Enzymatic oxidation of xenobiotic chemicals.
Studies with biomimetic models can yield considerable insight into mechanisms of enzymatic catalysis. The discussion above indicates how such information has been important in the cases of flavoproteins, hemoproteins, and, to a lesser extent, the copper protein dopamine beta-hydroxylase. Some of the moieties that we generally accept as intermediates (i.e., high-valent iron oxygen complex in cytochrome P-450 reactions) would be extremely hard to characterize were it not for biomimetic models and more stable analogs such as peroxidase Compound I complexes. Although biomimetic models can be useful, we do need to keep them in perspective. It is possible to alter ligands and aspects of the environment in a way that may not reflect the active site of the protein. Eventually, the model work needs to be carried back to the proteins. We have seen that diagnostic substrates can be of considerable use in understanding enzymes and examples of elucidation of mechanisms through the use of rearrangements, mechanism-based inactivation, isotope labeling, kinetic isotope effects, and free energy relationships have been given. The point should be made that a myriad of approaches need to be applied to the study of each enzyme, for there is potential for misleading information if total reliance is placed on a single approach. The point also needs to be made that in the future we need information concerning the structures of the active sites of enzymes in order to fully understand them. Of the enzymes considered here, only a bacterial form of cytochrome P-450 (P-450cam) has been crystallized. The challenge to determine the three-dimensional structures of these enzymes, particularly the intrinsic membrane proteins, is formidable, yet our further understanding of the mechanisms of enzyme catalysis will remain elusive as long as we have to speak of putative specific residues, domains, and distances in anecdotal terms. The point should be made that there is actually some commonality among many of the catalytic mechanisms of oxidation, even among proteins with different structures and prosthetic groups. Thus, we see that cytochrome P-450 has some elements of a peroxidase and vice versa; indeed, the chemistry at the prosthetic group is probably very similar and the overall chemistry seems to be induced by the protein structure. The copper protein dopamine beta-hydroxylase appears to proceed with chemistry similar to that of the hemoprotein cytochrome P-450 and, although not so thoroughly studied, the non-heme iron protein P. oleovarans omega-hydroxylase.(ABSTRACT TRUNCATED AT 400 WORDS)
Guengerich
F P
FP
University of Illinois, Urbana.
D000818:Animals; D001711:Biotransformation; D002384:Catalysis; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010544:Peroxidases / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism*
D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D010544:Peroxidases