F Guengerich

Summary

Affiliation: Vanderbilt University
Country: USA

Publications

  1. ncbi request reprint Where is toxicology headed in the future?
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Drug Metab Rev 36:475-86. 2004
  2. pmc New trends in cytochrome p450 research at the half-century mark
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 288:17063-4. 2013
  3. pmc Unusual cytochrome p450 enzymes and reactions
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 288:17065-73. 2013
  4. pmc Thematic minireview series: metals in biology 2013
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    J Biol Chem 288:13164. 2013
  5. pmc Thematic minireview series: Metals in Biology 2012
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 287:13508-9. 2012
  6. pmc Thematic minireview series: metals in biology
    F Peter Guengerich
    Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 284:18557. 2009
  7. doi request reprint Thematic series: metals in biology
    F Peter Guengerich
    Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 284:709. 2009
  8. ncbi request reprint Mechanisms of cytochrome P450 substrate oxidation: MiniReview
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Nashville, TN 37232 0146, USA
    J Biochem Mol Toxicol 21:163-8. 2007
  9. ncbi request reprint Principles of covalent binding of reactive metabolites and examples of activation of bis-electrophiles by conjugation
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23 rd and Pierce Avenues, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 433:369-78. 2005
  10. ncbi request reprint Applying mechanisms of chemical toxicity to predict drug safety
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 20:344-69. 2007

Research Grants

  1. Metabolism of Carcinogens and Drugs by Human P450s
    F Guengerich; Fiscal Year: 2007
  2. TRAINING PROGRAM IN ENVIRONMENTAL TOXICOLOGY
    F Guengerich; Fiscal Year: 2007
  3. Polymerase Interactions with Carcinogen-modified DNA
    F Guengerich; Fiscal Year: 2007
  4. Polymerase Interactions with Carcinogen-modified DNA
    F Guengerich; Fiscal Year: 2009
  5. BIOACTIVATION OF HALOGENATED HYDROCARBONS
    F Peter Guengerich; Fiscal Year: 2010
  6. POLYMERASE INTERACTIONS WITH CARCINOGEN MODIFIED DNA
    F Guengerich; Fiscal Year: 2004
  7. Metabolism of Carcinogens and Drugs by Human P450s
    F Guengerich; Fiscal Year: 2005
  8. BIOACTIVATION OF HALOGENATED HYDROCARBONS
    F Guengerich; Fiscal Year: 2005
  9. Polymerase Interactions with Carcinogen-modified DNA
    F Peter Guengerich; Fiscal Year: 2010

Detail Information

Publications92

  1. ncbi request reprint Where is toxicology headed in the future?
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Drug Metab Rev 36:475-86. 2004
    ..The hope is that toxicology will be able to be much more predictive in the future; a great need exists in the pharmaceutical industry. The shape of academic toxicology is also changing...
  2. pmc New trends in cytochrome p450 research at the half-century mark
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 288:17063-4. 2013
    ..The four minireviews in this thematic series deal with the unusual aspects of catalytic reactions and electron transfer pathway organization, the structural diversity of P450s, and the expanding roles of P450s in disease and medicine...
  3. pmc Unusual cytochrome p450 enzymes and reactions
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 288:17065-73. 2013
    ..In some cases, P450s are fused to protein partners. Other P450s catalyze non-redox isomerization reactions. A number of permutations on the P450 theme reveal the diversity of cytochrome P450 form and function...
  4. pmc Thematic minireview series: metals in biology 2013
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    J Biol Chem 288:13164. 2013
    ....
  5. pmc Thematic minireview series: Metals in Biology 2012
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 287:13508-9. 2012
    ....
  6. pmc Thematic minireview series: metals in biology
    F Peter Guengerich
    Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 284:18557. 2009
    ..Zinc deficiency is discussed in another, and the arsenic minireview deals with the toxic and some potentially useful applications of the biological effects...
  7. doi request reprint Thematic series: metals in biology
    F Peter Guengerich
    Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 284:709. 2009
    ..The three minireviews deal with regulation of iron homeostasis, the roles of copper metabolism in cell regulation and disease, and the functions of selenoproteins...
  8. ncbi request reprint Mechanisms of cytochrome P450 substrate oxidation: MiniReview
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Nashville, TN 37232 0146, USA
    J Biochem Mol Toxicol 21:163-8. 2007
    ..Some of the complexity is due to slow conformational changes in the proteins that occur on the same timescale as other steps...
