Cytochrome P450 catalysis

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... 

Scheme 2.10 Consensus mechanism of cytochrome P450 catalysis (S = substrate) [61, 62, 72].

One of the most intriguing reactions in the chytochrome P450 catalysis is the transfer of second electron and dioxygen activation, which appears to be a key step of the entire process. The chemical nature of reactive oxidizing species appears in the coordination sphere of heme iron and the mechanism of hydroxylation of organic compounds, saturated hydrocarbons in particular, is a much debated question in the field of the cytochrome P450 catalysis. To solve this problem, an entire arsenal of modern experimental and theoretical methods are employed. The catalytic pathway of cytochrome P450cam from Pseudomonas putida obtained on the basis of X-ray analysis at atomic resolution is presented in Fig. 3.10. 

Fig. 2 Postulated mechanism of cytochrome P450 catalysis. Net reaction Substrate + 2e + 2H -P O2 —> substrate — O + H2O.

Ortiz de Montellano, P.R. and R.A. Stearns (1987). Timing of the radical recombination step in cytochrome P450 catalysis with ring-strained probes. J. Am. Chem. Soc. 109, 3415-3420. 

Guengerich, F.P (2002). Rate-limiting steps in cytochrome P450 catalysis. Biol. Chem. 383, 1553-1564. 

Atkins, W.M., W.D. Lu, and D.L. Cook (2002). Is there a toxicological advantage for non-hyperbolic kinetics in cytochrome P450 catalysis Functional allostery from distributive catalysis. J. Biol Chem. Ill, 33258-33266. 

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Krest CM, Onderko EL, Yosca TH, Calixto JC, Karp RE, Livada J, Rittle J, Green MT (2013) Reactive intermediates in cytochrome p450 catalysis. J Biol Chem 288 17074-17081... 

Fig. 4.14 Probes designed to test for the involvement of radical cation intermediates in cytochrome P450 catalysis...

The growth in the studies of nomnammalian cytochrome P450 systems, particularly those of plants and microbes, has unearthed a rich and nnforeseen complexity of cytochrome P450-catalyzed transformations. The breadth of cytochrome P450 catalysis will snrely continue to grow as these still relatively imexplored biological domains reveal the diversity of aims to which... 

Newcomb M, Chandrasena REP (2005) Highly reactive electrophilic oxidants in cytochrome P450 catalysis. Biochem Biophys Res Commun 338 394-403... 

Zhang H, Gay SC, Shah M, Foroozesh M, Liu J, Osawa Y, Zhang Q, Stout CD, Halpert JR, Hollenberg PF (2013) Potent mechanism-based inactivation of cytochrome P450 2B4 by 9-ethynylphen-anthrene implications for allosteric modulation of cytochrome P450 catalysis. Biochemistry 52 355-364... 

Zhang H, Lin HL, Walker VJ, Hamdane D, Hollenberg PF (2009) tert-Butylphenylacetylene is a potent mechanism-based inactivator of cytochrome P450 2B4 inhibition of cytochrome P450 catalysis by ste-ric hindrance. Mol Pharmacol 76 1011-1018... 

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Li S, LP Wackett (1993) Reductive dehalogenation by cytochrome P450(,j jy[ substrate binding and catalysis. Biochemistry 32 9355-9361. 

In the field of enzyme catalysis, heme-proteins such as cytochrome P450, for example, exhibit both types of 0-0 bond cleavages in organic hydroperoxides and peroxy acids (178). Heterolytic cleavage of HOOH/ROOH yields H20 or the corresponding alcohol, ROH and a ferryl-oxo intermediate (Scheme 4). Homolytic 0-0 bond cleavage results in the formation of a hydroxyl (HO ) or an alkoxyl (RO ) radical and an iron-bound hydroxyl radical. 

Zhou L, Erickson RR, Hardwick JP, Park SS, Wrighton SA, et al. 1997a. Catalysis of the cysteine conjugation and protein binding of acetaminophen by microsomes from a human lymphoblast line transfected with the cDNAs of various forms of human cytochrome P450. J Pharmacol Exp Ther 281 785-790. 

Guengerich, P.P. and Macdonald, T.L. (1984) Chemical mechanism of catalysis by cytochrome P450 a unify view, Acc. Chem. Res. 17, 9-16. 

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