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.

Novel tools for targeting PCBs and PCB metabolites using ssDNA aptamers

“…OH-PCB metabolites are also substrates for sulfotransferases, which is a family of enzymes that catalyzes sulfate conjugates both in vitro and in vivo (Dhakal et al, 2012;Ekuase et al, 2015;Grimm et al, 2013), specifically, a major human cytosolic sulfotransferase, hSULT1A1 (Grimm et al, 2013). These OH-PCBs and PCB sulfate conjugates have a high-affinity towards the thyroid hormone transport protein transthyretin (TTR) and interfere with the physiological functions of thyroid system by competing with L-thyroxine (T4) for its binding sites (Grimm et al, 2013).…”

“…However, the detection of small amounts of these compounds in biological matrices from epidemiological and laboratory studies remain a challenge. There are few research papers that report in vitro (Ekuase et al, 2015;Li et al, 2015;Morck, Larsen, & Wehler, 2002;Zhao, Narang, Ding, & Eadon, 2004) and in vivo (Daubeze & Narbonne, 1984;Morales & Matthews, 1979;Pereg et al, 2001) studies for the detection of protein modification using different methods.…”