  9. ncbi request reprint Principles of covalent binding of reactive metabolites and examples of activation of bis-electrophiles by conjugation
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23 rd and Pierce Avenues, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 433:369-78. 2005
    ..The phenomenon of thiol conjugation to increase mutagenicity is widespread among bis-electrophiles...
  10. ncbi request reprint Applying mechanisms of chemical toxicity to predict drug safety
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 20:344-69. 2007
    ..However, progress has been made using several approaches. Some examples of the application of studies of wide-scale biological responses are now available, with incorporation into development paradigms...
  11. pmc Measurement of cytochrome P450 and NADPH-cytochrome P450 reductase
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Nat Protoc 4:1245-51. 2009
    ..Each assay can be completed in 5-10 min. Detailed explanations for the rationale of particular sequences in the protocols are provided, along with potential confounding problems...
  12. ncbi request reprint Generation of reactive intermediates
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    J Biochem Mol Toxicol 19:173-4. 2005
  13. ncbi request reprint Life and times in biochemical toxicology
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Int J Toxicol 24:5-21. 2005
    ..The challenges ahead are considerable but there is renewed excitement in the potential of the field. As in the past, further advances in the field of toxicology will require the input of knowledge from many disciplines...
  14. ncbi request reprint Reduction of cytochrome b5 by NADPH-cytochrome P450 reductase
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 440:204-11. 2005
    ..07 s(-1)), very fast reduction, and dissociation. In vesicles, encounter is rapid and the slow step (approximately 3 s(-1)) is reduction within a complex less favorable for reduction than in the non-vesicle systems...
  15. pmc A malleable catalyst dominates the metabolism of drugs
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Proc Natl Acad Sci U S A 103:13565-6. 2006
  16. ncbi request reprint Function of human cytochrome P450s: characterization of the orphans
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Biochem Biophys Res Commun 338:465-9. 2005
    ..Limited information is available about the sites of mRNA expression of some of these orphans. Some strategies for characterization are discussed...
  17. pmc Cytochrome P450s and other enzymes in drug metabolism and toxicity
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
    AAPS J 8:E101-11. 2006
    ..In the article we consider what fraction of drug toxicity actually involves metabolism, and we examine how species and human interindividual variations affect pharmacokinetics and toxicity...
  18. ncbi request reprint Interactions of carcinogen-bound DNA with individual DNA polymerases
    F Peter Guengerich
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Rev 106:420-52. 2006
  19. ncbi request reprint Rate-limiting steps in oxidations catalyzed by rabbit cytochrome P450 1A2
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 43:10775-88. 2004
    ....
  20. ncbi request reprint Update information on drug metabolism systems--2009, part I
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Curr Drug Metab 11:1-3. 2010
    ..Today it is common to design discovery and development efforts focused on critical human phenomena from the very start, with animal studies supporting the efficacy and safety efforts...
  21. pmc Orphans in the human cytochrome P450 superfamily: approaches to discovering functions and relevance in pharmacology
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, Tennessee 37232 0146, USA
    Pharmacol Rev 63:684-99. 2011
    ..Current information on what are still considered "orphan" P450s is presented. The potential for application of some of these approaches to other enzyme systems is also discussed...
  22. pmc Thematic minireview series on biological applications of mass spectrometry
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 286:25417. 2011
    ..Examples presented here include drug metabolism, lipid analysis, metabolomics, quantitative proteomics, direct analysis of intact proteins, and imaging of both small molecules and proteins in tissues...
  23. pmc Approaches to deorphanization of human and microbial cytochrome P450 enzymes
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Biochim Biophys Acta 1814:139-45. 2011
    ..One current limitation is that too many fatty acid oxidations have been identified and we are probably missing more relevant substrates, possibly due to limits of sensitivity...
  24. ncbi request reprint Mechanisms of drug toxicity and relevance to pharmaceutical development
    F Peter Guengerich
    Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Drug Metab Pharmacokinet 26:3-14. 2011
    ..The development of more useful biomarkers and short-term assays for rapid screening of drug toxicity early in the drug discovery/development process is a major goal, and some progress has been made using "omics" approaches...
  25. ncbi request reprint O6-alkylguanine-DNA alkyltransferase: low pKa and high reactivity of cysteine 145
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Biochemistry 42:10965-70. 2003
    ..The high reactivity of hAGT Cys145 is postulated to be important in normal catalytic function, in cross-linking reactions involving bis-electrophiles, and in inhibition of the DNA repair function of hAGT by electrophiles...
