Chlorinated biphenyl quinones and phenyl-2,5-benzoquinone differentially modify the catalytic activity of human hydroxysteroid sulfotransferase hSULT2A1

Xiaoyan Qin; Hans-Joachim Lehmler; Lynn M Teesch; Larry W Robertson; Michael W Duffel

doi:10.1021/tx400207q

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Chlorinated biphenyl quinones and phenyl-2,5-benzoquinone differentially modify the catalytic activity of human hydroxysteroid sulfotransferase hSULT2A1

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Chlorinated biphenyl quinones and phenyl-2,5-benzoquinone differentially modify the catalytic activity of human hydroxysteroid sulfotransferase hSULT2A1

Xiaoyan Qin, Hans-Joachim Lehmler, Lynn M Teesch, Larry W Robertson and Michael W Duffel

Chemical research in toxicology, Vol.26(10), pp.1474-1485

10/21/2013

DOI: 10.1021/tx400207q

PMCID: PMC3846294

PMID: 24059442

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Abstract

Human hydroxysteroid sulfotransferase (hSULT2A1) catalyzes the sulfation of a broad range of environmental chemicals, drugs, and other xenobiotics in addition to endogenous compounds that include hydroxysteroids and bile acids. Polychlorinated biphenyls (PCBs) are persistent environmental contaminants, and oxidized metabolites of PCBs may play significant roles in the etiology of their adverse health effects. Quinones derived from the oxidative metabolism of PCBs (PCB-quinones) react with nucleophilic sites in proteins and also undergo redox cycling to generate reactive oxygen species. This, along with the sensitivity of hSULT2A1 to oxidative modification at cysteine residues, led us to hypothesize that electrophilic PCB-quinones react with hSULT2A1 to alter its catalytic function. Thus, we examined the effects of four phenylbenzoquinones on the ability of hSULT2A1 to catalyze the sulfation of the endogenous substrate, dehydroepiandrosterone (DHEA). The quinones studied were 2'-chlorophenyl-2,5-benzoquinone (2'-Cl-BQ), 4'-chlorophenyl-2,5-benzoquinone (4'-Cl-BQ), 4'-chlorophenyl-3,6-dichloro-2,5-benzoquinone (3,6,4'-triCl-BQ), and phenyl-2,5-benzoquinone (PBQ). At all concentrations examined, pretreatment of hSULT2A1 with the PCB-quinones decreased the catalytic activity of hSULT2A1. Pretreatment with low concentrations of PBQ, however, increased the catalytic activity of the enzyme, while higher concentrations inhibited catalysis. A decrease in substrate inhibition with DHEA was seen following preincubation of hSULT2A1 with all of the quinones. Proteolytic digestion of the enzyme followed by LC/MS analysis indicated PCB-quinone- and PBQ-adducts at Cys55 and Cys199, as well as oxidation products at methionines in the protein. Equilibrium binding experiments and molecular modeling suggested that changes due to these modifications may affect the nucleotide binding site and the entrance to the sulfuryl acceptor binding site of hSULT2A1.

Protein Structure, Tertiary

Sulfotransferases - genetics

Biocatalysis

Humans

Recombinant Proteins - chemistry

Benzoquinones - chemistry

Recombinant Proteins - genetics

Chromatography, High Pressure Liquid

Cysteine - chemistry

Polychlorinated Biphenyls - metabolism

Recombinant Proteins - biosynthesis

Tandem Mass Spectrometry

Polychlorinated Biphenyls - chemistry

Methionine - chemistry

Protein Binding

Dehydroepiandrosterone - chemistry

Sulfotransferases - metabolism

Kinetics

Dehydroepiandrosterone - metabolism

Binding Sites

Benzoquinones - metabolism

Peptides - analysis

Sulfotransferases - chemistry

Details

Title: Subtitle: Chlorinated biphenyl quinones and phenyl-2,5-benzoquinone differentially modify the catalytic activity of human hydroxysteroid sulfotransferase hSULT2A1
Creators: Xiaoyan Qin - Interdisciplinary Graduate Program in Human Toxicology, University of Iowa , Iowa City, Iowa 52242, United States
Hans-Joachim Lehmler
Lynn M Teesch
Larry W Robertson
Michael W Duffel
Resource Type: Journal article
Publication Details: Chemical research in toxicology, Vol.26(10), pp.1474-1485
DOI: 10.1021/tx400207q
PMID: 24059442
PMCID: PMC3846294
NLM abbreviation: Chem Res Toxicol
ISSN: 0893-228X
eISSN: 1520-5010
Publisher: United States
Grant note: P42 ES013661 / NIEHS NIH HHS P30 ES005605 / NIEHS NIH HHS P30 ES05605 / NIEHS NIH HHS
Language: English
Date published: 10/21/2013
Academic Unit: Occupational and Environmental Health; Core Research Facilities; Iowa Neuroscience Institute; Pharmaceutical Sciences and Experimental Therapeutics; Iowa Superfund Research Program; Medicine Administration; Medicinal and Natural Products Chemistry
Record Identifier: 9984001080802771

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