title: Mechanistic insights into the specificity of human cytosolic sulfotransferase 2A1 (hSULT2A1) for hydroxylated polychlorinated biphenyls through the use of fluoro-tagged probes.
abstract: Determining the relationships between the structures of substrates and inhibitors and their interactions with drug-metabolizing enzymes is of prime importance in predicting the toxic potential of new and legacy xenobiotics. Traditionally, quantitative structure activity relationship (QSAR) studies are performed with many distinct compounds. Based on the chemical properties of the tested compounds, complex relationships can be established so that models can be developed to predict toxicity of novel compounds. In this study, the use of fluorinated analogues as supplemental QSAR compounds was investigated. Substituting fluorine induces changes in electronic and steric properties of the substrate without substantially changing the chemical backbone of the substrate. In vitro assays were performed using purified human cytosolic sulfotransferase hSULT2A1 as a model enzyme. A mono-hydroxylated polychlorinated biphenyl (4-OH PCB 14) and its four possible mono-fluoro analogues were used as test compounds. Remarkable similarities were found between this approach and previously published QSAR studies for hSULT2A1. Both studies implicate the importance of dipole moment and dihedral angle as being important to PCB structure in respect to being substrates for hSULT2A1. We conclude that mono-fluorinated analogues of a target substrate can be a useful tool to study the structure activity relationships for enzyme specificity.
authors.affiliation: Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, IA, USA.
authors.forename: E J
authors.initials: EJ
authors.lastname: Ekuase
authors.affiliation: Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA, USA. thomas.vanterve@nih.gov.|Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The Netherlands. thomas.vanterve@nih.gov.|Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA. thomas.vanterve@nih.gov.|Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, 27709, NC, USA. thomas.vanterve@nih.gov.
authors.forename: T J
authors.initials: TJ
authors.lastname: van 't Erve
authors.affiliation: Department of Chemistry, The University of Iowa, Iowa City, IA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rahaman
authors.affiliation: Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA, USA.|Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA.
authors.forename: L W
authors.initials: LW
authors.lastname: Robertson
authors.affiliation: Department of Pharmaceutical Sciences and Experimental Therapeutics, The University of Iowa, Iowa City, IA, USA.|Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Duffel
authors.affiliation: Department of Occupational and Environmental Health, The University of Iowa, Iowa City, IA, USA.|Institute of Life Sciences, Saxion University of Applied Sciences, Enschede, The Netherlands.|Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA, USA.|LuthePharma, Fabrikstrasse 2, 48599, Gronau, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Luthe
mesh_terms: D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism; D021281:Quantitative Structure-Activity Relationship; D015238:Sulfotransferases / Q000737:chemistry* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D011078:Polychlorinated Biphenyls; D015238:Sulfotransferases; C028152:alcohol sulfotransferase
keywords: 4-Hydroxy-3,5-dichlorobiphenyl; Computational chemistry; F-tagged probes; Hydroxylated polychlorinated biphenyls; Polychlorinated biphenyls; QSAR; Sulfotransferase; hSULT2A1