Human Cytosolic Sulfotransferases

描述(由申请者提供)：本项目的总体目标是研究人胞浆磺基转移酶(Sults)的生化和生理功能。胞质硫化物负责许多药物和外源物质的硫酸盐化，从而在第二相代谢和排泄中发挥主要作用。此外，许多硫磺参与内源性化合物的新陈代谢，包括单胺类神经递质以及类固醇和甲状腺激素。类固醇硫酸盐在生物上是不活跃的，因为它们不结合和激活它们适当的受体。人类在类固醇激素的合成和代谢方面是相对独特的，这是因为在肾上腺发育后合成了高水平的肾上腺雄激素，以及在胎儿发育期间合成了高水平的肾上腺雄激素和雌激素。在人类中，大多数肾上腺雄激素和雌激素以硫酸酯的形式循环，并在硫酸酶活性清除硫酸盐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。硫酸盐部分的存在抑制了类固醇的进一步代谢。 在本提案中，我们将重点研究三种主要的人类类固醇的生化、分子和功能特性：(1)SULT1E1，负责雌激素的高亲和力和活性调节；(2)SULT2A1，参与肾上腺DHEA-硫酸盐的合成和分泌；(3)SULT2B1b，最近被发现的一种选择性3β-羟基类固醇硫化的异构体。我们推测，这些结果在正常和疾病激素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。我们提出了以下具体目标：(1)研究类固醇硫酸盐在调节人类前列腺组织反应性中的作用；(2)研究SULT2B1b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SULT2A1基因中特定的单核苷酸多态性在DHEA和DHEA-硫酸盐合成中的作用。

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.