Laboratory of Structural Biology, National Institute of Environmental Health Sciences, North Carolina, USA.
Environ Health Perspect. 2013 Oct;121(10):1194-9. doi: 10.1289/ehp.1306902. Epub 2013 Aug 19.
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 (e.g., 3-OH-BDE-47) have been suggested to inhibit estrogen sulfotransferase, potentially affecting estrogen metabolism.
Our primary goal was to understand the structural mechanism for inhibition of the hormone-metabolizing enzyme estrogen sulfotransferase by certain BFRs. We also sought to understand various factors that facilitate the binding of flame retardants in the enzyme binding pocket.
We used X-ray crystallography to obtain atomic detail of the binding modes of TBBPA and 3-OH-BDE-47 to estrogen sulfotransferase for comparison with binding of the endogenous substrate estradiol.
The crystal structures reveal how BFRs mimic estradiol binding as well as the various interactions between the compounds and protein residues that facilitate its binding. In addition, the structures provide insights into the ability of the sulfotransferase substrate binding pocket to accommodate a range of halogenated compounds that satisfy minimal structural criteria.
Our results show how BFRs or their metabolites can bind to and inhibit a key hormone-metabolizing enzyme, potentially causing endocrine disruption.
溴化阻燃剂（BFRs）广泛应用于多种消费品，由于其可能对内分泌干扰、免疫毒性、生殖毒性和神经毒性等健康问题产生影响，因此受到了研究关注。四溴双酚 A（TBBPA）是使用最广泛的 BFR，某些多溴联苯醚同系物（如 3-OH-BDE-47）的人类代谢物被认为可以抑制雌激素硫酸转移酶，从而可能影响雌激素代谢。
我们的主要目标是了解某些 BFR 抑制激素代谢酶雌激素硫酸转移酶的结构机制。我们还试图了解促进阻燃剂在酶结合口袋中结合的各种因素。
我们使用 X 射线晶体学获得了 TBBPA 和 3-OH-BDE-47 与雌激素硫酸转移酶结合模式的原子细节，以便与内源性底物雌二醇的结合进行比较。
晶体结构揭示了 BFR 如何模拟雌二醇的结合，以及化合物与蛋白残基之间的各种相互作用，这些相互作用促进了其结合。此外，这些结构还提供了有关硫酸转移酶底物结合口袋容纳满足最小结构标准的一系列卤代化合物的能力的见解。
我们的研究结果表明，BFR 或其代谢物可以与关键的激素代谢酶结合并抑制其活性，从而可能导致内分泌干扰。