  26. pmc Multi-step oxidations catalyzed by cytochrome P450 enzymes: Processive vs. distributive kinetics and the issue of carbonyl oxidation in chemical mechanisms
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 507:126-34. 2011
    ..If carbonyl hydration and dehydration are slow, the mechanism may be set by the carbonyl hydration status...
  27. pmc Characterizing proteins of unknown function: orphan cytochrome p450 enzymes as a paradigm
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Mol Interv 10:153-63. 2010
    ..The myriad of possibilities is too enormous to screen one reaction at a time, thus metabolomic or proteomic screens with complex biological samples are promising current strategies...
  28. ncbi request reprint Cytochrome P450: what have we learned and what are the future issues?
    F Peter Guengerich
    Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Drug Metab Rev 36:159-97. 2004
    ....
  29. ncbi request reprint Generation of new protein kinase inhibitors utilizing cytochrome p450 mutant enzymes for indigoid synthesis
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    J Med Chem 47:3236-41. 2004
    ..The general strategy may have additional applications...
  30. ncbi request reprint Cytochromes P450, drugs, and diseases
    F Peter Guengerich
    Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, Nashville, TN 37232 0146, USA
    Mol Interv 3:194-204. 2003
  31. ncbi request reprint Cytochrome p450 and chemical toxicology
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 21:70-83. 2008
    ....
  32. ncbi request reprint Expansion of substrate specificity of cytochrome P450 2A6 by random and site-directed mutagenesis
    Zhong Liu Wu
    Department of Biochemistry and the Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 280:41090-100. 2005
    ..The N2297Q change is postulated to generate a hydrogen bond between Gln and the substrate oxygen. Thus, the substrate specificity of P450 2A6 was expanded, and new products were obtained in this study...
  33. ncbi request reprint Diversity in the oxidation of substrates by cytochrome P450 2D6: lack of an obligatory role of aspartate 301-substrate electrostatic bonding
    F Peter Guengerich
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 41:11025-34. 2002
    ....
  34. ncbi request reprint Enhancement of 7-methoxyresorufin O-demethylation activity of human cytochrome P450 1A2 by molecular breeding
    Donghak Kim
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 683 Robinson Research Building, 23rd and Pierce Avenues, Nashville, TN 37232 01465, USA
    Arch Biochem Biophys 432:102-8. 2004
    ..This approach has potential value in understanding P450 1A2 and generating engineered enzymes with enhanced catalytic activity...
  35. pmc Structure-function relationships in miscoding by Sulfolobus solfataricus DNA polymerase Dpo4: guanine N2,N2-dimethyl substitution produces inactive and miscoding polymerase complexes
    Huidong Zhang
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 284:17687-99. 2009
    ..Collectively, these results explain, in a detailed manner, the basis for the reduced efficiency and fidelity of Dpo4-catalyzed bypass of N2,N2-Me2G compared with mono-substituted N2-alkyl G adducts...
  36. ncbi request reprint Selection of human cytochrome P450 1A2 mutants with enhanced catalytic activity for heterocyclic amine N-hydroxylation
    Donghak Kim
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 43:981-8. 2004
    ....
  37. doi request reprint Cooperativity of cytochrome P450 1A2: interactions of 1,4-phenylene diisocyanide and 1-isopropoxy-4-nitrobenzene
    Emre M Isin
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 473:69-75. 2008
    ..Consistent with this view, Ph(NC)2 inhibited the oxidation of 1-isopropoxy-4-nitrobenzene and other substrates...
  38. ncbi request reprint Analysis of coumarin 7-hydroxylation activity of cytochrome P450 2A6 using random mutagenesis
    Donghak Kim
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 280:40319-27. 2005
    ..The attenuation is caused in part to lower binding affinity for NADPH-P450 reductase, but the K476E mutant did not achieve the wild-type coumarin 7-hydroxylation activity even at high reductase concentrations...
  39. ncbi request reprint Electron transport pathway for a Streptomyces cytochrome P450: cytochrome P450 105D5-catalyzed fatty acid hydroxylation in Streptomyces coelicolor A3(2)
    Young Jin Chun
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 282:17486-500. 2007
    ..Thus, an electron transfer pathway to a functional Streptomyces P450 has been established...
  40. ncbi request reprint Translesion synthesis across bulky N2-alkyl guanine DNA adducts by human DNA polymerase kappa
    Jeong Yun Choi
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 281:21062-72. 2006
    ....
  41. doi request reprint Cooperativity in oxidation reactions catalyzed by cytochrome P450 1A2: highly cooperative pyrene hydroxylation and multiphasic kinetics of ligand binding
    Christal D Sohl
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 283:7293-308. 2008
    ..Elements of this mechanism may be relevant to other cases of P450 cooperativity...
