This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Nitroanisoles are environmental pollutants whose toxic potential depends on the efficiency of biological processes. While xanthine oxidase activates nitroanisoles to carcinogenic mutagens, cytochrome P450s, most notably CYP2E1, oxidize nitroanisoles to readily excreted metabolites, thereby committing nitroanisoles to detoxification. Thus, the efficiency of CYP2E1 activity toward nitroanisoles is a potentially important determinant for risk posed by exposure to those pollutants. Kinetic profiling for CYP2E1 has been an important tool to assess the activation and detoxification of many small molecular weight compounds. Unlike traditional enzymes, CYP2E1 catalysis may involve multiple binding sites that alter the metabolism of compounds. Recently, we explained unusual non-hyperbolic kinetics for 4-nitrophenol oxidation through the presence of an effector site, which when occupied, suppressed the reaction. Lack of knowledge of this mechanism could lead to incorrect estimates for the clearance of pollutants from the body, hence toxicity from exposure. In the proposed project, we will test the hypothesis that the efficiency of CYP2E1 oxidation of nitroanisoles to nontoxic products depends on the occupancy of an effector site. Specifically, we will: (1) determine the kinetic mechanisms for nitroanisole metabolism;(2) construct computer models for CYP2E1 complexes with substrates and effectors to predict non-hyperbolic reaction kinetics;(3) identify binding site residues for monocyclic molecules through photoaffinity labeling;and (4) confirm the functional role for effector site residues through site-directed mutagenesis. Collectively, these findings will generate models to interpret and predict the efficiency of detoxification of nitroanisoles as well as provide tools for future toxicological studies.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-7 (01))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
Zip Code
Allison, Devin; Delancey, Evan; Ramey, Hunter et al. (2017) Synthesis and antimicrobial studies of novel derivatives of 4-(4-formyl-3-phenyl-1H-pyrazol-1-yl)benzoic acid as potent anti-Acinetobacter baumannii agents. Bioorg Med Chem Lett 27:387-392
MacNicol, Melanie C; Cragle, Chad E; McDaniel, F Kennedy et al. (2017) Evasion of regulatory phosphorylation by an alternatively spliced isoform of Musashi2. Sci Rep 7:11503
Gao, Bo; Li, Guojun; Liu, Juntao et al. (2017) Identification of driver modules in pan-cancer via coordinating coverage and exclusivity. Oncotarget 8:36115-36126
Rahmatallah, Yasir; Zybailov, Boris; Emmert-Streib, Frank et al. (2017) GSAR: Bioconductor package for Gene Set analysis in R. BMC Bioinformatics 18:61
Liu, Juntao; Li, Guojun; Chang, Zheng et al. (2016) BinPacker: Packing-Based De Novo Transcriptome Assembly from RNA-seq Data. PLoS Comput Biol 12:e1004772
Luo, Heng; Ye, Hao; Ng, Hui Wen et al. (2016) sNebula, a network-based algorithm to predict binding between human leukocyte antigens and peptides. Sci Rep 6:32115
Yu, Alexander; Demirel, Doga; Halic, Tansel et al. (2016) Virtual Intraoperative Cholangiogram Using WebCL. Stud Health Technol Inform 220:459-64
Wang, Zhenjia; Li, Guojun; Robinson, Robert W et al. (2016) UniBic: Sequential row-based biclustering algorithm for analysis of gene expression data. Sci Rep 6:23466
Rahmatallah, Yasir; Emmert-Streib, Frank; Glazko, Galina (2016) Gene set analysis approaches for RNA-seq data: performance evaluation and application guideline. Brief Bioinform 17:393-407
Beckford, Floyd A; Brock, Alyssa; Gonzalez-SarrĂ­as, Antonio et al. (2016) Cytotoxic gallium complexes containing thiosemicarbazones derived from 9-anthraldehyde: Molecular docking with biomolecules. J Mol Struct 1121:156-166

Showing the most recent 10 out of 223 publications