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CYP Comparison

The rate and the site of metabolism for xenobiotics are due to a complex mixture of recognition, shape and chemical reactivity. The human cytochrome P450 shape in proximity to the reactive heme plays a fundamental role in molecular recognition and orientation. Thus, the CYP cavity shape modulates the likelihood of a compound reacting with the enzyme, since it has to enter into the cavity, reach the reactive site (the heme), adopt a stable orientation to allow the reaction to occur and subsequently exit from the cavity. Different cytochromes show different cavity shape, and in silico prediction cannot neglect their key role. [Pg.112]

The Pathfinder approach was used to compare the CYP cavities of CYP2C9 [8], 2D6 [9], and 3A4 [10], the most important human cytochrome enzymes. CYP2C9 and 3A4 were available as protein crystal structures whilst an homology model was used for 2D6. Frequency distribution plots (Fig. 5.8) were obtained from non-superposed CYP structures, selecting the iron in the heme moiety as a root departure path. [Pg.112]

These qualitative statements are due to a simple graphical analysis of the cavity frequency distribution plot compared in Fig. 5.8. However, each cavity can be inspected and compared in detail. For example, the peak indicated by the arrow in Fig. 5.8 for 3A4 corresponds to the path-distance pairs reported in red color in Fig. 5.8(d). They end up far away from the heme in a subpocket region generated by the residues Leu 211 and Tyr 307. This subpocket is not present in the other CYPs and can be involved in a selective recognition of the substrate molecule. [Pg.112]

The reported procedure can be used to map the entire active site of an enzyme, or, if linked with appropriate statistical analysis, the selective regions in a protein family. [Pg.112]


Yamamoto T, Itoga H, Kohno Y, Nagata K, Yamazoe Y. Prediction of oral clearance from in vitro metabolic data using recombinant CYPs comparison among... [Pg.259]


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