  42. ncbi request reprint Kinetic evidence for inefficient and error-prone bypass across bulky N2-guanine DNA adducts by human DNA polymerase iota
    Jeong Yun Choi
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 281:12315-24. 2006
    ..Thus, polymerization by pol iota is severely inhibited by a bulky group at G N2 despite an advantageous mode of Hoogsteen base pairing; pol iota may play a limited role in translesion synthesis on bulky N2-G adducts in cells...
  43. pmc Modulation of the structure, catalytic activity, and fidelity of African swine fever virus DNA polymerase X by a reversible disulfide switch
    Markus W Voehler
    Department of Chemistry and Center in Molecular Toxicology, Vanderbilt University, Nashville, Tennessee 37235, USA
    J Biol Chem 284:18434-44. 2009
    ..Thus, DNA polymerase fidelity is altered by the redox state of the enzyme and its related conformational changes...
  44. ncbi request reprint Adduct size limits efficient and error-free bypass across bulky N2-guanine DNA lesions by human DNA polymerase eta
    Jeong Yun Choi
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    J Mol Biol 352:72-90. 2005
    ....
  45. ncbi request reprint Cytochrome P450 3A4-catalyzed testosterone 6beta-hydroxylation stereochemistry, kinetic deuterium isotope effects, and rate-limiting steps
    Joel A Krauser
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 280:19496-506. 2005
    ..Thus P450 3A4 is an enzyme with regioselective flexibility but also considerable regioselectivity and stereoselectivity in product formation, not necessarily dominated by the ease of C-H bond breaking...
  46. pmc Oxidation of N-Nitrosoalkylamines by human cytochrome P450 2A6: sequential oxidation to aldehydes and carboxylic acids and analysis of reaction steps
    Goutam Chowdhury
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 285:8031-44. 2010
    ..e. of DMN or DEN to an aldehyde)...
  47. ncbi request reprint Formation and reduction of aryl and heterocyclic nitroso compounds and significance in the flux of hydroxylamines
    Donghak Kim
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Chem Res Toxicol 17:529-36. 2004
    ..Both IQ-NHOH and IQ-N=O were mutagenic in a bacterial tester system devoid of p450 and NPR; the mutagenicity of both was decreased by expression of NPR, consistent with the reduction of these compounds observed with purified NPR...
  48. pmc Metal ion interactions in the DNA cleavage/ligation active site of human topoisomerase IIalpha
    Joseph E Deweese
    Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 48:8940-7. 2009
    ..Furthermore, we propose that M(1)(2+) interacts with E461, D543, and D545 and M(2)(2+) interacts with E461 and D541...
  49. pmc Effect of N2-guanyl modifications on early steps in catalysis of polymerization by Sulfolobus solfataricus P2 DNA polymerase Dpo4 T239W
    Huidong Zhang
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232 0146, USA
    J Mol Biol 395:1007-18. 2010
    ..With the larger adducts (>or=(2-naphthyl)methyl), the absence of fluorescence changes suggests impaired ability to undergo an appropriate conformational change, consistent with previous structural work...
  50. pmc Human cytochrome P450 4F11: heterologous expression in bacteria, purification, and characterization of catalytic function
    Zhongmei Tang
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 494:86-93. 2010
    ..P450 4F11 also exhibited low activity for some drug N-demethylation reactions but none for activation of several pro-carcinogens...
  51. doi request reprint Reactions of glyceraldehyde 3-phosphate dehydrogenase sulfhydryl groups with bis-electrophiles produce DNA-protein cross-links but not mutations
    Elisabeth M Loecken
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Chem Res Toxicol 21:453-8. 2008
    ....
  52. ncbi request reprint Analysis of DNA adducts formed in vivo in rats and mice from 1,2-dibromoethane, 1,2-dichloroethane, dibromomethane, and dichloromethane using HPLC/accelerator mass spectrometry and relevance to risk estimates
    Kengo Watanabe
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Chem Res Toxicol 20:1594-600. 2007
    ..The results may be used to address issues in human risk assessment...
  53. ncbi request reprint Formation and mass spectrometric analysis of DNA and nucleoside adducts by S-(1-acetoxymethyl)glutathione and by glutathione S-transferase-mediated activation of dihalomethanes
    Glenn A Marsch
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Chem Res Toxicol 17:45-54. 2004
    ....
