HUMAN CYTOSOLIC SULFOTRANSFERASES

该项目的总体目标是研究人类胞质磺基转移酶（ST）的生物化学和分子生物学，并了解硫酸化在正常和癌性人体组织中药物，外源性物质和内源性底物代谢中的作用。 硫酸化作用参与许多内源性化合物的代谢和活性调节，包括类固醇和甲状腺激素、单胺神经递质、维生素和胆汁酸。 类固醇激素的硫酸化在调节人体组织中的激素活性方面很重要。 类固醇硫酸盐是无活性的，因为类固醇硫酸盐不与其受体结合并启动细胞反应。 至少有六种人ST可以硫酸化雌激素化合物;然而，由于其对β-雌二醇（E2）的高亲和力，雌激素ST（EST，SULT 1 E1）是参与雌激素应答组织（如子宫内膜和乳腺）中雌激素失活的ST。在此赠款的前几个资助期内，已确定的人类胞质ST的数量已增加到10个。 很少有人知道这些新发现的ST形式的蛋白质化学或分子生物学。更少的是已知的ST亚型的生理功能。 我们相信，这些基本的生化信息将提高我们对人类药物代谢的理解，并为药物设计和治疗提供信息，同时增加我们对硫酸化在细胞生理学中的功能的了解。 我们还发现了一种新型的人ST样蛋白，BR-STL，选择性地表达在人脑组织中。因此，这项建议的重点是调查的ST在调节雌激素反应的正常和癌性乳腺细胞的作用，以及最近已确定的三种新的人类胞质ST的表征。 本研究的具体目的是：1）分析EST和PSTs在人正常和癌性乳腺组织中的表达和调节雌激素活性的作用; 2）表征最近描述的人STs、ST 2B 1a、ST 2B 1b和ST 1C 1以及ST样蛋白BR-STL的性质和功能。

The overall goal of this project is to investigate the biochemistry and molecular biology of the human cytosolic sulfotransferases (STs) and to understand the role of sulfation in the metabolism of drugs, xenobiotics and endogenous substrates in normal and cancerous human tissues. Sulfation is involved in the metabolism and regulation of activity of many endogenous compounds including steroid and thyroid hormones, monoamine neurotransmitters, vitamins, and bile acids. The sulfation of steroid hormones is important in the regulation of hormonal activity in human tissues. Steroid sulfates are inactive because steroid sulfates do not bind to their receptors and initiate a cellular response. At least six human STs can sulfate estrogenic compounds; however, because of its high affinity for beta- estradiol (E2), estrogen ST (EST, SULT1E1) is the ST involved in inactivating estrogens in estrogen responsive tissues such as endometrium and breast. During the previous funding periods of this grant, the number of identified human cytosolic STs has increased to ten. Little is known as to the protein chemistry or molecular biology of these newly identified forms of ST. Even less is known about the physiological functions of the ST isoforms. We believe that this fundamental biochemical information will improve our understanding of human drug metabolism and provide information for drug design and therapy as well as increase our knowledge of the functions of sulfation in cellular physiology. We have also identified a novel form of human ST-like protein, BR-STL, selectively expressed in human brain tissues. Thus, this proposal focuses on the investigation of the role of the STs in regulating estrogen responsiveness of normal and cancerous breast cells, as well as on the characterization of three novel human cytosolic STs which have been recently identified. The Specific Aims of this proposal are: 1) to analyze the expression and role of EST and the PSTs in regulating estrogenic activity in human normal and cancerous breast tissue and 2) to characterize the properties and functions of the recently described human STs, ST2B1a, ST2B1b and ST1C1, and the ST-like protein BR-STL.