Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes

Meunier, Bernard; Visser, Sam P. de; Shaik, Sason

doi:10.1021/cr020443g

Cited by 2,133 publications

(1,936 citation statements)

References 262 publications

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“…[1][2][3][4] Despite several industrial applications such as the oxidation of cyclohexane and p-xylene, which use O 2 as the oxidant and manganese or cobalt based catalysts, the development of practical oxidation catalysts and a thorough mechanistic understanding of alkane oxidation processes continue to provide great challenges in catalysis research. A number of different classes of alkane oxidation catalysts have been developed during the last 50 years, including the cobalt and manganese acetate catalyst systems used industrially, 5 the heme-based iron complexes containing porphyrin-type ligands used in nature, 6,7 polyoxometalates [8][9][10] and more recently, non-heme iron based catalyst systems. [11][12][13][14][15][16][17] The metal catalysts are typically combined with oxidants, which can have different oxo transfer abilities 18 , for example H 2 O 2 , O 2 , ClO -, PhIO, O 3 or N 2 O, whereby the first two oxidants are economically and environmentally the most attractive oxidants.…”

Section: Introductionmentioning

confidence: 99%

Towards robust alkane oxidation catalysts: electronic variations in non-heme iron(ii) complexes and their effect in catalytic alkane oxidation

et al. 2009

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A series of non-heme iron(II) bis(triflate) complexes containing linear and tripodal tetradentate ligands has been prepared. Electron withdrawing and electron donating substituents in the para position of the pyridine ligands as well the effect of pyrazine versus pyridine and sulphur or oxygen donors instead of nitrogen donors have been investigated. The electronic effects induced by these substituents influence the strength of the ligand field. UV-vis spectroscopy and magnetic susceptibility studies have been used to quantify these effects and VT 1 H and 19 F NMR spectroscopy as well as X-ray diffraction have been used to elucidate structural and geometrical aspects of these complexes. The catalytic properties of the iron(II) complexes as catalysts for the oxidation of cyclohexane with hydrogen peroxide have been evaluated. In the strongly oxidising environment required to oxidise alkanes, catalyst stability determines the overall catalytic efficiency of a given catalyst, which can be related to the ligand field strength and the basicity of the ligand and its propensity to undergo oxidation.2

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Section: Introductionmentioning

confidence: 99%

Towards robust alkane oxidation catalysts: electronic variations in non-heme iron(ii) complexes and their effect in catalytic alkane oxidation

et al. 2009

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“…The decay of this intermediate involved a diffusion controlled protonation from its pH dependence and a deuterium isotope effect of 2. Lys 14 has been identified as a participating 2 nd sphere residue (mutation of this residue decreases the turnover rate by a factor of [20][21][22][23][24][25][26][27][28][29][30] and has been proposed to assist superoxide binding to the active site. 19,20 Though no intermediate has been trapped with the physiological substrate superoxide, Olivier et.…”

Section: Introductionmentioning

confidence: 99%

Sulfur K-Edge X-ray Absorption Spectroscopy and Density Functional Theory Calculations on Superoxide Reductase: Role of the Axial Thiolate in Reactivity

