On the Catalytic Mechanism of (<i>S</i>)‐2‐Hydroxypropylphosphonic Acid Epoxidase (HppE): A Hybrid DFT Study

Miłaczewska, Anna; Brocławik, Ewa; Borowski, Tomasz

doi:10.1002/chem.201202825

Cited by 27 publications

(33 citation statements)

References 68 publications

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“…We found that the dioxygen molecule prefers to bind to the iron in a side‐on mode as suggested from the experiment . Most theoretical studies on the nonheme iron enzymes predicted a high spin septet ground state for the Fe−O 2 complex . Here too, the septet state with the side‐on conformation ( 7 1 side‐on in Figure A) was found to be the most stable one, and then was set as the reference point of 0 kcal mol −1 .…”

Section: Resultssupporting

confidence: 53%

Mechanistic Insights into a Stibene Cleavage Oxygenase NOV1 from Quantum Mechanical/Molecular Mechanical Calculations

Lai

2019

ChemistryOpen

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NOV1, a stilbene cleavage oxygenase, catalyzes the cleavage of the central double bond of stilbenes to two phenolic aldehydes, using a 4‐His Fe(II) center and dioxygen. Herein, we use in‐protein quantum mechanical/molecular mechanical (QM/MM) calculations to elucidate the reaction mechanism of the central double bond cleavage of phytoalexin resveratrol by NOV1. Our results showed that the oxygen molecule prefers to bind to the iron center in a side‐on fashion, as suggested from the experiment. The quintet Fe−O 2 complex with the side‐on superoxo antiferromagnetic coupled to the resveratrol radical is identified as the reactive oxygen species. The QM/MM results support the dioxygenase mechanism involving a dioxetane intermediate with a rate‐limiting barrier of 10.0 kcal mol −1 . The alternative pathway through an epoxide intermediate is ruled out due to a larger rate‐limiting barrier (26.8 kcal mol −1 ). These findings provide important insight into the catalytic mechanism of carotenoid cleavage oxygenases and also the dioxygen activation of non‐heme enzymes.

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Section: Resultssupporting

confidence: 53%

Mechanistic Insights into a Stibene Cleavage Oxygenase NOV1 from Quantum Mechanical/Molecular Mechanical Calculations

Lai

2019

ChemistryOpen

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“…13,37 The same proton relay channel could use the newly formed water molecule to activate the ferryl oxygen through protonation in a similar manner as in these iron porphyrin model systems. More generally, ferryl protonation could play a significant role in the reactivity and selectivity of non-heme iron proteins such as the α-ketoglutarate-dependent halogenase SyrB2 38 and in ( S )-2-hydroxypropyl-phosphonic acid epoxidase (HppE), 39 which mediates the unusual epoxide formation in the biosynthesis of fosfomycin. In these cases, simultaneous ferryl protonation and substrate hydrogen abstraction could both facilitate C–H bond scission and disfavor hydroxylation of the incipient substrate radical.…”

