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. 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

Nguyen LP, Hsu EL, Chowdhury G, Dostalek M, Guengerich FP, Bradfield CA. d-Amino acid oxidase generates agonists of the aryl hydrocarbon receptor from d-tryptophan. Chem Res Toxicol. 2009 [Epub ahead of print]

Chowdhury G, Dostalek M, Hsu EL, Nguyen LP, Stec DF, Bradfield CA, Guengerich FP. Structural identification of diindole agonists of the aryl hydrocarbon receptor derived from degradation of indole-3-pyruvic acid. Chem Res Toxicol. 2009 [Epub ahead of print]

Zhang H, Beckman JW, Guengerich FP. Frameshift deletion by sulfolobus solfataricus P2 DNA polymerase Dpo4 T239W is selective for purines and involves normal conformational change followed by slow phosphodiester bond formation. J Biol Chem. 2009 [Epub ahead of print]

Sangar MC, Anandatheerthavarada HK, Martin MV, Guengerich FP, Avadhani NG. Identification of genetic variants of human cytochrome P450 2D6 with impaired mitochondrial targeting. Mol Genet Metab. 2009 [Epub ahead of print]

Deweese JE, Guengerich FP, Burgin AB, Osheroff N. Metal ion interactions in the DNA cleavage/ligation active site of human topoisomerase IIalpha. Biochemistry. 2009 48:8940-8947.

Cheng Q, Sohl CD, Guengerich FP. High-throughput fluorescence assay of cytochrome P450 3A4. Nat Protoc. 2009 4:1258-1261.

Sohl CD, Cheng Q, Guengerich FP. Chromatographic assays of drug oxidation by human cytochrome P450 3A4. Nat Protoc. 2009 4:1252-1257.

Guengerich FP, Martin MV, Sohl CD, Cheng Q. Measurement of cytochrome P450 and NADPH-cytochrome P450 reductase. Nat Protoc. 2009 4:124512-51.

Zhang H, Bren U, Kozekov ID, Rizzo CJ, Stec DF, Guengerich FP. Steric and electrostatic effects at the C2 atom substituent influence replication and miscoding of the DNA deamination product deoxyxanthosine and analogs by DNA polymerases. J Mol Biol. 2009 392:251-269.

Nagashima S, Shimizu M, Yano H, Murayama N, Kumai T, Kobayashi S, Guengerich FP, Yamazaki H. Inter-individual variation in flavin-containing monooxygenase 3 in livers from Japanese: correlation with hepatic transcription factors. Drug Metab Pharmacokinet. 2009 24:218-225.

Shimada T, Tanaka K, Takenaka S, Foroozesh MK, Murayama N, Yamazaki H, Guengerich FP, Komori M. Reverse type I binding spectra of human cytochrome P450 1B1 induced by flavonoid, stilbene, pyrene, naphthalene, phenanthrene, and biphenyl derivatives that inhibit catalytic activity: a structure-function
relationship study. Chem Res Toxicol. 2009 22:1325-1333.

Grobe N, Zhang B, Fisinger U, Kutchan TM, Zenk MH, Guengerich FP. Mammalian cytochrome P450 enzymes catalyze the phenol-coupling step in endogenous morphine biosynthesis. J Biol Chem. 2009 284:24425-24431.

Wu ZL, Qiao J, Zhang ZG, Guengerich FP, Liu Y, Pei XQ. Enhanced bacterial expression of several mammalian cytochrome P450s by codon optimization and chaperone coexpression. Biotechnol Lett. 2009 31:1589-593.

Shimada T, Murajama N, Tanaka K, Takenaka S, Imai Y, Hopkins NE, Foroozesh MK, Alworth WL, Yamazaki H, Guengerich FP, Komori M. Interaction of polycyclic aromatic hydrocarbons with human cytochrome P450 1B1 in inhibiting catalytic activity. Chem Res Toxicol. 2008 21:2313-2323.

