Hydrogen Atom vs. Hydride Transfer in Cytochrome P450 Oxidations: A Combined Mass Spectrometry and Computational Study

Reinhard, Fabián G. Cantú; Fornarini, Simonetta; Crestoni, Maria Elisa; Visser, Sam P. de

doi:10.1002/ejic.201800273

Cited by 7 publications

(5 citation statements)

References 79 publications

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“…This enables studies on full proteins that keep the orientation and constraints of the enzyme in the model. These studies are reasonably accurate, and recent benchmark and calibration studies that compare a range of density functional theory methods versus experimental rate constants, kinetic isotope effects, and spectroscopic parameters are in good agreement [187][188][189][190][191][192][193].…”

Section: Computational Studies On Nonheme Iron Hydroxylases and Halogmentioning

confidence: 59%

A Comparative Review on the Catalytic Mechanism of Nonheme Iron Hydroxylases and Halogenases

Timmins

Visser

2018

Catalysts

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Enzymatic halogenation and haloperoxidation are unusual processes in biology; however, a range of halogenases and haloperoxidases exist that are able to transfer an aliphatic or aromatic C–H bond into C–Cl/C–Br. Haloperoxidases utilize hydrogen peroxide, and in a reaction with halides (Cl−/Br−), they react to form hypohalides (OCl−/OBr−) that subsequently react with substrate by halide transfer. There are three types of haloperoxidases, namely the iron-heme, nonheme vanadium, and flavin-dependent haloperoxidases that are reviewed here. In addition, there are the nonheme iron halogenases that show structural and functional similarity to the nonheme iron hydroxylases and form an iron(IV)-oxo active species from a reaction of molecular oxygen with α-ketoglutarate on an iron(II) center. They subsequently transfer a halide (Cl−/Br−) to an aliphatic C–H bond. We review the mechanism and function of nonheme iron halogenases and hydroxylases and show recent computational modelling studies of our group on the hectochlorin biosynthesis enzyme and prolyl-4-hydroxylase as examples of nonheme iron halogenases and hydroxylases. These studies have established the catalytic mechanism of these enzymes and show the importance of substrate and oxidant positioning on the stereo-, chemo- and regioselectivity of the reaction that takes place.

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Section: Computational Studies On Nonheme Iron Hydroxylases and Halogmentioning

confidence: 59%

A Comparative Review on the Catalytic Mechanism of Nonheme Iron Hydroxylases and Halogenases

Timmins

Visser

2018

Catalysts

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“…The C–O bond in the TS for the p -CN derivative is significantly shorter than those for the other derivatives, which indicates it has a tighter transition state than the other substrates. To put these values in perspective, the C–O distances are longer than those reported for the rebound step in cycloheptatriene hydroxylation by an iron(IV)(oxo)(pentafluorophenyl-porphyrin) complex, which found doublet and quartet spin transition states with C–O distances of 1.831 and 2.053 Å . Calculations for the small aliphatic substrates methane and propene and iron(IV)(oxo)(porphine) lead to much longer C–O distances of 2.556 and 2.427 Å, respectively, in the rebound transition states .…”

Section: Computational Studiesmentioning

confidence: 81%

“…To put these values in perspective, the C−O distances are longer than those reported for the rebound step in cycloheptatriene hydroxylation by an iron(IV)(oxo)(pentafluorophenyl-porphyrin) complex, which found doublet and quartet spin transition states with C−O distances of 1.831 and 2.053 Å. 65 Calculations for the small aliphatic substrates methane and propene and iron(IV)(oxo)(porphine) lead to much longer C−O distances of 2.556 and 2.427 Å, respectively, in the rebound transition states. 12 Long C−O distances were also found for the rebound transition states during methane hydroxylation by μ-nitrido-bridged diiron(IV)-oxo porphyrinoid complexes.…”

Section: ■ Computational Studiesmentioning

confidence: 85%

Hydroxyl Transfer to Carbon Radicals by Mn(OH) vs Fe(OH) Corrole Complexes

et al. 2020

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The transfer of OH• from metal-hydroxo species to carbon radicals (R•) to give hydroxylated products (ROH) is a fundamental process in metal-mediated heme and nonheme C-H bond oxidations. This step, often referred to as the hydroxyl "rebound" step, is typically very fast, making direct study of this process challenging if not impossible. In this report, we describe the reactions of the synthetic models M(OH)(ttppc) (M = Fe (1), Mn (3); ttppc = 5,10,4,6

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“…These QM/MM methods have been described in details elsewhere [ 55 , 56 , 62 , 63 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ] and were extensively benchmarked and calibrated against experimental data. In particular, rate constants of small model complexes were reproduced excellently as compared to experimental data for oxygen atom transfer by iron (IV)-oxo and iron (IV)-imido species [ 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ]. In addition, reduction potentials were reproduced well [ 102 , 103 ].…”

Section: Methodsmentioning

confidence: 86%

Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes

Postils

Saint-André

Timmins

et al. 2018

IJMS

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The cytochromes P450 are drug metabolizing enzymes in the body that typically react with substrates through a monoxygenation reaction. During the catalytic cycle two reduction and protonation steps generate a high-valent iron (IV)-oxo heme cation radical species called Compound I. However, with sufficient reduction equivalents present, the catalytic cycle should be able to continue to the reduced species of Compound I, called Compound II, rather than a reaction of Compound I with substrate. In particular, since electron transfer is usually on faster timescales than atom transfer, we considered this process feasible and decided to investigate the reaction computationally. In this work we present a computational study using density functional theory methods on active site model complexes alongside quantum mechanics/molecular mechanics calculations on full enzyme structures of cytochrome P450 enzymes. Specifically, we focus on the relative reactivity of Compound I and II with a model substrate for O–H bond activation. We show that generally the barrier heights for hydrogen atom abstraction are higher in energy for Compound II than Compound I for O–H bond activation. Nevertheless, for the activation of such bonds, Compound II should still be an active oxidant under enzymatic conditions. As such, our computational modelling predicts that under high-reduction environments the cytochromes P450 can react with substrates via Compound II but the rates will be much slower.

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Hydrogen Atom vs. Hydride Transfer in Cytochrome P450 Oxidations: A Combined Mass Spectrometry and Computational Study

Cited by 7 publications

References 79 publications

A Comparative Review on the Catalytic Mechanism of Nonheme Iron Hydroxylases and Halogenases

A Comparative Review on the Catalytic Mechanism of Nonheme Iron Hydroxylases and Halogenases

Hydroxyl Transfer to Carbon Radicals by Mn(OH) vs Fe(OH) Corrole Complexes

Quantum Mechanics/Molecular Mechanics Studies on the Relative Reactivities of Compound I and II in Cytochrome P450 Enzymes

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