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Crystal structure of human estrogen sulfotransferase (SULT1E1) in complex with inactive cofactor PAP and brominated flame retardant TBBPA (tetrabromobisphenol A)Crystal structure of human estrogen sulfotransferase (SULT1E1) in complex with inactive cofactor PAP and brominated flame retardant TBBPA (tetrabromobisphenol A)
Structural highlights
FunctionST1E1_HUMAN Sulfotransferase that utilizes 3'-phospho-5'-adenylyl sulfate (PAPS) as sulfonate donor to catalyze the sulfate conjugation of estradiol and estrone. May play a role in the regulation of estrogen receptor activity by metabolizing free estradiol. Maximally sulfates beta-estradiol and estrone at concentrations of 20 nM. Also sulfates dehydroepiandrosterone, pregnenolone, ethinylestradiol, equalenin, diethylstilbesterol and 1-naphthol, at significantly higher concentrations; however, cortisol, testosterone and dopamine are not sulfated.[1] Publication Abstract from PubMedBACKGROUND: Brominated flame retardants (BFRs), used in many types of consumer goods are being studied because of concerns about possible health effects related to endocrine disruption, immunotoxicity, reproductive toxicity and neurotoxicity. Tetrabromobisphenol A (TBBPA), the most widely used BFR, and human metabolites of certain congeners of polybrominated diphenyl ether (ex. 3-OH-BDE-47) have been suggested to inhibit estrogen sulfotransferase, potentially affecting estrogen metabolism. OBJECTIVES: The primary goal was to understand the structural mechanism for inhibition of the hormone metabolizing enzyme estrogen sulfotransferase by certain BFRs. In this process we sought to understand various factors that facilitate the binding of flame retardants in the enzyme binding pocket. METHODS: X-ray crystallography was used to obtain atomic detail of the binding modes of TBBPA and 3-OH-BDE-47 to the estrogen sulfotransferase to be compared to binding of the endogenous substrate estradiol. RESULTS: The crystal structures reveal how BFRs mimic estradiol binding and the various interactions between the compounds and protein residues that facilitate its binding. Additionally, the structures provide insights into the ability of the sulfotransferase substrate binding pocket to accomodate a range of halogenated compounds that satisfy minimal structural criteria. CONCLUSIONS: Our results show how BFRs or their metabolites can bind to and inhibit a key hormone metabolizing enzyme potentially causing endocrine disruption. Mimicking of Estradiol Binding by Flame Retardants and Their Metabolites: A Crystallographic Analysis.,Gosavi RA, Knudsen GA, Birnbaum LS, Pedersen LC Environ Health Perspect. 2013 Aug 19. PMID:23959441[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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