Cytochrome rebound

Allylic rearrangements with 3,3,6,6-dj-cyclohexene occurred in 20% of the MMO hydroxylation products compared to 33% for cytochrome P-450. These two experiments suggest that, with M. trichospor-ium OB3b, a rebound reaction must occur with a greater rate constant than with cytochrome P-450, in accord with the radical clock substrate work. 

B3b system, although it certainly is not ruled out for the M. capsulatus (Bath) enzyme. In comparison to the cytochrome P-450 system, the hydroxylation mechanism for both MMO systems either has a rebound rate constant which is much larger and/or it takes place by an alternative pathway to classical radical rebound. 

Bowry VW, Ingold KU. A radical clock investigation of microsomal cytochrome-P-450 hydroxylation of hydrocarbons—rate of oxygen rebound. J Am Chem Soc 1991 113(15) 5699-5707. 

Newcomb M, Letadic MH, Putt DA, et al. An incredibly fast apparent oxygen rebound rate-constant for hydrocarbon hydroxylation by cytochrome-P-450 enzymes. J Am Chem Soc 1995 117(11) 3312—3313. 

Ogliaro F, Harris N, Cohen S, et al. A model rebound mechanism of hydroxylation by cytochrome P450 stepwise and effectively concerted pathways, and their reactivity patterns. J Am Chem Soc 2000 122(37) 8977-8989. 

He, X. and Ortiz de Montellano, P.R. (2004) Radical rebound mechanism in cytochrome P-450 catalyzed hydroxylation of multifaceted radical clocks a-and p-thujone. The Journal of Biological Chemistry, 279, 39479-39484. 

The mechanism of cytochrome P450 catalysis is probably constant across the system. It is determined by the ability of a high valent formal (FeO) species to carry out one-electron oxidations through the abstraction of hydrogen atoms or electrons. The resultant substrate radical can then recombine with the newly created hydroxyl radical (oxygen rebound) to form the oxidized metabolite. Where a heteroatom is the (rich) source of the electron more than one product is possible. There can be direct recombination to yield the heteroatom oxide or radical relocalization within the... 

F. Ogliaro, N. Harris, S. Cohen, M. Filatov, S. R de Visser, and S. Shaik, A Model Rebound Mechanism of Hydroxylation by Cytochrome P450. Stepwise and Effectively Concerted Pathways, and Their Reactivity Patterns, J. Am. Chem. Soc. 2000,122, 8977. Calculations explain puzzling aspects of cytochrome P450 hydroxylation reactions in terms of two, different, reactive spin states of the enzyme. 

Compared to baseline saquinavir pharmacokinetic parameters obtained in period 1, the use of garlic reduced the mean saquinavir area under the concentration-time curve (AUC) by 51%, and the maximum (Cmax) and minimum (Cmin) saquinavir concentrations by 54% and 49%, respectively. After a 10-day washout, the AUC, Cmax, and Cmin values were within a range of 60% to 70% of baseline values. The magnitude of the decline in concentration might result in therapeutic failure and viral rebound in patients with HIV. Based on the pharmacokinetic parameters obtained in period 3, it also appears that garlic might have a prolonged, albeit lesser, effect on saquinavir exposure. The effects of combined treatment with other protease inhibitors that are also potent cytochrome P-450 (CYP) enzymes modulators need to be further evaluated. 

S. Shaik, S. Cohen, S. P. de Visser, P. K. Sharma, D. Kumar, S. Kozuch, F. Ogliaro, D. Danovich, Eur. J. Inorg. Chem. 207 (2004). The Rebound Controversy An Overview and Theoretical Modeling of the Robound Step in C—H Hydroxylation by Cytochrome P450. 

Schoneboom JC, S Cohen, H Lin, S Shaik, W Thiel (2004) Quantum mechanical/molecular mechanical investigation of the mechanism of C-H hydroxylation of camphor by cytochrome P450(cam) Theory supports a two-state rebound mechanism. J. Am. Chem. Soc. 126 (12) 4017-4034... 

The radical rebound mechanism has been proposed and proved in several cases in reaction of hydroxylation catalyzed by cytochrome 450 and methane monooxigenase (Section 3.2)... 

Filatov, M., Harris, N., and Shaik, S. (1999) On the "rebound" mechanism of alkane hydroxylation by cytochrome P450 electronic structure of the intermediate and the electron transfer character in the rebound step. Angew. Chem., Int. Ed. 38, 3510-3512. 

Shaik and co-workers have carried out a number studies using density functional theory based quantum chemical and QM/MM techniques to examine various aspects of the mechanism of alkane hydroxylation by cytochrome P450.178 181 These studies included, for example, calculation of the potential energy surface for the so-called rebound mechanism with methane as a substrate for two spin states, the high spin (HS) quartet state and low spin (LS) doublet state. In the rebound mechanism, Compound I initially abstracts a... 

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