The “Somersault” Mechanism for the P-450 Hydroxylation of Hydrocarbons. The Intervention of Transient Inverted Metastable Hydroperoxides

Abstract

A series of model theoretical calculations are described that suggest a new mechanism for the oxidation step in enzymatic cytochrome P450 hydroxylation of saturated hydrocarbons. A new class of metastable metal hydroperoxides is described that involves the rearrangement of the ground-state metal hydroperoxide to its inverted isomeric form with a hydroxyl radical hydrogen bonded to the metal oxide (MO-OH --> MO....HO). The activation energy for this somersault motion of the FeO-OH group is 20.3 kcal/mol for the P450 model porphyrin iron(III) hydroperoxide [Por(SH)Fe(III)-OOH(-)] to produce the isomeric ferryl oxygen hydrogen bonded to an *OH radical [Por(SH)Fe(III)-O....HO(-)]. This isomeric metastable hydroperoxide, the proposed primary oxidant in the P450 hydroxylation reaction, is calculated to be 17.8 kcal/mol higher in energy than the ground-state iron(III) hydroperoxide Cpd 0. The first step of the proposed mechanism for isobutane oxidation is abstraction of a hydrogen atom from the C-H bond of isobutane by the hydrogen-bonded hydroxyl radical to produce a water molecule strongly hydrogen bonded to anionic Cpd II. The hydroxylation step involves a concerted but nonsynchronous transfer of a hydrogen atom from this newly formed, bound, water molecule to the ferryl oxygen with a concomitant rebound of the incipient *OH radical to the carbon radical of isobutane to produce the C-O bond of the final product, tert-butyl alcohol. The TS for the oxygen rebound step is 2 kcal/mol lower in energy than the hydrogen abstraction TS (DeltaE() = 19.5 kcal/mol). The overall proposed new mechanism is consistent with a lot of the ancillary experimental data for this enzymatic hydroxylation reaction.

Mechanistic Study on the Oxidation of Anthocyanidin Synthase by Quantum Mechanical Calculation

“…These values are too high and seem to be overestimated. Despite this, the findings that the rate-limiting step in the LCD 2 oxygenation process is the hydrogen atom abstraction reaction is consistent with several previous theoretical studies on the oxygenation mechanism by the ferryl (Fe(IV)ϭO/Fe(III)-O ⅐ ) species of cytochrome P-450 (36,41,42). Hence, the potential energy surfaces obtained in this study is considered to reflect the actual physiological phenomenon and the oxygenations at both C-3 and C-4 positions by ANS occur spontaneously under the condition of room temperature.…”

“…Hence, the potential energy surfaces obtained in this study is considered to reflect the actual physiological phenomenon and the oxygenations at both C-3 and C-4 positions by ANS occur spontaneously under the condition of room temperature. It is well investigated experimentally (40,46) and theoretically (36,41,42) that ferryl species have high reactivity. Thus, the excess enthalpy for the oxygenation process may be supplied by the production of ferryl species, which precedes the oxygenation of substrate.…”

New Trends in Oxidative Functionalization of Carbon–Hydrogen Bonds: A Review

“…It is possible to compare the platinum complex Cl2Pt II (OH2)2 (A) with a wasp, which "pricks" (activates) alkanes using its sting (coordinated hydroxyl radical). It is useful to remember that Bach and Dmitrenko [292] proposed a mechanism of alkane oxidation catalyzed by cytochrome P450. It involves the rearrangement (somersault motion) of the metal hydroperoxide to its inverted isomeric form with a hydroxyl radical that is hydrogen bonded to the metal oxide: MO-OH → M=O … HO • .…”

Hydrogen Peroxide Decomposition by a Non‐Heme Iron(III) Catalase Mimic: A DFT Study

“…However, formation of Compound I has also been proposed for enzymes which lack such a strategically positioned acid-base catalyst (e.g., P450 cam ). [48,52] In such cases, a water molecule in the enzyme pocket has been proposed to contribute to the protonation step. [48] This has been questioned, because it has been found that the terminal oxygen atom of the hydroperoxyl ligand of Fe III porphyrins has a much lower (by 30-40 kcal mol…”