Structural Study of Sulfotransferases

工作概述：磺基转移酶的代谢是一种生物信号的失活，如类固醇激素，也是一种防御环境毒物和致癌物的系统。面对几乎无限数量的结构不同的化学物质，这些酶表现出广泛的底物专一性。因此，研究决定底物特异性的结构原理对于预测代谢及其对人类对化学物质的易感性的后果是很重要的。在研究中，我们使用了X射线结晶学和定点突变。我们已经解决了雌激素、羟基类固醇和苯酚磺基转移酶的晶体结构，这些结构为理解磺基转移酶催化的反应机理提供了洞察力。基于晶体结构的定点突变定义了一个狭窄的门，它决定了底物的特异性，也决定了所有胞浆磺基转移酶的公共二聚体界面。磺基转移酶和糖基转移酶参与蛋白多糖的糖胺多糖合成。我们解决了硫酸乙酰肝素N-脱乙酰酶/N-磺基转移酶和葡萄糖醛酸基转移酶1的晶体结构。

Summary of Work: Metabolism by sulfotransferases is an inactivation of biological signals such as steroid hormones and also a defense system against environmental toxicants and carcinogens. To encounter virtually unlimited numbers of structurally diverse chemiclas, these enzymes exhibit broad substrate specificity. Thus, it is important to investigate the structural principle determining the substrate specificity in order to predict the metabolisms and the resulted consequences to human susceptibililty to chemical exposure. For the investigation, we have used x-ray crystallography and site-directed mutagenesis. We have solved the crystal structure of estrogen, hydroxyteroid, and phenol sulfotransferases.These structures provided the insight into understanding the reaction mechanism catalyzed by sulfotransferase. Site-directed mutagenesis based on the crytal structres defined a stricture-like gate that determines substrate specificity and also the common dimer interface for all cytosolic sulfotransferase. Sulfotransferases and glycosyltransferases are involved in glycosaminylglycan synthesis of proteoglycans. We have solved the crystal structures of heparan sulfate N-deacetylase/N-sulfotrabsferase and glucuronosyltransferase 1.