Section: Discussionmentioning

confidence: 99%

Ferryl Protonation in Oxoiron(IV) Porphyrins and Its Role in Oxygen Transfer

Boaz

Bell

Groves³

2015

J. Am. Chem. Soc.

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Ferryl porphyrins, P−FeIV=O, are central reactive intermediates in the catalytic cycles of numerous heme proteins and a variety of model systems. There has been considerable interest in elucidating factors, such as terminal oxo basicity, that may control ferryl reactivity. Here, the sulfonated, water-soluble ferryl porphyrin complexes tetramesitylporphyrin, oxoFeIVTMPS (FeTMPS-II), its 2,6-dichlorophenyl analogue, oxoFeIVTDClPS (FeTDClPS-II), and two other analogues are shown to be protonated under turnover conditions to produce the corresponding bis-aqua-iron(III) porphyrin cation radicals. The results reveal a novel internal electromeric equilibrium, P−FeIV=O ⇆ P+−FeIII(OH2)2. Reversible pKa values in the range of 4–6.3 have been measured for this process by pH-jump, UV–vis spectroscopy. Ferryl protonation has important ramifications for C–H bond cleavage reactions mediated by oxoiron(IV) porphyrin cation radicals in protic media. Both solvent O–H and substrate C–H deuterium kinetic isotope effects are observed for these reactions, indicating that hydrocarbon oxidation by these oxoiron(IV) porphyrin cation radicals occurs via a solvent proton-coupled hydrogen atom transfer from the substrate that has not been previously described. The effective FeO–H bond dissociation energies for FeTMPS-II and FeTDClPS-II were estimated from similar kinetic reactivities of the corresponding oxoFeIVTMPS+ and oxoFeIVTDClPS+ species to be ~92–94 kcal/mol. Similar values were calculated from the two-proton P+−FeIII(OH2)2 pKaobs and the porphyrin oxidation potentials, despite a 230 mV range for the iron porphyrins examined. Thus, the iron porphyrin with the lower ring oxidation potential has a compensating higher basicity of the ferryl oxygen. The solvent-derived proton adds significantly to the driving force for C–H bond scission.

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“…In this respect, it is interesting to mention the QM-cluster study on the chemistry of hydroxypropylphosphonic acid epoxidase (HppE), where favorable binding of O2 to the iron center and reasonable barriers for substrate oxidation were obtained using DFT. [124] However, it transpired from later experiments that the enzyme is inactive with O2; it hardly even binds it, and it actually employs H2O2 as oxidant. [125] Answering why the QM-cluster calculations failed to detect the flaw in the assumptions would need a separate, higher-level study, but one can expect that the effects of the neglected or approximated environment may be quite significant for the step when O2 is transferred from aqueous solution through the protein cavities to the iron within the active site pocket, and may be less so for the inner-sphere chemistry occurring thereafter.…”

Section: Miscellaneous Monoiron Systemsmentioning

confidence: 99%

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

et al. 2016

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In this minireview, we provide an account of the current state-of-the-art developments in the area of mono-and binuclear non-heme enzymes (NHFe and NHFe2) and the smaller NHFe(2) synthetic models, mostly from a theoretical and computational perspective. The sheer complexity, and at the same time the beauty, of the NHFe(2) world represent a challenge for both experimental as well as theoretical methods. We emphasize that the concerted progress on both theoretical and experimental side is a conditio sine qua non for future understanding, exploration and utilization of the NHFe(2) systems.After briefly discussing the current challenges and advances in the computational methodology, we review the recent spectroscopic and computational studies of NHFe(2) enzymatic and inorganic systems and highlight the correlations between various experimental data (spectroscopic, kinetic, thermodynamic, electrochemical) and computations. Throughout, we attempt to keep in mind the most fascinating and attractive phenomenon in the NHFe(2) chemistry which is the fact that despite the strong oxidative power of many reactive intermediates, the NHFe(2) enzymes perform catalysis with high selectivity. We conclude with our personal viewpoint and hope that further developments in quantum chemistry and especially in the field of multireference wave function methods are needed to have a solid theoretical basis for the NHFe(2) studies, mostly by providing benchmarking and calibration of the computationally efficient and easy-to-use DFT methods.

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On the Catalytic Mechanism of (S)‐2‐Hydroxypropylphosphonic Acid Epoxidase (HppE): A Hybrid DFT Study

Cited by 27 publications

References 68 publications

Mechanistic Insights into a Stibene Cleavage Oxygenase NOV1 from Quantum Mechanical/Molecular Mechanical Calculations

Mechanistic Insights into a Stibene Cleavage Oxygenase NOV1 from Quantum Mechanical/Molecular Mechanical Calculations

Ferryl Protonation in Oxoiron(IV) Porphyrins and Its Role in Oxygen Transfer

Mono- and binuclear non-heme iron chemistry from a theoretical perspective

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