P450 functional models

Nitric oxide reactivity toward P450 functional models... 

Metallo-phthallocyanine (MePc) complexes are known as mild oxygenation catalysts for alkanes and alkenes and as functional models for enzymes, more in particular for monooxygenases like Cytochrome P450.[44] Among the many possible supports for such complexes, zeolite FAU topologies1451 are excellent materials for their encapsulation. [46 50] The low solubility of Me Pc complexes in general and their tendency to form adducts even in solution, giving rise to self-oxidation and subsequent self-destruction phenomena, make them the ideal candidates for their distribution as individual species on a solid support. 

Masumoto, H. Takeuchi, K. Ohta, S. and Hirobe, M. Application of chemical P450 model systems to studies on drug metabolism. I. Phencyclidine A multi-functional model substrate. Chem Pharm Bull 3Hl) m- 19, 1989. 

Renaud, J.P., C. Cullin, D. Pompon, P. Beaune, and D. Mansuy (1990). Expression of human liver cytochrome P450 1IIA4 in yeast. A functional model for the hepatic enzyme. Eur. J. Biochem. 194 889-896. 

KO mice Marked species differences in substrate specificity, activity, and induction limit translation Compensation by other enzymes, transporters, or receptors upon deletion of single gene Functional redundancy limits interpretation P450s KO models generally not useful due to species differences Transporters compound transporter KO models can be used to assess contributions to CNS penetration and oral bioavailabUity Nuclear receptors compound PXR/CAR and AhR mice useful for some induction liabilities where species-specific activation is not observed... 

Szklarz GD, Halpert JR. Use of homology modeling in conjunction with site-directed mutagenesis for analysis of structure-function relationships of mammalian cytochromes P450. Life Sci 1997 61 2507-20. 

Szklarz GD, Graham SE, Paulsen MD. Molecular modeling of mammalian cytochromes P450 application to study enzyme function. Vitamins Hormones 2000 58 53-87. 

More recently, an indirect method of electrochemical detoxification of organisms has been put into practice. It is based on a model of the detoxifying function of the liver. A normal liver produces cytochrome P450, which assures the hydroxylation... 

S.3 Cytochrome P450 Model Compounds Functional. Ferric-peroxo species are part of the cytochrome P450 catalytic cycle as discussed previously in Section 7.4.4. For instance, these ferric-peroxo moieties are known to act as nucleophiles attacking aldehydic carbon atoms in oxidative deformylations to produce aromatic species.An example of this work, establishing the nucleophilic nature of [(porphyrin)Fe (02)] complexes, was achieved for alkene epoxidation reactions by J. S. Valentine and co-workers. The electron-deficient compound menadione (see Figure 7.18) yielded menadione epoxide when reacted with a [(porphyrin)Fe X02)] complex. 

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