Cytochrome P450 protein

Figure 8.1 Schematic of a typical cytochrome P450 protein showing the approximate locations for the heme binding domain, the proline-rich region and the I helix.

Cytochrome P450 Protein Modeling and Ligand Docking... 

Jean P, Pothier J, Dansette PM, et al. Automated multiple analysis of protein structures application to homology modeling of cytochromes P450. Proteins 1997 28 388-404. 

Batard, Y., Robineau, T., Durst, F., Werck-Reichart, D., and Didierjean, L., Use of Helianthus tuberosus Cytochrome P450 Protein CYP76B1 for Improved Resistance to Phenylurea Herbicides and Pesticides in Transgenic Plants and for Soil and groundwater bioremediation, U.S. Patent 6376753, 2002. 

VETTER, H.P., MANGOLD, U. SCHRODER, G., MARNER, F.J., WERCK REICHERT, D., SCHRODER, J., Molecular analysis and heterologous expression of an inducible cytochrome P450 protein from periwinkle (Catharanhtus roseus L.)., Plant Physiol., 1992,100,998-1007... 

MANGOLD, U EICHEL, J., BATSCHAUER, A., LENZ, A., KAISER, T SPANGENBERG, G., WERCK-REICHHART, D, SCHRODER, J., Gene and cDNA for plant cytochrome P450 proteins (CYP 72 family) from Catharanthus roseus and transgenic expression in tobacco and Arabidopsis thaliana., Plant Sci., 1994, 96, 129-136. 

Table 5 Metabolic Activation of Chemical Carcinogens by Rat Hepatic Cytochrome P450 Proteins ...

George J, Murray M, Byth K, et al. (1995) Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. 

Ortiz de Montellano PR, ed. Cytochrome P450 Structure, Mechanism, and Biochemistry. 2nd edition. 1995. Plenum Press, New York. Sigel A, Sigel H, Sigel RKO, eds. The Ubiquitous Roles of Cytochrome P450 Proteins, Volume 3 Metal Ions in Life Sciences. 2007. John Wiley Sons, Ltd., Chichester, UK. 

The cytochrome P450 system, found in microsomal and inner mitochondrial membranes (Figure IOC), consists of two enzymes NADPH-cytochrome P450 reductase and cytochrome 450 In each reaction two electrons are transferred one at a time from NADPH to a cytochrome P450 protein by NADPH cytochrome P450 reductase. The latter enzyme is a flavoprotein that contains both FAD and FMN in a ratio of 1 1 per mole of enzyme. 

The 2 CYPIA proteins have been isolated from the livers of a number of animal species, purified, and shown to share extensive structural similarity and to display similar substrate specificity. The human orthologue of CYP1A2 has been isolated from liver and shown to metabolize the same substrates, and to play the same role in carcinogen activation, as the rodent proteins [9]. The human CYPlAl has not been purified but it has been expressed in mammalian cells like the rodent orthologue, it catalyses the oxidation of polycyclic aromatic hydrocarbons and the N-oxidation of aromatic amines [10]. This apparent similarity in substrate specificity between the human and rodent CYPIA proteins would indicate that where CYPIA is involved, toxicological data can, in principle, be extrapolated to man with more confidence. Of the cytochrome P450 proteins so far characterized, the CYPl family appears to be the most conserved within the phylogenetic tree [11]. 

Although other xenobiotic-metabolizing cytochrome P450 proteins may activate a very limited number of chemicals, and at relatively low rates when compared with the CYPl family, the latter is considered the most important in chemical carcinogenesis, and possibly also in the aetiology of human cancer, for the following reasons ... 

Polymorphism in cytochrome P450 proteins has often been linked to human cancer risk... 

The realization that the toxicological fate of a chemical may be determined largely by the nature of the cytochrome P450 proteins with which it interacts, as this determines the site of oxidation and consequently the formation of reactive intermediates, led us to consider the possibility of devising a means by which the particular enzymic catalyst of the metabolism of a given chemical could be predicted. Since the CYPIA proteins are undoubtedly the most closely linked to chemical carcinogenesis, it was natural that they were the prime object of attention. 

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