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Binding Interactions of Hydroxylated Polychlorinated Biphenyls (OHPCBs) with Human Hydroxysteroid Sulfotransferase hSULT2A1

机译：羟基化多氯联苯（OHPCBs）与人类羟基类固醇硫转移酶hSULT2A1的结合相互作用

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摘要

Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and exposure to PCBs and their hydroxylated metabolites (OHPCBs) has been associated with various adverse health effects. The mammalian cytosolic sulfotransferases (SULTs) catalyze the sulfation of OHPCBs, and the interaction of OHPCBs with both the SULT1 and SULT2 families of these enzymes has received attention both with respect to metabolic disposition of these molecules and the potential mechanisms for their roles in endocrine disruption. We have previously shown that OHPCBs interact with human hydroxysteroid sulfotransferase hSULT2A1, an enzyme that catalyzes the sulfation of dehydroepiandrosterone (DHEA), other alcohol-containing steroids, bile acids, and many xenobiotics. The objective of our current studies is to investigate the mechanism of inhibition of hSULT2A1 by OHPCBs by combining inhibition kinetics with determination of equilibrium binding constants and molecular modeling of potential interactions. Examination of the effects of fifteen OHPCBs on the sulfation of DHEA catalyzed by hSULT2A1 showed predominantly noncompetitive inhibition patterns. This was observed for OHPCBs that were substrates for sulfation reactions catalyzed by the enzyme as well as those that solely inhibited the sulfation of DHEA. Equilibrium binding experiments and molecular modeling studies indicated that the OHPCBs bind at the binding site for DHEA on the enzyme, and that the observed noncompetitive patterns of inhibition are consistent with binding in more than one orientation to more than one enzyme complex. These results have implications for the roles of SULTs in the toxicology of OHPCBs, while also providing molecular probes of the complexity of substrate/inhibitor interactions with hSULT2A1.
机译：多氯联苯（PCB）是持久的环境污染物，接触PCB及其羟基化代谢物（OHPCB）与多种不良健康影响相关。哺乳动物的胞质磺基转移酶（SULTs）催化OHPCBs的硫酸化，并且OHPCBs与这些酶的SULT1和SULT2家族的相互作用在这些分子的代谢处置以及它们在内分泌破坏中的作用的潜在机制方面均受到关注。 。先前我们已经证明，OHPCBs与人羟基类固醇磺基转移酶hSULT2A1相互作用，该酶催化脱氢表雄酮（DHEA），其他含醇类固醇，胆汁酸和许多异生物素的硫酸化。我们当前研究的目的是通过结合抑制动力学，确定平衡结合常数和潜在相互作用的分子模型，研究OHPCB抑制hSULT2A1的机制。检查15个OHPCB对hSULT2A1催化的DHEA硫酸化的影响主要显示为非竞争性抑制模式。对于作为酶催化的硫酸盐化反应底物的OHPCBs，以及仅抑制DHEA硫酸盐化的那些OHOHPCBs，都可以观察到这一点。平衡结合实验和分子模型研究表明，OHPCBs在酶上DHEA的结合位点上结合，并且观察到的非竞争性抑制模式与以一种以上方向结合到一种以上酶复合物上是一致的。这些结果暗示了SULTs在OHPCBs毒理学中的作用，同时还提供了与hSULT2A1进行底物/抑制剂相互作用的复杂性的分子探针。

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