  54. ncbi request reprint Kinetics and thermodynamics of ligand binding by cytochrome P450 3A4
    Emre M Isin
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 281:9127-36. 2006
    ..The P450 3A4 binding process is more complex than a two-state system, and the overlap of rates of some of the events with subsequent steps is proposed to underlie the observed cooperativity...
  55. ncbi request reprint Biosynthesis of new indigoid inhibitors of protein kinases using recombinant cytochrome P450 2A6
    Zhongliu Liu Wu
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23rd and Pierce Avenues, Nashville, Tennessee 37232 0146, USA
    Chem Biodivers 2:51-65. 2005
    ..Thus, this system has the potential to generate new indigoids with therapeutic potential...
  56. ncbi request reprint Multiple sequential steps involved in the binding of inhibitors to cytochrome P450 3A4
    Emre M Isin
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 282:6863-74. 2007
    ..We propose a three-step minimal model for inhibitor binding, developed with kinetic simulations, consistent with our previously reported model for the binding of substrates, although it is possible that even more steps are involved...
  57. ncbi request reprint Interactions of mammalian cytochrome P450, NADPH-cytochrome P450 reductase, and cytochrome b(5) enzymes
    Tsutomu Shimada
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23rd and Pierce Avenues, Nashville, TN 37232 0146, USA
    Arch Biochem Biophys 435:207-16. 2005
    ....
  58. pmc Translesion synthesis across 1,N2-ethenoguanine by human DNA polymerases
    Jeong Yun Choi
    Department of Biochemistry and Chemistry, Vanderbilt University, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 19:879-86. 2006
    ..This pattern differs with the same oligonucleotide sequences and 1,N(2)-epsilon-G observed using Dpo4, emphasizing the importance of pols in mutagenesis events...
  59. ncbi request reprint Activation of bis-electrophiles to mutagenic conjugates by human O6-alkylguanine-DNA alkyltransferase
    J Gerardo Valadez
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Chem Res Toxicol 17:972-82. 2004
    ..These observations are of relevance in considering toxicity and risks of some chemicals used in industrial applications...
  60. ncbi request reprint Inhibition of human cytochrome P450 1A1-, 1A2-, and 1B1-mediated activation of procarcinogens to genotoxic metabolites by polycyclic aromatic hydrocarbons
    Tsutomu Shimada
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 606 Light Hall, 2215 Garland Avenue, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 19:288-94. 2006
    ....
  61. ncbi request reprint Differential DNA recognition and cleavage by EcoRI dependent on the dynamic equilibrium between the two forms of the malondialdehyde-deoxyguanosine adduct
    Laurie A VanderVeen
    Department of Biochemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and Vanderbilt Ingram Comprehensive Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 44:5024-33. 2005
    ..Comparison of the solution structures of DNA adducts and the crystal structure of EcoRI complexed to substrate suggest a model to explain the functional differences...
  62. pmc 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
    Jeff W Beckman
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    J Biol Chem 283:36711-23. 2008
    ....
  63. ncbi request reprint Translesion synthesis across O6-alkylguanine DNA adducts by recombinant human DNA polymerases
    Jeong Yun Choi
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 23rd and Pierce Avenues, Nashville, TN 37232 0146, USA
    J Biol Chem 281:38244-56. 2006
    ..The results with pol eta may be relevant to some mutations previously reported with O(6)-alkylG adducts in mammalian cells...
  64. ncbi request reprint Misincorporation and stalling at O(6)-methylguanine and O(6)-benzylguanine: evidence for inactive polymerase complexes
    Adrienne M Woodside
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 41:1039-50. 2002
    ..In summary, several lines of evidence indicate that the existence of a nonproductive polymerase complex best explains polymerase kinetics at DNA-carcinogen adducts, specifically O(6)-alkylguanine...
  65. ncbi request reprint Microsomal oxidation of tribromoethylene and reactions of tribromoethylene oxide
    Tadao Yoshioka
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 15:1414-20. 2002
    ..We conclude that the proposed scheme of hydrolysis of halogenated epoxides follows the expected halide order and that this can be used to rationalize patterns of hydrolysis and reactivity of other halogenated epoxides...
  66. ncbi request reprint Tetrachloroethylene oxide: hydrolytic products and reactions with phosphate and lysine
    Tadao Yoshioka
    Department of Biochemistry, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, TN 37232 0146, USA
    Chem Res Toxicol 15:1096-105. 2002
    ..The formation of Cl(3)CCO(2)H in cytochrome P450 reactions is postulated to result from intramolecular migration within an enzyme intermediate...
