Drug Metabolism by Cytochrome P450 Enzymes: What Distinguishes the Pathways Leading to Substrate Hydroxylation Over Desaturation?

Ji, Li; Faponle, Abayomi S.; Quesne, Matthew G.; Sainna, Mala A.; Zhang, Jing; Franke, Alicja; Kumar, Devesh; Eldik, Rudi van; Liu, Weiping; Visser, Sam P. de

doi:10.1002/chem.201500329

Cited by 115 publications

(95 citation statements)

References 88 publications

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“…As such these electrophilic addition barriers reflect a radical-type pathway with an initial one-electron transfer similarly to, e.g. aliphatic hydrogen atom abstraction barriers [49][50][51][52] We would like to emphasize that in structure 2+ with arenes will result in a direct proton transfer from the ipso-position to either the meta-carbon atom to form ketone or to the oxygen atom to give phenol. As can be seen from the relative distances in 2 I 1 , the meta-carbon atom is at a distance of 1.938 Å from the ipso-proton, whereas the distance between ipso-proton and phenolate oxygen atom is at a larger distance of 2.081 Å.…”

Section: The Studies Presented In This Work Use Density Functional Thmentioning

confidence: 99%

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

2016

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Iron(III)-hydroperoxo complexes are found in various nonheme iron enzymes as catalytic cycle intermediates; however, little is known on their catalytic properties. Recent work of Banse and coworkers on a biomimetic nonheme iron(III)-hydroperoxo complex provided evidence of its involvement in reactivity with arenes. This contrasts the behavior of heme iron(III)-hydroperoxo complexes that are known to be sluggish oxidants. In order to gain insight into the reaction mechanism of the biomimetic iron(III)-hydroperoxo complex with arenes we performed a computational (density functional theory) study. The calculations show that iron(III)-hydroperoxo reacts with substrates via low free energies of activation that should be accessible at room temperature. Moreover, dominant ketone reaction product is observed as primary products rather than the thermodynamically more stable phenols. These product distributions are analyzed and the calculations show that charge interaction between the iron(III)-hydroxo group and the substrate in the intermediate state pushes the transferring proton to the metacarbon atom of substrate and guides the selectivity of ketone formation. These studies show that the relative ratio of ketone versus phenol as primary products can be affected by external interactions of the oxidant with substrate. Moreover, iron(III)-hydroperoxo complexes are shown to selectively give ketone products, whereas iron(IV)-oxo complexes will react with arenes to form phenols instead.

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Section: The Studies Presented In This Work Use Density Functional Thmentioning

confidence: 99%

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

2016

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“…These values compare well with previous studies of aliphatic and aromatic hydroxylation by iron(IV)-oxo porphyrin cation radical complexes. [12,[16][17][18] Thereafter, we completed the investigation of 4 Figure 3 with a rate-determining electrophilic addition barrier TS15 leading to a cationic intermediate I15. Similarly to the toluene data reported above, 2 TS15 is below 4 TS15 as seen before in aromatic hydroxylation by P450 CpdI models.…”

Section: Theorymentioning

confidence: 99%

A Systematic Account on Aromatic Hydroxylation by a Cytochrome P450 Model Compound I: A Low‐Pressure Mass Spectrometry and Computational Study

Reinhard

Sainna

Upadhyay

et al. 2016

Chemistry A European J

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Cytochrome P450 enzymes are heme containing monooxygenases that mainly react through oxygen atom transfer. Specific features of substrate and oxidant that determine the reaction rate constant for oxygen atom transfer are still poorly understood and, therefore, we did a systematic gas-phase study on reactions by iron(IV)-oxo porphyrin cation radical structures with arenes. We present here the first results obtained by using Fourier transform-ion cyclotron resonance mass spectrometry and provide rate constants and product distributions for the assayed reactions. Product distributions and kinetic isotope effect studies implicate a rate determining aromatic hydroxylation reaction that correlates with the ionization energy of the substrate and no evidence of aliphatic hydroxylation products is observed. To further understand the details of the reaction mechanism, a computational study on a model complex was performed. These studies confirm the experimental hypothesis of dominant aromatic over aliphatic hydroxylation and show that the lack of an axial ligand affects the aliphatic pathways. Moreover, a two parabola valence bond model is used to rationalize the rate constant and identify key properties of the oxidant and substrate that drive the reaction. In particular, the work shows that aromatic hydroxylation rates correlate with the ionization energy of the substrate as well as with the electron affinity of the oxidant.

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“…isozyme through the modulation of Fe-OH conformations via hydrogen bonds, [237] it had only a partial success in explaining the desaturation over epimerization/hydroxylation selectivity in the α-KGNHFe carbapenem synthase. [92] Besides substrate positioning, oxidant positioning might be a viable strategy of Nature as well.…”

Section: Chemoselectivitymentioning

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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Drug Metabolism by Cytochrome P450 Enzymes: What Distinguishes the Pathways Leading to Substrate Hydroxylation Over Desaturation?

Cited by 115 publications

References 88 publications

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

Arene activation by a nonheme iron(III)–hydroperoxo complex: pathways leading to phenol and ketone products

A Systematic Account on Aromatic Hydroxylation by a Cytochrome P450 Model Compound I: A Low‐Pressure Mass Spectrometry and Computational Study

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

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