Mechanistic insights into the specificity of human cytosolic sulfotransferase 2A1 (hSULT2A1) for hydroxylated polychlorinated biphenyls through the use of fluoro-tagged probes
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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.
KeywordsF-tagged probes QSAR hSULT2A1 Polychlorinated biphenyls Hydroxylated polychlorinated biphenyls Sulfotransferase Computational chemistry 4-Hydroxy-3,5-dichlorobiphenyl
This work was supported by the National Institutes of Health through research grants R01 CA038683 and P42ES 013661. We also acknowledge programmatic support through the University of Iowa Environmental Health Sciences Research Center (NIH grant P30 ES05605). Partial support was provided to Dr. Gregor Luthe by the Alexander von Humboldt Foundation. The project was financially supported by the Tech for Future fund, an initiative of the Saxion and Windesheim Universities of Applied Sciences and the regional government Overijsel, The Netherlands. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the granting agencies.
Conflict of Interest
The authors state that no conflict of interest exists.
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