Lecture: Chemical Mechanisms of Catalysis by Cytochrome P450 Enzymes: New Aspects of Cytochrome P450 Oxidations of Alkaloids, Vitamins, & Steroids 

Lecturer: Prof. F. Peter Guengerich, Vanderbilt University, USA 

Time: 9:30 am, Apr 19, 2016 

Location: Meeting Room 214 of Administration Building 

Research Description:

Prof. F. Peter Guengerich’s research laboratory is interested in the chemical and biological mechanisms by which drugs and cancer-causing chemicals are processed and the relevance to drug development, toxicity, and diseases. Their 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. They use approaches of site-directed and random mutagenesis, kinetic analysis, isotope effects, and substrate-activity relationships to understand the catalytic mechanisms of the human cytochrome P450 enzymes. They also focus on the bioactivation of halogenated hydrocarbons and bifunctional electrophiles by conjugation with the tripeptide glutathione (GSH) by GSH transferases or a DNA repair protein (O⁶-alkylguanine transferase). Studies on the polymerases involve the use of modified oligonucleotides, steady-state and pre-steady-state kinetics and x-ray diffraction to understand how carcinogen-DNA adducts cause polymerases to stall and misincorporate bases.  

Selected publications:

1.         Su, Y., Egli, M., and Guengerich, F. P. (2016) Mechanism of Ribonucleotide Incorporation by Human DNA Polymerase η. Journal of Biological Chemistry 291, 3747-3756 

2.         Chang, S.-c., Fedeles, B. I., Wu, J., Delaney, J. C., Li, D., Zhao, L., Christov, P. P., Yau, E., Singh, V., Jost, M., Drennan, C. L., Marnett, L. J., Rizzo, C. J., Levine, S. S., Guengerich, F. P., and Essigmann, J. M. (2015) Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo. Nucleic Acids Research 43, 5489-5500 

3.         Chowdhury, G., Cho, S.-H., Pegg, A. E., and Guengerich, F. P. (2013) Detection and Characterization of Ethylene Dibromide-Derived DNA-Crosslinks Formed with O(6)-Alkylguanine-DNA Alkyltransferase. Angewandte Chemie (International ed. in English) 52, 12879-12882 

4.        Zhao, L., Christov, P. P., Kozekov, I. D., Pence, M. G., Pallan, P. S., Rizzo, C. J., Egli, M., and Guengerich, F. P. (2012) Replication of N(2),3-Ethenoguanine by DNA Polymerases. Angewandte Chemie (International ed. in English) 51, 5466-5469 

5.         Cheng, Q., Lamb, D. C., Kelly, S. L., Lei, L., and Guengerich, F. P. (2010) Cyclization of a Cellular Dipentaenone by Streptomyces coelicolor Cytochrome P450 154A1 without Oxidation/Reduction. Journal of the American Chemical Society 132, 15173-15175 

6.         Cheng, Q., Sohl, C. D., and Guengerich, F. P. (2009) High-throughput fluorescence assay of cytochrome P450 3A4. Nature protocols 4, 10.1038/nprot.2009.1123 

7.         Guengerich, F. P., Martin, M. V., Sohl, C. D., and Cheng, Q. (2009) Measurement of cytochrome P450 and NADPH–cytochrome P450 reductase. Nature protocols 4, 10.1038/nprot.2009.1121 

8.         Sohl, C. D., Cheng, Q., and Guengerich, F. P. (2009) Chromatographic assays of drug oxidation by human cytochrome P450 3A4. Nature protocols 4, 10.1038/nprot.2009.1122 

9.         Chowdhury, G., and Guengerich, F. P. (2008) Direct Detection and Mapping of Sites of Base Modification in DNA Fragments by Tandem Mass Spectrometry. Angewandte Chemie International Edition 47, 381-384 

10.       Sanchez-Ponce, R., and Guengerich, F. P. (2007) Untargeted Analysis of Mass Spectrometry Data for Elucidation of Metabolites and Function of Enzymes. Analytical Chemistry 79, 3355-3362 

11.       Guengerich, F. P. (2006) A malleable catalyst dominates the metabolism of drugs. Proceedings of the National Academy of Sciences of the United States of America 103, 13565-13566 

12.       Guengerich, F. P. (2006) Interactions of Carcinogen-Bound DNA with Individual DNA Polymerases. Chemical Reviews 106, 420-452 

13.       Liebler, D. C., and Guengerich, F. P. (2005) Elucidating mechanisms of drug-induced toxicity. Nature Reviews Drug Discovery 4, 410-420