Zhang H, Eoff RL, Kozekov ID, Rizzo CJ, Egli M, Guengerich FP. Structure-function relationships in miscoding by Sulfolobus solfataricus DNA polymerase Dpo4: guanine N2,N2-dimethyl substitution produces inactive and miscoding polymerase complexes. J Biol Chem. 2009 284:17687-17699.

Irimia A, Eoff RL, Guengerich FP, Egli M. Structural and functional elucidation of the mechanism promoting error-prone synthesis by human DNA polymerase kappa opposite the 7,8-dihydro-8-oxo-2'-deoxyguanosine adduct. J Biol Chem. 2009 284:22467-22480.

Eoff RL, Sanchez-Ponce R, Guengerich FP. Conformational changes during nucleotide selection by Sulfolobus solfataricus DNA polymerase Dpo4. J Biol Chem. 2009 284:21090-21099.

Chowdhury G, Guengerich FP. Tandem mass spectrometry-based detection of c4'-oxidized abasic sites at specific positions in DNA fragments. Chem Res Toxicol. 2009 22:1310-1319.

Eoff RL, Stafford JB, Szekely J, Rizzo CJ, Egli M, Guengerich FP, Marnett LJ. Structural and functional analysis of Sulfolobus solfataricus Y-family DNA polymerase Dpo4-catalyzed bypass of the malondialdehyde-deoxyguanosine adduct. Biochemistry. 2009 48:7079-7088.

Sangar MC, Anandatheerthavarada HK, Tang W, Prabu SK, Martin MV, Dostalek M, Guengerich FP, Avadhani NG. Human liver mitochondrial cytochrome P450 2D6--individual variations and implications in drug metabolism. FEBS J. 2009 276:3440-3453.

Voehler MW, Eoff RL, McDonald WH, Guengerich FP, Stone MP. Modulation of the structure, catalytic activity, and fidelity of African swine fever virus DNA polymerase X by a reversible disulfide switch. J Biol Chem. 2009 284:18434-18444.

Christov PP, Angel KC, Guengerich FP, Rizzo CJ. Replication past the N5-methyl-formamidopyrimidine lesion of deoxyguanosine by DNA polymerases and an improved procedure for sequence analysis of in vitro bypass products by mass spectrometry. Chem Res Toxicol. 2009 22:1086-1095.

Choi JY, Lim S, Eoff RL, Guengerich FP. Kinetic analysis of base-pairing preference for nucleotide incorporation opposite template pyrimidines by human DNA polymerase iota. J Mol Biol. 2009 389:264-274.

Loecken EM, Dasari S, Hill S, Tabb DL, Guengerich FP. The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems. Chem Res Toxicol. 2009 22:1069-1076.

Guengerich FP. Thematic minireview series: metals in biology. J Biol Chem. 2009 284:18557.

Tang Z, Martin MV, Guengerich FP. Elucidation of functions of human cytochrome P450 enzymes: identification of endogenous substrates in tissue extracts using metabolomic and isotopic labeling approaches. Anal Chem. 2009 81:3071-3078.

Brown KL, Bren U, Stone MP, Guengerich FP. Inherent stereospecificity in the reaction of aflatoxin B(1) 8,9-epoxide with deoxyguanosine and efficiency of DNA catalysis. Chem Res Toxicol. 2009 22:913-917.

Guengerich FP. Introduction: Human metabolites in safety testing (MIST) issue. Chem Res Toxicol. 2009 22:237-238.

Knutson CG, Rubinson EH, Akingbade D, Anderson CS, Stec DF, Petrova KV, Kozekov ID, Guengerich FP, Rizzo CJ, Marnett LJ. Oxidation and glycolytic cleavage of etheno and propano DNA base adducts. Biochemistry. 2009 48:800-809.

Stafford JB, Eoff RL, Kozekova A, Rizzo CJ, Guengerich FP, Marnett LJ. Translesion DNA synthesis by human DNA polymerase eta on templates containing a pyrimidopurinone deoxyguanosine adduct, 3-(2'-deoxy-beta-d-erythro-pentofuranosyl)pyrimido-[1,2-a]purin-10(3H)-one. Biochemistry. 2009 48:471-480.