  67. pmc Structure of the 1,N2-etheno-2'-deoxyguanosine adduct in duplex DNA at pH 8.6
    Ganesh Shanmugam
    Department of Chemistry, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, and the Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, USA
    Chem Res Toxicol 20:1601-11. 2007
    ..The 5'-neighbor T(5).A(20) base pair was destabilized with respect to Watson-Crick base pairing. The refined structure predicted a bend in the helical axis associated with the adduct site...
  68. ncbi request reprint Complex reactions catalyzed by cytochrome P450 enzymes
    Emre M Isin
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, 638 Robinson Research Building, 23rd and Pierce Avenues, Nashville, TN 37232 0146, USA
    Biochim Biophys Acta 1770:314-29. 2007
    ..g., aristolochic acid), ring contraction (piperidine nitroxide radical), oxidation of troglitazone, cleavage of amino oxazoles and a 1,2,4-oxadiazole ring, bioactivation of a dihydrobenzoxathiin, and oxidative aryl migration...
  69. pmc Structure of the 1,N(2)-etheno-2'-deoxyguanosine lesion in the 3'-G(epsilon dG)T-5' sequence opposite a one-base deletion
    Ganesh Shanmugam
    Department of Chemistry, Vanderbilt Institute of Chemical Biology, Center in MolecularToxicology, and Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, USA
    Biochemistry 49:2615-26. 2010
    ....
  70. pmc In vitro bypass of the major malondialdehyde- and base propenal-derived DNA adduct by human Y-family DNA polymerases κ, ι, and Rev1
    Leena Maddukuri
    A B Hancock Jr Memorial Laboratory for Cancer Research, Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 49:8415-24. 2010
    ..The results indicate that DNA hPol κ or the combined action of hPol ι or Rev1 and hPol κ bypass M(1)dG residues in DNA and generate products that are consistent with some of the mutations induced by M(1)dG in mammalian cells...
  71. pmc The C8-2'-deoxyguanosine adduct of 2-amino-3-methylimidazo[1,2-d]naphthalene, a carbocyclic analogue of the potent mutagen 2-amino-3-methylimidazo[4,5-f]quinoline, is a block to replication in vitro
    Plamen P Christov
    Department of Chemistry and Biochemistry, Vanderbilt University, Nashville, Tennessee 37235 1822, USA
    Chem Res Toxicol 23:1076-88. 2010
    ..coli pol IV or pol V) is required for its bypass, and this accounts for the greatly attenuated mutagenicity in the Ames assays as compared with IQ...
  72. pmc Structural and functional analysis of Sulfolobus solfataricus Y-family DNA polymerase Dpo4-catalyzed bypass of the malondialdehyde-deoxyguanosine adduct
    Robert L Eoff
    Department of Chemistry, A B Hancock Jr Memorial Laboratory for Cancer Research, Vanderbilt Institute of Chemical Biology, Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Biochemistry 48:7079-88. 2009
    ..The results are consistent with the reported mutagenicity of M1dG and illustrate how the lesion may affect replication events...
  73. pmc The bis-electrophile diepoxybutane cross-links DNA to human histones but does not result in enhanced mutagenesis in recombinant systems
    Elisabeth M Loecken
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 22:1069-76. 2009
    ..The extent of DNA cross-linking of isolated histone H2b was similar to that of AGT, suggesting that differences in postcross-linking events explain the difference in mutagenesis...
  74. pmc 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
    Jennifer B Stafford
    Department of Chemistry, A B Hancock, Jr, Memorial Laboratory for Cancer Research, Center in Molecular Toxicology, Vanderbilt Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    Biochemistry 48:471-80. 2009
    ..Human DNA polymerase eta bypass may lead to M(1)dG to dT and frameshift but likely not M(1)dG to dA mutations during DNA replication...
  75. ncbi request reprint Kinetics of nucleotide incorporation opposite polycyclic aromatic hydrocarbon-DNA adducts by processive bacteriophage T7 DNA polymerase
    Hong Zang
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Chem Res Toxicol 18:389-400. 2005
    ..The effect of these bulky PAH adducts is either to attenuate rates of conformational changes or to introduce an additional conformation problem but not to alter the inherent affinity of the polymerase for DNA or dNTPs...
  76. pmc 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
    Plamen P Christov
    Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235 1822, USA
    Chem Res Toxicol 22:1086-95. 2009
    ....
