F. Peter Guengerich, Ph.D.

Harry Pearson Broquist Professor of Biochemistry 
Director of the Center in Molecular Toxicology 
Interim Chair, Department of Biochemistry
Ph.D., Vanderbilt University, 1973 (Biochemistry)

Major areas of interest include the metabolism of carcinogens and drugs by cytochrome P450 enzymes, the bioactivation of halogenated hydrocarbons, and polymerase interactions with carcinogen-modified DNA. Several approaches are being used to understand the catalytic mechanisms of the human cytochrome P450 enzymes, including site-directed and random mutagenesis, kinetic analysis, isotope effects, and substrate-activity relationships. One major area of interest is the identification of reactions catalyzed by the "orphan" P450s, those in humans and also Streptomyces that do not have characterized functions yet. Work on halogenated hydrocarbons is done with trichloroethylene, ethylene dibromide, and methylene dihalides and the adducts they form. Glutathione transferase-mediated bioactivation is under investigation, as well as in the case of some bifunctional electrophiles. Studies on the polymerases involve the use of modified oligonucleotides, steady-state and pre-steady-state kinetics, and physical approaches such as x-ray diffraction. A major goal is to understand how carcinogen-DNA adducts cause polymerases to stall and misincorporate bases.

Recent Publications

Shinkyo, R., and Guengerich, F.P. (2011) J. Biol. Chem. 286, 4632-4643. “Cytochrome P450 7A1 Cholesterol 7alpha-Hydroxylation. Individual Reaction Steps in the Catalytic Cycle and Rate-limiting Ferric Iron Reduction.”

Akiyoshi, T., Saito, T., Murase, S., Miyazaki, M., Murayama, N., Yamazaki, H., Guengerich, F.P., Nakamura, K., Yamamoto, K., and Ohtani, H. (2011) Drug Metab. Dispos. 39, 724-728.“Genetic Variation of Cytochrome P450 3A4 Affects the Inhibitory Profiles of Its Inhibitors.”

Yamazaki, H., Suemizu, H., Igaya, S., Shimizu, M., Shibata, N., Nakamura, M., Chowdhury, G., and Guengerich, F.P. (2011) Chem. Res. Toxicol. 24, 287-289. “In Vivo Formation of a Glutathione Conjugate Derived from Thalidomide in Humanized uPA-NOG Mice.”

Amunom, I., Stephens, L.J., Tamasi, V., Cai, J., Conklin, D.J., Srivastava, S., Martin, M.V., Guengerich, F.P., and Prough, R.A. (2011) Chem. Res. Toxicol. 24, 1223-1230. “Cytochromes P450 Catalyze the Reduction of alpha,beta-Unsaturated Aldehydes.”

Xiao, Y., Shinko, R., and Guengerich, F.P. (2011) Drug Metab. Dispos. 39, 944-946. “Cytochrome P450 2S1 is Reduced by NADPH-Cytrochrome P450 Reductase.”

Shanmugam, G., Kozekov, I., Rizzo, C., Guengerich, F.P., and Stone, M.P. (2011) Chem. Res. Toxicol. 24, 1071-1079. “1,N2-Etheno-2’-deoxyguanosine Adopts the syn Conformation About the Glycosyl Bond When Mismatched with Deoxyadenosine.”

Shinkyo, R., and Guengerich, F.P. (2011) J. Biol. Chem. 286, 18426-18433. “Inhibition of Human Cytochrome P450 3A4 by Cholesterol.”

Salamanca-Pinzón, G.S., and Guengerich, F.P. (2011) Protein Exp. Purif. 79, 231-236. ”A Tricistronic Human Adrenodoxin Reductase-Adrenodoxin-Cytrochrome P450 27A1 Vector System for Substrate Hydroxylation in Escherichia coli.”

Choi, J-Y., Eoff, R.L., Wang, J., Pence, M.G., Martin, M.V., Kim, E-J., Folkmann, L.M., and Guengerich, F.P. (2011) J. Biol. Chem 286, 31180-31193. “Roles of the Four DNA Polymerases of the Crenarchaeon Sulfolobus solfataricus and Accessory Proteins in DNA Replication.”

Shimada, T., Murayama, N., Tanaka, K., Takenaka, S., Guengerich, F.P., Yamazaki, H., and Komori, M. (2011) Chem. Res. Toxicol. 24, 1327-1337. “Spectral Modification and Catalytic Inhibition of Human Cytochromes P450 1A1, 1A2, 1B1, 2A6, and 2A13 by Four Chemopreventive Organoselenium Compounds.”

Shinkyo, R., Xu, L., Tallman, K.A., Cheng, Q., Porter, N.A., and Guengerich, F.P. (2011, in press) J. Biol. Chem. “Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate.”

Guengerich, F.P., Eoff, R.L., and Choi, J-Y., (2011) in, Chemical Carcinogenesis (Penning, T.M., Ed.) Springer, Berlin (part of Current Cancer Res. El-Diery, W., Series Ed.), pp. 345-373. “By-pass DNA Polymerases.” (Review)

Guengerich, F.P., Tang, Z., Cheng, Q., and Salamanca-Pinzón, S.G. (2011) Biochem. Biophys. Acta. 1814, 139-145. “Approaches to Deorphanization of Human and Microbial Cytochrome P450 Enzymes.” (Review)

Guengerich, F.P. Sohl, C.D., and Chowdhury, G. (2011) Arch. Biochem. Biophys. 507, 126-134. “Multi-step Oxidations Catalyzed by Cytochrome P450 Enzymes: Processive vs. Distributive Kinetics and the Issue of Carbonyl Oxidation in Chemical Mechanisms.”(Review)

Guengerich, F.P. (2011) Drug Metab. Pharmacokin. 26, 3-14. “Mechanisms of Drug Toxicity and Role of Bioactivation.” (Review)

Guengerich, F.P., and Cheng, Q. (2011) Pharmacol. Rev. 63, 684-699. “Orphans in the Human Cytochrome P450 Family: Approaches to Discovering Function and Relevance to Pharmacology.” (Review)