F. Peter Guengerich, Ph.D.

Harry Pearson Broquist Professor of Biochemistry 
Director of the Center in Molecular Toxicology 
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. 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

Eoff RL, Irimia A, Egli M, Guengerich FP. Sulfolobus solfataricus DNA polymerase Dpo4 is partially inhibited by “wobble” pairing between O6-methylguanine and cytosine but accurate bypass is preferred. J Biol Chem 282:1456-1467, 2007.

Isin EM, Guengerich FP. Multiple sequential steps involved in the binding of inhibitors to cytochrome P450 3A4. J Biol Chem 282:6863-6874, 2007.

Shimada T, Murayama N, Okada K, Funae Y, Yamazaki H, Guengerich FP. Different mechanisms for inhibition of human cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic inhibitors. Chem Res Toxicol 20:489-496, 2007.

Eoff RL, Angel KC, Egli M, Guengerich FP. Molecular basis of selectivity of nucleoside triphosphate incorporation opposite O6-benzylguanine by Sulfolobus solfataricus DNA polymerase: steady-state and pre-steady-state kinetics and X-ray crystallography of correct and incorrect pairing. J Biol Chem 282:13573-13584, 2007.

Sanchez-Ponce R, Guengerich FP. Untargeted analysis of mass spectrometry data for elucidation of function of new enzymes. Anal Chem 79:3355-3362, 2007.

Chun Y-J, Shimada T, Sanchez-Ponce R, Martin MV, Lei L, Zhao B, Kelly SL, Waterman MR, Lamb DC, Guengerich FP. Electron transfer pathways for a Streptomyces cytochrome P450. Cytochrome P450 105D5-catalyzed fatty acid hydroxylation in Streptomyces coelicolor A3(2). J Biol Chem 282:17486-17500, 2007.

Kolvenbach B, Schlaich N, Raoui Z, Prell J, Zühlke S, Schäfter A, Guengerich FP, Corvini PFX. Degradation of bisphenol A. Does ipso-substitution apply to phenols para-substituted by a quartenary C-alpha structure? Appl Environ Microbiol 73, 4476-4784, 2007.

Eoff RL, Irimia A, Angel K, Egli M, Guengerich FP. Hydogen bonding of 7,8-dihydro-8-oxodeoxyguanosine with a charged residue in the little finger domain determines miscoding events in Sulfolobus solfataricus DNA polymerase Dpo4. J Biol Chem 282:19831-19843, 2007. (selected as a Paper of the Week)

Bren U, Guengerich FP, Marvi J. Guanine alkylation by the potent carcinogen aflatoxin B1: quantum-chemical calculations. Chem Res Toxicol 20:1134-1140, 2007.

Watanabe K, Liberman RG, Skipper PL, Tannenbaum SR, Guengerich FP. Analysis of DNA adducts formed in vivo in rats and mice from 1,2-dibromoethane, 1,2- dichloromethane, dibromomethane, and dichloromethane using HPLC/1 accelerator mass spectrometry and relevance to risk estimates. Chem Res Toxicol 20:1594-1600, 2007.

Shanmugam G, Goodenough AK, Kozekov ID, Guengerich FP, Rizzo CJ, Stone MP. Structure of the 1, N2-etheno-2?-deoxyguanosine adduct in duplex DNA at pH 8.6. Chem Res Toxicol 20:1601-1611, 2007.

Dostalek M, Brooks JD, Hardy KD, Milne GL, Moore MM, Sharma S, Morrow JD, Guengerich FP. In Vivo oxidative damage in rats is associated with barbiturate response but not other cytochrome P450 inducers. Mol Pharmacol 72:1419-1424, 2007.

Irimia A, Eoff RL, Pollon PS, Guengerich FP, Egli M. Structure and Activity of Y-class DNA Polymerase Dpo4 from Sulfolobus solfataricus with Template Containing the Hydrophobic Thymine Analog 2, 4-Difluorotoluene.” J Biol Chem 282:36421-36433, 2007.