  77. pmc Cytochrome P450 2S1 is reduced by NADPH-cytochrome P450 reductase
    Yi Xiao
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
    Drug Metab Dispos 39:944-6. 2011
    ..The reduction kinetics of P450 2S1 were rapid, as measured by stopped-flow kinetics. These results confirm that P450 2S1 can be reduced by NADPH-P450 reductase and suggest normal mixed-function oxidase roles of P450 2S1 to be revealed...
  78. ncbi request reprint Roles of NADPH-P450 reductase and apo- and holo-cytochrome b5 on xenobiotic oxidations catalyzed by 12 recombinant human cytochrome P450s expressed in membranes of Escherichia coli
    Hiroshi Yamazaki
    Faculty of Pharmaceutical Sciences, Kanazawa University, 13 1 Takara machi, Kanazawa 920 0934, Japan
    Protein Expr Purif 24:329-37. 2002
    ..P450/NPR membrane systems containing b5 are useful models for prediction of the rates for liver microsomal P450-dependent drug oxidations...
  79. ncbi request reprint The alkaloid rutaecarpine is a selective inhibitor of cytochrome P450 1A in mouse and human liver microsomes
    Yune Fang Ueng
    National Research Institute of Chinese Medicine, Taipei, Taiwan, Republic of China
    Drug Metab Dispos 30:349-53. 2002
    ..These results indicated that rutaecarpine was a potent inhibitor of CYP1A2 in both mouse and human liver microsomes...
  80. ncbi request reprint 1,N(2)-ethenoguanine, a mutagenic DNA adduct, is a primary substrate of Escherichia coli mismatch-specific uracil-DNA glycosylase and human alkylpurine-DNA-N-glycosylase
    Murat Saparbaev
    Groupe Réparation de l ADN, Unité Mixte de Recherche 8532 CNRS, Laboratoire de Biotechnologies et Pharmacologie Génétique Appliquée Ecole Normale Supérieure Cachan, Institut Gustave Roussy, 94805 Villejuif Cedex, France
    J Biol Chem 277:26987-93. 2002
    ..Taken together these observations suggest a possible role for these proteins in counteracting the genotoxic effects of 1,N(2)-epsilonG residues in vivo...
  81. ncbi request reprint Paradoxical enhancement of the toxicity of 1,2-dibromoethane by O6-alkylguanine-DNA alkyltransferase
    Liping Liu
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 277:37920-8. 2002
    ..In the presence of DNA, the DNA-binding function of AGT facilitates formation of DNA adducts. In the absence of DNA, the intermediate undergoes hydrolytic decomposition to form AGT-Cys(145)-SCH(2)CH(2)OH...
  82. pmc Transcription processing at 1,N2-ethenoguanine by human RNA polymerase II and bacteriophage T7 RNA polymerase
    Alexandra Dimitri
    Department of Biology, New York University, New York, NY 10003, USA
    J Mol Biol 375:353-66. 2008
    ..Thus, our data suggest that this repair pathway is likely engaged in the clearance of the 1,N(2)-epsilon G from actively transcribed DNA...
  83. ncbi request reprint Kinetic analysis of oxidation of coumarins by human cytochrome P450 2A6
    Chul Ho Yun
    Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500 757, Republic of Korea
    J Biol Chem 280:12279-91. 2005
    ..The inherent difficulty of chemistry of substrate oxidation and the lack of proclivity toward a linear pathway leading to product formation explain the inefficiency of the enzyme relative to highly efficient bacterial P450s...
  84. ncbi request reprint Heterologous expression and characterization of wild-type human cytochrome P450 1A2 without conventional N-terminal modification in Escherichia coli
    Dong Hyun Kim
    School of Biological Sciences and Technology and Hormone Research Center, Chonnam National University, 300 Yongbong Dong, Buk Gu, Gwangju 500 757, Republic of Korea
    Protein Expr Purif 57:188-200. 2008
    ..These results reveal that the overall enzymatic properties of wild-type CYP1A2 enzyme are quite similar to those of modified CYP1A2, although its active site environment seems to differ from that of the modified enzyme...
  85. ncbi request reprint Roles of human liver cytochrome P450 3A4 and 1A2 enzymes in the oxidation of myristicin
    Chul Ho Yun
    Department of Genetic Engineering, Pai Chai University, 439 6 Doma dong, Seo Ku, Taejon 302 735, South Korea
    Toxicol Lett 137:143-50. 2003
    ..These results provide evidence that CYP3A4 (and possibly other CYP3A enzymes) and CYP1A2 play roles in the formation of the major metabolite, 5-allyl-1-methoxy-2,3-dihydroxybenzene...