et al. 2007

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Superoxide reductase (SOR) is a non-heme iron enzyme which reduces superoxide to peroxide at a diffusion-controlled rate. Sulfur K-edge x-ray absorption spectroscopy (XAS) is used to investigate the ground state electronic structure of the resting high-spin and CN − bound low-spin Fe III forms of the 1Fe SOR from Pyrococcus furiosus. A computational model with constrained Imidazole rings (necessary for reproducing spin states), H-bonding interaction to the thiolate (necessary for reproducing Fe-S bond covalency of the high-spin and low-spin forms) and H-bonding to axial ligand (necessary to reproduce the ground state of the low-spin form) was developed and then used to investigate the enzymatic reaction mechanism. Reaction of the resting ferrous site with superoxide and protonation leading to a high-spin Fe III -OOH species and its subsequent protonation resulting in H 2 O 2 release is calculated to be the most energetically favorable reaction pathway. Our results suggest that the thiolate acts as a covalent anionic ligand. Replacing the thiolate with a neutral noncovalent ligand makes protonation very endothermic and greatly raises the reduction potential. The covalent nature of the thiolate weakens the Fe III bond to the proximal Oxygen of this hydroperoxo species, which raises its pK a by an additional 5 log units relative to a primarily anionic ligand facilitating its protonation. A comparison with Cytochrome P450 indicates that the stronger equatorial ligand field from the porphyrin results in a low-spin Fe III -OOH species which would not be capable of efficient H 2 O 2 release due to a spin-crossing barrier associated with formation of a high spin 5C Fe III product. Additionally, the presence of the di-anionic porphyrin π ring in Cytochrome P450 allows O-O heterolysis forming a Fe IV -oxo porphyrin radical species, which is calculated to be extremely unfavorable for the non-heme SOR ligand environment. Finally the 5C Fe III site which results from the product release at the end of the O 2 − reduction cycle is calculated to be capable of reacting with a second O 2 − resulting in superoxide dismutase (SOD) activity. However in contrast to FeSOD the 5C Fe III site of SOR which is more positive is calculated to have a high affinity for the binding a 6 th anionic ligand which would inhibit its SOD activity.

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“…5,6,7,8,9 Metal-sulfur based active sites are abundant in nature, performing a wide variety of functions, including redox catalysis (e.g. O 2 activation of cytochrome P450), 10 small-molecule activation (e.g. nitrogenase, CO dehydrogenase), 11 Lewis acid catalysis (e.g.…”

Section: Introductionmentioning

confidence: 99%

Sulfur K-Edge XAS and DFT Calculations on P450 Model Complexes: Effects of Hydrogen Bonding on Electronic Structure and Redox Potentials

et al. 2005

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Hydrogen bonding is generally thought to play an important role in tuning the electronic structure and reactivity of metal-sulfur sites in proteins. To develop a quantitative understanding of this effect, S K-edge X-ray absorption spectroscopy (XAS) has been employed to directly probe ligand-metal bond covalency, where it has been found that protein active sites are significantly less covalent than their related model complexes. Sulfur K-edge XAS data are reported here on a series of P450 model complexes with increasing H-bonding to the ligated thiolate from its substituent. The XAS spectroscopic results show a dramatic decrease in pre-edge intensity. DFT calculations reproduce these effects and show that the observed changes are in fact solely due to H-bonding and not from the inductive effect of the substituent on the thiolate. These calculations also indicate that the Hbonding interaction in these systems is mainly dipolar in nature. The −2.5 kcal/mole energy of the H-bonding interaction was small relative to the large change in ligand-metal bond covalency (30%) observed in the data. A bond decomposition analysis of the total energy is developed to correlate the pre-edge intensity change to the change in Fe-S bonding interaction on H-bonding. This effect is greater for the reduced than the oxidized state, leading to a 330 mV increase in the redox potential. A simple model shows that E° should vary approximately linearly with the covalency of the Fe-S bond in the oxidized state, which can be determined directly from S K-edge XAS.

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Mechanism of Oxidation Reactions Catalyzed by Cytochrome P450 Enzymes

Cited by 2,133 publications

References 262 publications

Towards robust alkane oxidation catalysts: electronic variations in non-heme iron(ii) complexes and their effect in catalytic alkane oxidation

Towards robust alkane oxidation catalysts: electronic variations in non-heme iron(ii) complexes and their effect in catalytic alkane oxidation

Sulfur K-Edge X-ray Absorption Spectroscopy and Density Functional Theory Calculations on Superoxide Reductase: Role of the Axial Thiolate in Reactivity

Sulfur K-Edge XAS and DFT Calculations on P450 Model Complexes: Effects of Hydrogen Bonding on Electronic Structure and Redox Potentials

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