Kal, Subhasree; Que, Lawrence

doi:10.1002/ange.201903465

Cited by 11 publications

(2 citation statements)

References 34 publications

(88 reference statements)

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“…Nonheme diiron monooxygenases constitute a big family of metalloenzymes that are widely involved in oxidative metabolism and biosynthesis. − One superfamily of nonheme diiron monooxygenases is the bacterial multicomponent monooxygenases (BMMs). − Upon O 2 activation, these enzymes are able to perform a panoply of oxidative transformations. For instance, soluble methane monooxygenase (sMMO) is capable of oxidizing the C–H bond of methane at ambient temperature and pressure, − while N-oxygenases AurF and CmlI are able to carry out the six-electron oxidation of aminoarenes to nitroarenes, a key step in the biosynthesis of antibiotics. − Among the mostly studied nonheme diiron monooxygenases, BMMs require additional electrons from external reductants to reduce Fe(III)Fe(III) to Fe(II)Fe(II), which is necessary for the initiation of oxygen activation. ,,,,− Unlike BMMs, myo-inositol oxygenase (MIOX) catalyzes the oxygen activation and conversion of myo-inositol (MI) to d -glucuronic acid (GlcUA) in the absence of additional reductants, − which thus represents a noncanonical nonheme diiron monooxygenase. This catalytic transformation is also the first step in the catabolism of MI, which is the sugar backbone of inositol phosphates and phosphoinositides and is associated with an array of diabetic and metabolic diseases. − …”

Section: Introductionmentioning

confidence: 99%

Spin-Regulated Inner-Sphere Electron Transfer Enables Efficient O—O Bond Activation in Nonheme Diiron Monooxygenase MIOX

Liu

Yan

et al. 2021

ACS Catal.

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The combined molecular dynamics (MD) simulations and quantum mechanical/molecular mechanics (QM/MM) calculations have been performed to address the longstanding issue of the "dioxygen activation" by the nonheme diiron monooxygenase myo-inositol oxygenase (MIOX). MIOX utilizes a mixed-valence Fe2(III)Fe1(II) cluster for catalysis. It is well recognized that the Fe2(III) site is responsible for the substrate myo-inositol (MI) binding, while the Fe1(II) site is responsible for O 2 binding and activation. However, it is enigmatic how the O−O bond of oxygen is reductively cleaved in the absence of additional reductants. In this study, we demonstrate a spin-regulated inner-sphere electron-transfer mechanism that is involved in the catalytic reactions of MIOX. Because of the Pauli principle and exchangeenhanced reactivity, the spin-regulated inner-sphere electron transfer enables the formation of an unprecedented Fe2(III)Fe1(II)-peroxyhemiketal intermediate that is responsible for the reductive O−O cleavage. In contrast to Fe1(III)-mediated O−O cleavage in the Fe2(II)Fe1(III)-peroxyhemiketal intermediate proposed previously, our calculations demonstrate that the proton transfer-triggered Fe1−O cleavage in Fe2(III)Fe1(II)-peroxyhemiketal intermediate is the most favorable pathway, leading to MI-OOH intermediate and the Fe1(II) species. The following Fe1(II)-mediated O−O homolysis in MI-OOH generates the substrate radical and Fe(III)−OH species, during which the Fe1(IV)O intermediate would be bypassed. Thus, our calculations show that both Fe sites are cooperately involved in O 2 activation in MIOX and such cooperation is well regulated by the spin-dependent innersphere electron transfer. These findings of O 2 activation by MIOX may have far-reaching implications on other related nonheme diiron monooxygenases.

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Section: Introductionmentioning

confidence: 99%

Spin-Regulated Inner-Sphere Electron Transfer Enables Efficient O—O Bond Activation in Nonheme Diiron Monooxygenase MIOX

Liu

Yan

et al. 2021

ACS Catal.