  86. ncbi request reprint Characterization of a mutagenic DNA adduct formed from 1,2-dibromoethane by O6-alkylguanine-DNA alkyltransferase
    Liping Liu
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Biol Chem 279:4250-9. 2004
    ....
  87. ncbi request reprint Effect of alterations of key active site residues in O6-alkylguanine-DNA Alkyltransferase on its ability to modulate the genotoxicity of 1,2-dibromoethane
    Liping Liu
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Chem Res Toxicol 20:155-63. 2007
    ....
  88. ncbi request reprint Activation of aminophenylnorharman, aminomethylphenylnorharman and aminophenylharman to genotoxic metabolites by human N-acetyltransferases and cytochrome P450 enzymes expressed in Salmonella typhimurium umu tester strains
    Yoshimitsu Oda
    Osaka Prefectural Institute of Public Health, 3 69 Nanakichi 1 chome, Higashinari ku, Osaka 537 0025, Japan
    Mutagenesis 21:411-6. 2006
    ..From these results, it is concluded that APNH, AMPNH and APH are mainly bioactivated by P450 1A2 and NAT2, followed by NAT1 enzymes. P450 1A1 was also found to activate AMPNH at relatively slower rates...
  89. ncbi request reprint Testosterone 1 beta-hydroxylation by human cytochrome P450 3A4
    Joel A Krauser
    Department of Biochemistry and Center in Molecular Toxicology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232 0146, USA
    Eur J Biochem 271:3962-9. 2004
    ..Of several human P450s examined, only P450 3A4 formed this product. The product was also formed in human liver microsomes...
  90. ncbi request reprint Functional characterization of four allelic variants of human cytochrome P450 1A2
    Huijia Zhou
    Department of Chemistry and Biochemistry, Guelph Waterloo Centre for Graduate Work in Chemistry and Biochemistry, University of Guelph, Ont N1G 2W1, Guelph, Canada
    Arch Biochem Biophys 422:23-30. 2004
    ..The other three variants had subtly different catalytic activities compared to the wild-type enzyme...
  91. ncbi request reprint Guanine alkylation by the potent carcinogen aflatoxin B1: quantum chemical calculations
    Urban Bren
    National Institute of Chemistry, Hajdrihova 19, SI 1001 Ljubljana, Slovenia
    Chem Res Toxicol 20:1134-40. 2007
    ..This explains why the planar region of related mycotoxins sterigmatocystin and aflatoxin G 1 could have been evolutionarily optimized in a different way...

Research Grants31

  1. Metabolism of Carcinogens and Drugs by Human P450s
    F Guengerich; Fiscal Year: 2007
    ....
  2. TRAINING PROGRAM IN ENVIRONMENTAL TOXICOLOGY
    F Guengerich; Fiscal Year: 2007
    ..Molecular toxicology is recognized as a strong program, and the institution has continued its commitment to making Vanderbilt a leading center for training in this area. ..
  3. Polymerase Interactions with Carcinogen-modified DNA
    F Guengerich; Fiscal Year: 2007
    ..The overall goal is understanding molecular mechanisms of mutagenesis and relevance to chemical carcinogenesis. ..
  4. Polymerase Interactions with Carcinogen-modified DNA
    F Guengerich; Fiscal Year: 2009
    ..The overall goal is understanding molecular mechanisms of mutagenesis and relevance to chemical carcinogenesis. ..
  5. BIOACTIVATION OF HALOGENATED HYDROCARBONS
    F Peter Guengerich; Fiscal Year: 2010
    ..abstract_text> ..
  6. POLYMERASE INTERACTIONS WITH CARCINOGEN MODIFIED DNA
    F Guengerich; Fiscal Year: 2004
    ..The overall goal is understanding molecular mechanisms of mutagenesis as a part of chemical carcinogenesis. ..
  7. Metabolism of Carcinogens and Drugs by Human P450s
    F Guengerich; Fiscal Year: 2005
    ..Successful completion of these collective studies should provide better understanding of the ways in which human P450s catalyze oxidation of carcinogens and drugs and the significance of variations in these enzymes. ..
  8. BIOACTIVATION OF HALOGENATED HYDROCARBONS
    F Guengerich; Fiscal Year: 2005
    ..These experiments involving enzymatic oxidation and conjugation reactions are intended to help define important concepts that can be applied to other halogenated hydrocarbons and to other cancer suspect chemicals as well. ..
  9. Polymerase Interactions with Carcinogen-modified DNA
    F Peter Guengerich; Fiscal Year: 2010
    ..The goals of this project involve understanding how the DNA polymerases make such mistakes. ..