Human Cytosolic Sulfotransferases

描述（由申请人提供）：本项目的总体目标是研究人胞质磺基转移酶（SULT）的生物化学和生理功能。细胞溶质SULT负责许多药物和外源性物质的硫酸化，从而在2相代谢和排泄中发挥主要作用。此外，许多SULT参与内源性化合物的代谢，包括单胺神经递质以及类固醇和甲状腺激素。类固醇硫酸盐是生物学上无活性的，因为它们不结合和激活其适当的受体。人类在类固醇激素合成和代谢方面相对独特，这是由于肾上腺初显后合成的肾上腺雄激素水平较高，以及胎儿发育期间合成的肾上腺雄激素和雌激素水平较高。在人类中，大多数肾上腺雄激素和雌激素以硫酸酯形式循环，并在硫酸酯酶活性去除硫酸基团后为活性类固醇提供储存库。然后，类固醇可以在靶组织中转化为不同的潜在活性形式。硫酸根部分的存在抑制类固醇的进一步代谢。 在本提案中，我们将重点关注三种主要的人类类固醇SULT的生化、分子和功能特性的表征：（1）SULT 1 E1，其负责雌激素的高亲和力和活性调节，（2）SULT 2A 1，其参与肾上腺中DHEA-硫酸盐的合成和分泌，和（3）SULT 2B 1b，最近描述的对3 β-羟基类固醇的硫酸化具有选择性的同种型。我们推测，这些SULT在正常和患病的类固醇反应组织中的组织特异性表达将对这些组织中类固醇的活性和合成产生重要影响。提出了以下具体目标：（1）研究类固醇硫酸化在调节人前列腺组织反应性中的作用，（2）研究SULT 2B 1b在人胎盘和乳腺细胞中的亚细胞定位，（3）研究非裔美国人特有的SULT 2A 1基因中特定单核苷酸多态性对DHEA和DHEA硫酸盐合成的作用。

DESCRIPTION (provided by applicant): The overall goal of this project is to investigate the biochemistry and physiological functions of the human cytosolic sulfotransferases (SULTs). The cytosolic SULTs are responsible for the sulfation of many drugs and xenobiotics and thereby play a major role in Phase 2 metabolism and excretion. Additionally, many of the SULTs are involved in the metabolism of endogenous compounds including monoamine neurotransmitters as well as steroid and thyroid hormones. Steroid sulfates are biologically inactive since they do not bind and activate their appropriate receptors. Humans are relatively unique in steroid hormone synthesis and metabolism due to the high levels of adrenal androgens synthesized after adrenarche as well as the high levels of adrenal androgens and estrogens synthesized during fetal development. In humans, most adrenal androgens and estrogens circulate as sulfate esters and provide a reservoir for active steroids following the removal of the sulfate group by sulfatase activity. The steroids can then be converted to different potentially active forms in target tissues. The presence of the sulfate moiety inhibits the further metabolism of the steroids. In this proposal, we will focus on the characterization of biochemical, molecular and functional properties of the three major human steroid SULTs: (1) SULT1E1 which is responsible for the high affinity and regulation of activity of estrogens, (2) SULT2A1 which is involved in the synthesis and secretion of DHEA-sulfate in the adrenal, and (3) SULT2B1b, a recently described isoform selective for the sulfation of 3beta-hydroxysteroids. We hypothesize that the tissue specific expression of these SULTs in normal and diseased hormone-responsive tissues will have important effects on the activity and synthesis of steroids within those tissues. The following specific aims are proposed: (1) to investigate the role of steroid sulfation in the regulation of human prostate tissue responsiveness, (2) to investigate the subcellular localization of SULT2B1b in human placental and breast cells, and (3) to investigate the role of specific single nucleotide polymorphisms in the SULT2A1 gene unique to African-Americans on DHEA and DHEA-sulfate synthesis.