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One oxidant, many pathways: a theoretical perspective of monooxygenation mechanisms by cytochrome P450 enzymes

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Abstract

Density functional theoretical studies of monooxygenation reactivity of the high-valent oxoiron(IV) porphyrin cation-radical compound of cytochrome P450, the so-called Compound I, and of its precursor, the ferric(III)-hydroperoxide species, are described. The degeneracy of the spin states of Compound I, its electron deficiency, and dense orbital manifold lead to two-state and multi-state reactivity scenarios and may thereby create reactivity patterns as though belonging to two or more different oxidants. Most of the controversies in the experimental data are reconciled using Compound I as the sole competent oxidant. Theory finds ferric(III)-hydroperoxide to be a very sluggish oxidant, noncompetitive with Compound I. If and when Compound I is absent, P450 oxidation will logically proceed by another form, but this has to be more reactive than ferric(III)-hydroperoxide. Theoretical studies are conducted to pinpoint such an oxidant for P450.

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Notes

  1. A possible such scenario that can be imagined is that, in the T252A mutant enzyme, water access to the pocket is essential for subsequent protonation of Cpd 0; camphor blocks water access to the protein pocket, and hence Cpd I cannot be formed, while other substrates, e.g. camphene, may allow water entrance, which thereby leads to protonation of Cpd 0 and subsequent formation of Cpd I. In the double mutant a different topography may allow water molecules even in the presence of camphor, and hence the D251N/T252A mutant is capable of camphor hydroxylation

Abbreviations

Cpd I:

Compound I

DFT:

density functional theory

MSR:

multi-state reactivity

PIE:

product isotope effect

TSR:

two-state reactivity

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Acknowledgements

This research is supported by an ISF grant. J. Jones is thanked for instructive comments.

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Authors and Affiliations

  1. Department of Organic Chemistry and the Lise Meitner Minerva Center for Computational Quantum Chemistry, Hebrew University, 91904 , Jerusalem, Israel

    Sason Shaik, Samuël P. de Visser & Devesh Kumar

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  1. Sason Shaik
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  2. Samuël P. de Visser
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  3. Devesh Kumar
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Correspondence to Sason Shaik.

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Shaik, S., de Visser, S.P. & Kumar, D. One oxidant, many pathways: a theoretical perspective of monooxygenation mechanisms by cytochrome P450 enzymes. J Biol Inorg Chem 9, 661–668 (2004). https://doi.org/10.1007/s00775-004-0576-6

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  • DOI: https://doi.org/10.1007/s00775-004-0576-6

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