Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

Edugie J Ekuase; Hans-Joachim Lehmler; Larry W Robertson; Michael W Duffel

doi:10.1016/j.cbi.2014.01.018

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Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

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Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1

Edugie J Ekuase, Hans-Joachim Lehmler, Larry W Robertson and Michael W Duffel

Chemico-biological interactions, Vol.212(1), pp.56-64

04/05/2014

DOI: 10.1016/j.cbi.2014.01.018

PMCID: PMC3994546

PMID: 24508592

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Abstract

•We studied the mechanism of inhibition of hSULT2A1 by hydroxylated PCBs (OHPCBs).•The OHPCBs studied bind at the sulfuryl-acceptor binding site of hSULT2A1.•This binding may occur with different orientations of the OHPCB.•The results suggest binding of OHPCBs to more than one form of hSULT2A1. 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.

hSULT2A1

Hydroxylated polychlorinated biphenyl

OHPCB

Sulfotransferase

PCB

ISRP Project 3 2015-2020

Details

Title: Subtitle: Binding interactions of hydroxylated polychlorinated biphenyls (OHPCBs) with human hydroxysteroid sulfotransferase hSULT2A1
Creators: Edugie J Ekuase - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States
Hans-Joachim Lehmler - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, United States
Larry W Robertson - Department of Occupational and Environmental Health, College of Public Health, University of Iowa, Iowa City, IA 52242, United States
Michael W Duffel - Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA 52242, United States
Resource Type: Journal article
Publication Details: Chemico-biological interactions, Vol.212(1), pp.56-64
DOI: 10.1016/j.cbi.2014.01.018
PMID: 24508592
PMCID: PMC3994546
NLM abbreviation: Chem Biol Interact
ISSN: 0009-2797
eISSN: 1872-7786
Publisher: Elsevier Ireland Ltd
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: P42 ES013661, R01 ES017425; DOI: 10.13039/100000066, name: National Institute of Environmental Health Sciences, award: R01 CA038683, NIEHS/NIH P30 ES05605; name: University of Iowa Environmental Health Sciences Research Center
Language: English
Date published: 04/05/2014
Academic Unit: Occupational and Environmental Health; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicinal and Natural Products Chemistry
Record Identifier: 9984000925202771

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