Kim D-H, Kim K-H, Isin EM, Guengerich FP, Chae HZ, Ahn T, Yun C-H. Heterologous Expression and characterization of wild-type human cytochrome P450 1A2 without conventional N-Terminal modification in Escheriehia coli. Prot Expr Purif 57:188-200, 2008.

Dimitri A, Goodenough AK, Guengerich FP, Broyde S, Scicchifano DA. Transcription processing at 1,N2 ethenoguanine by human RNA polymerase II and bacteriophage T7 RNA polymerase. J Mol Biol 375:353-366, 2008.

Loecken EM, Guengerich FP. Reactions of bis-electrophiles with glyceraldehyde 3-phosphate dehydrogenase sulfhydryl groups produce DNA crosslinks but not mutations. Chem Res Toxicol 21:453-458, 2008.

Sohl CD, Isin EM, Eoff RL, Marsch GA, Stec DF, Guengerich FP. Cooperativity in oxidation reactions by cytochrome P450 1A2. Highly cooperative pyrene hydroxylation and multiphasic kinetics of ligand binding. J Biol Chem 283:7293-7308, 2008.

Shanmugan G, Goodenough AK, Kozekov ID, Guengerich FP, Rizzo CJ, Stone MJ. Structure of the 1,N2 ethenodeoxyguanosine adduct opposite cytosine in duplex DNA: Hoogsteen base pairing at pH 5.2. Chem Res Toxicol 283, 7293-7308, 2008.

Bodreddigari S, Jones LK, Egner PA, Groopman JD, Sutter CH, Roeback BD, Guengerich FP, Kensler TW, Sutter TR. Protection against aflatoxin b1-induced cytotoxicity by expression of the cloned aflatoxin B1-aldehyde reductases rat AKR7A1 and human AKR7A3. Chem Res Toxicol 21:1134-1142, 2008.

Isin EM, Sohl CD, Eoff RL, Guengerich FP. Cooperativity of cytochrome P450 1A2: interaction of 1,4-phenylene diisocyanide and 1-alkoxy-4-nitrobenzenes. Arch Biochem Biophys 473:69-75, 2008.

Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum P, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Mehrabian M, Drake TA, Lusis AJ, Serikawa KA, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R. Mapping the genetic architecture of gene expression in human liver. PLoS Biol 6:e107, 2008.

Dostalek M, Hardy KD, Milne GL, Morrow JD, Chen C, Gonzalez FJ, Gu J, Ding X, Johnson DA, Johnson JA, Martin MV, Guengerich FP. Development of oxidative stress by cytochrome P450 induction in rodents is selective for barbiturates and related to loss of pyridine nucleotide-dependent protective systems. J Biol Chem 283:17147-17157, 2008.

Stark K, Dostalek M, Guengerich FP. Expression and purification of orphan cytochrome P450 4X1 and oxidation of anandamide. FEBS J. 275:3706-3717, 2008.

Choi J-Y, Guengerich FP. Kinetic analysis of translesion synthesis opposite bulky N2- and O6-alkyl guanine DNA adducts by human DNA polymerase REV1. J Biol Chem 283:23645-23655, 2008.

Miyazaki M, Nakamura K, Fujita Y, Guengerich FP, Yamamoto K, Horiuchi, R. Functional characterization of single nucleotide polymorphisms with amino acid substitution in cytochrome P450 3A4. Drug Metab Dispos, in press, 2008.

Stark K, Wu Z-L, Bartleson CJ, Guengerich FP. mRNA Distribution and heterologous expression of orphan cytochrome P450 20A1. Drug Metab Dispos, in press, 2008.

Fang Q, Noronha AM, Wilds CJ, Tubbs JL, Tainer JA, Chowdhury G, Guengerich FP, Pegg AE. Repair of O6-G-alkyl-O6-G interstrand cross-link by O6-alkylguanine-DNA alkyltransferase. Biochemistry, in press, 2008.