Cytochrome alkane hydroxylation

Fasan, R., Chen, M.M., Crook, N.C. et al. (2007) Engineered alkane-hydroxylating cytochrome P450 (BM3) exhibiting nativelike catalytic properties. Angewandte Chemie (International Edition in English), 46 (44), 8414-8418. 

D KIE associated with alkane hydroxylation by cytochromes P-450 and intermolec-ular D KIE in the alkane hydroxylations catalysed by manganese and iron porphyrin complexes... 

Yoshizawa K, T Kamachi, Y Shiota (2001) A theoretical study of the dynamic behavior of alkane hydroxylation by a compound I model of cytochrome P450. J. Am. Chem. Soc. 123 (40) 9806-9816... 

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. 

One motivation for the characterization of the above compounds has been to more fully understand the involvement of such higher valent manganese porphyrin complexes in model systems which imitate the catalytic activity of monooxygenase cytochrome P-450 and related enzymes. The catalytic cycle of cytochrome P-450 appears to involve the binding and reduction of molecular oxygen at a haem centre followed by the ultimate formation of a reactive iron oxo complex which is responsible for oxidation of the substrate. For example, cytochrome P-450 is able to catalyse alkane hydroxylation with great selectivity. 

Alkane hydroxylation is carri out in nature by a variety of enzymes, but the ones that have attracted most attention are the cytochrome P-450 dependent systems found, for example, in mammalian liver. In the liver they serve to detoxify lipid soluble species, such as drugs, by making them more water soluble and hence more easily eliminated. For some substrates, such as certain arenes, the hydroxylation in fact makes these substrates more toxic, by converting them to epoxides which then alkylate liver DNA. The ultimate source of the 0-atom used in the hydroxylation is O2, but only one of the two 0-atoms of the O2 is incorporated in the substrate, the other is reduced to H2O. This means two reducing equivalents are also required. Because they introduce only one 0-atom from O2 into the substrate, these enzymes are called monooxygenases (equation 59). 

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... 

The first report of a simple iron porphyrin system that effected stereospecific olefin epoxidation and alkane hydroxylation was reported in 1979 (Scheme 1.7). This system introduced the use of iodosylbenzene as an oxygen-transfer agent to mimic the chemistry of cytochrome P450. ... 

Harris, N., S. Cohen, M. Filatov, F. Ogliaro, and S. Shaik (2000). Two-state reactivity in the rebound step of alkane hydroxylation by cytochrome P-450 Origins of free radicals with finite lifetimes. Angew. Chem. nt. Ed. 39, 2003-2007. 

Ogliaro, F, M. Filatov, and S. Shaik (2000). Alkane hydroxylation by cytochrome P450 Is kinetic isotope effect a reliable probe of transition state structure Eur. J. Inorg. Chem. 2455-2458. 

Atkins, W.M. and S.G. Sligar (1989). Molecular recognition in cytochrome P450— alteration of regioselective alkane hydroxylation via protein engineering. J. Am. Chem. Soc. Ill, 2715-2717. 

TT-cation radical complexes.In the reactions, oxoiron(IV) porphyrin rr-cation radicals of electron-rich porphyrins reacted fast with ROOH (i.e., catalase and peroxidase type of chemistry one-electron oxidation of ROOH) (Scheme 2, pathway A). On the other hand, oxoiron(IV) porphyrin rr-cation radicals of electron-deficient porphyrins reacted fast with olefins to yield epoxide products (i.e., cytochrome P450 type of chemistry oxygen atom transfer) (Scheme 2, pathway B). These results demonstrated that electron-deficient iron porphyrin complexes are better catalysts in hydrocarbon oxygenations by hydroperoxides, since these complexes can avoid the facile decomposition of oxoiron intermediates by ROOH (Scheme 2, pathway A). Indeed, highly electron-deficient iron(III) porphyrin complexes efficiently catalyze alkane hydroxylations by H2O2 in aprotic solvents. 

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