The intent of the present project is to exploit the self-catalyzed prosthetic heme alkylation associated with xenobiotic metabolism to characterize the mechanism and the active site of cytochrome P-450 enzymes. In addition, the toxicological consequences of cytochrome P-450 inactivation, and its possible utility in the case of isozyme-specific agents, is also to be examined. Experiments are proposed to: (a) determine where in the catalytic sequence heme alkylation diverges from metabolite formation, (b) define the role of free radicals in heme alkylation, and the importance of radical cation intermediates in normal catalysis by cytochrome P-450, (e) outline the topology of the active site of these enzymes, (f) develop isozyme-specific suicide substrates for cytocchrome P-450, particularly for isozymes involved in lipid metabollism, (g) clarify the inhibition of heme adducts with heme biosynthetic enzymes.
| de Montellano, Paul R Ortiz (2018) 1-Aminobenzotriazole: A Mechanism-Based Cytochrome P450 Inhibitor and Probe of Cytochrome P450 Biology. Med Chem (Los Angeles) 8: |
| Zhao, Yan; Wan, Debin; Yang, Jun et al. (2016) Catalytic Activities of Tumor-Specific Human Cytochrome P450 CYP2W1 Toward Endogenous Substrates. Drug Metab Dispos 44:771-80 |
| Conner, Kip P; Cruce, Alex A; Krzyaniak, Matthew D et al. (2015) Drug modulation of water-heme interactions in low-spin P450 complexes of CYP2C9d and CYP125A1. Biochemistry 54:1198-207 |
| Basudhar, Debashree; Madrona, Yarrow; Kandel, Sylvie et al. (2015) Analysis of cytochrome P450 CYP119 ligand-dependent conformational dynamics by two-dimensional NMR and X-ray crystallography. J Biol Chem 290:10000-17 |
| Varfaj, Fatbardha; Zulkifli, Siti N A; Park, Hyoung-Goo et al. (2014) Carbon-carbon bond cleavage in activation of the prodrug nabumetone. Drug Metab Dispos 42:828-38 |
| Frank, Daniel J; Madrona, Yarrow; Ortiz de Montellano, Paul R (2014) Cholesterol ester oxidation by mycobacterial cytochrome P450. J Biol Chem 289:30417-25 |
| Conner, Kip P; Schimpf, Alina M; Cruce, Alex A et al. (2014) Strength of axial water ligation in substrate-free cytochrome P450s is isoform dependent. Biochemistry 53:1428-34 |
| Nishida, Clinton R; Everett, Steven; Ortiz de Montellano, Paul R (2013) Specificity determinants of CYP1B1 estradiol hydroxylation. Mol Pharmacol 84:451-8 |
| Straub, Wesley E; Nishida, Clinton R; de Montellano, Paul R Ortiz (2013) Expression in Escherichia coli of a cytochrome P450 enzyme with a cobalt protoporphyrin IX prosthetic group. Methods Mol Biol 987:107-13 |
| Ortiz de Montellano, Paul R (2013) Cytochrome P450-activated prodrugs. Future Med Chem 5:213-28 |
Showing the most recent 10 out of 154 publications