Zhang H, Eoff RL, Kozekov ID, Rizzo CJ, Egli M, Guengerich FP. Versatility of Y-family Sulfolobus solfataricus DNA polymerase Dpo4 in translesion synthesis past bulky N2-alkylguanine adducts. J Biol Chem. 2009 284:3563-3576.

Beckman JW, Wang Q, Guengerich FP. Kinetic analysis of correct nucleotide insertion by a Y-family DNA polymerase reveals conformational changes both prior to and following phosphodiester bond formation as detected by tryptophan fluorescence. J Biol Chem. 2008 283:36711-36723.

Zhang ZG, Liu Y, Guengerich FP, Matse JH, Chen J, Wu ZL. Identification of amino acid residues involved in 4-chloroindole 3-hydroxylation by cytochrome P450 2A6 using screening of random libraries. J Biotechnol. 2009 139:12-18.

Okada Y, Murayama N, Yanagida C, Shimizu M, Guengerich FP, Yamazaki H. Drug interactions of thalidomide with midazolam and cyclosporine A: heterotropic cooperativity of human cytochrome P450 3A5. Drug Metab Dispos. 2009 37:18-23.

Fang Q, Noronha AM, Murphy SP, Wilds CJ, Tubbs JL, Tainer JA, Chowdhury G, Guengerich FP, Pegg AE. Repair of O6-G-alkyl-O6-G interstrand cross-links by human O6-alkylguanine-DNA alkyltransferase. Biochemistry. 2008 47:10892-10903.

Guengerich FP. Thematic series: metals in biology. J Biol Chem. 2009 284:709.

Shanmugam G, Kozekov ID, Guengerich FP, Rizzo CJ, Stone MP. Structure of the 1,N2-ethenodeoxyguanosine adduct opposite cytosine in duplex DNA: Hoogsteen base pairing at pH 5.2. Chem Res Toxicol. 2008 21:1795-1805.

Miyazaki M, Nakamura K, Fujita Y, Guengerich FP, Horiuchi R, Yamamoto K. Defective activity of recombinant cytochromes P450 3A4.2 and 3A4.16 in oxidation of midazolam, nifedipine, and testosterone. Drug Metab Dispos. 2008 36:2287-2291.

Isin EM, Guengerich FP. Substrate binding to cytochromes P450. Anal Bioanal Chem. 2008 392:1019-1030. Review.

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

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

Stark K, Wu ZL, Bartleson CJ, Guengerich FP. mRNA distribution and heterologous expression of orphan cytochrome P450 20A1. Drug Metab Dispos. 2008 36:1930-1937.

Schadt EE, Molony C, Chudin E, Hao K, Yang X, Lum PY, Kasarskis A, Zhang B, Wang S, Suver C, Zhu J, Millstein J, Sieberts S, Lamb J, GuhaThakurta D, Derry J, Storey JD, Avila-Campillo I, Kruger MJ, Johnson JM, Rohl CA, van Nas A, Mehrabian M, Drake TA, Lusis AJ, Smith RC, Guengerich FP, Strom SC, Schuetz E, Rushmore TH, Ulrich R. Mapping the genetic architecture of gene expression in human liver. PLoS Biol. 2008 6:e107.

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. 2008 283:17147-17157.

Bodreddigari S, Jones LK, Egner PA, Groopman JD, Sutter CH, Roebuck 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. 2008 21:1134-1142.

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

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

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

Guengerich FP. Cytochrome p450 and chemical toxicology. Chem Res Toxicol. 2008 21:70-83. Review.

Kim DH, Kim KH, Isin EM, Guengerich FP, Chae HZ, Ahn T, Yun CH. Heterologous expression and characterization of wild-type human cytochrome P450 1A2 without conventional N-terminal modification in Escherichia coli. Protein Expr Purif. 2008 57:188-200.

Chowdhury G, Guengerich FP. Direct detection and mapping of sites of base modification in DNA fragments by tandem mass spectrometry. Angew Chem Int Ed Engl. 2008 47:381-384.

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