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“…One superfamily of metalloenzymes can utilize non-heme diiron active sites for O 2 activation and reductions . These non-heme diiron enzymes catalyze many types of reactions, such as the challenging C–H activations occurring in sMMO, − BesC, , UndA, − PtmU3, and Δ9 Desaturase, − epoxidation of double bond occurring in BoxB, , N-oxygenation occurring in AurF − and CmlI, − as well as N-hydroxylation occurring in SznF. − …”

Section: Introductionmentioning

confidence: 99%

Peroxo-Diiron(III/III) as the Reactive Intermediate for N-Hydroxylation Reactions in the Multidomain Metalloenzyme SznF: Evidence from Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations

et al. 2023

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Upon oxygen activation, the non-heme diiron enzymes can generate various active species for oxidative transformations. In this work, the catalytic mechanism of the diiron active site (heme-oxygenase-like diiron oxidase (HDO) domain) in SznF has been comprehensively studied by molecular docking, classical molecular dynamics (MD) and quantum mechanical/molecular mechanical (QM/MM) MD simulations, and hybrid QM/MM calculations. The HDO domain of SznF catalyzes the selective hydroxylation of Nω-methyl-l-arginine (l-NMA) to generate Nδ-hydroxy-Nω-methyl-l-Arg (l-HMA) and Nδ,Nω-dihydroxy-Nω,-methyl-l-Arg (l-DHMA), which is a key step in the synthesis of the nitrosourea pharmacophore of the pancreatic cancer drug streptozotocin (SZN). Our study shows that the peroxo-diiron(III/III) intermediate in Sznf maintains a butterfly-like conformation, while the further protonation of the diiron(III/III) intermediate is found to be inaccessible and unfavorable thermodynamically. Among various mechanisms, we found that the most favorable mechanism involves the nucleophilic attack of the guanidium group onto the peroxo group of P1, which drives the heterolytic cleavage of the O–O bond. Moreover, the selectivity of N-hydroxylation by the peroxo-diiron(III/III) intermediate can be fully supported by MD simulations, suggesting that the peroxo-diiron(III/III) is the reactive intermediate for N-hydroxylation in SznF. The present study expands our understanding on the O2 activation and N-hydroxylation by the non-heme diiron enzymes.

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The Effect oftransAxial Isocyanide Ligands on Iron(II) Tetra‐NHC Complexes and their Reactivity in Olefin Epoxidation

et al. 2021

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The performance of trans axially substituted mono‐(2 a) and bis(tert‐butylisocyanide) (2 b) complexes derived from the highly active bio‐inspired iron(II) (pre‐ )catalyst 2 containing an equatorial macrocyclic tetra N‐heterocyclic carbene in homogenous olefin epoxidation catalysis is reported. H2O2 is used as oxidant in combination with the Lewis acid Sc(OTf)3 as additive resulting in a considerable improvement of catalytic activity. In contrast to other iron epoxidation catalysts, the introduction of π‐accepting isocyanide ligands does not improve the catalytic performance of 2 a and 2 b posed by cyclic voltammetry. However, besides their lower activity, a high temperature tolerance of both compounds is found as a unique feature for iron NHC epoxidation catalysts.

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Activation of a Non‐Heme Fe^III‐OOH by a Second Fe^III to Hydroxylate Strong C−H Bonds: Possible Implications for Soluble Methane Monooxygenase

Cited by 11 publications

References 34 publications

Spin-Regulated Inner-Sphere Electron Transfer Enables Efficient O—O Bond Activation in Nonheme Diiron Monooxygenase MIOX

Spin-Regulated Inner-Sphere Electron Transfer Enables Efficient O—O Bond Activation in Nonheme Diiron Monooxygenase MIOX

Peroxo-Diiron(III/III) as the Reactive Intermediate for N-Hydroxylation Reactions in the Multidomain Metalloenzyme SznF: Evidence from Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations

The Effect oftransAxial Isocyanide Ligands on Iron(II) Tetra‐NHC Complexes and their Reactivity in Olefin Epoxidation

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Activation of a Non‐Heme FeIII‐OOH by a Second FeIII to Hydroxylate Strong C−H Bonds: Possible Implications for Soluble Methane Monooxygenase

Cited by 11 publications

References 34 publications

Spin-Regulated Inner-Sphere Electron Transfer Enables Efficient O—O Bond Activation in Nonheme Diiron Monooxygenase MIOX

Spin-Regulated Inner-Sphere Electron Transfer Enables Efficient O—O Bond Activation in Nonheme Diiron Monooxygenase MIOX

Peroxo-Diiron(III/III) as the Reactive Intermediate for N-Hydroxylation Reactions in the Multidomain Metalloenzyme SznF: Evidence from Molecular Dynamics and Quantum Mechanical/Molecular Mechanical Calculations

The Effect oftransAxial Isocyanide Ligands on Iron(II) Tetra‐NHC Complexes and their Reactivity in Olefin Epoxidation

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Activation of a Non‐Heme Fe^III‐OOH by a Second Fe^III to Hydroxylate Strong C−H Bonds: Possible Implications for Soluble Methane Monooxygenase