Human Cytosolic Sulfotransferases

描述（由申请人提供）：本项目的总体目标是研究人细胞质硫转移酶（SULTs）的生物化学和生理功能。胞质SULTs负责许多药物和外源药物的磺化，因此在2期代谢和排泄中起主要作用。此外，许多sult参与内源性化合物的代谢，包括单胺类神经递质以及类固醇和甲状腺激素。类固醇硫酸盐是生物无活性的，因为它们不能结合和激活相应的受体。由于肾上腺素分泌后合成的肾上腺雄激素水平较高，以及胎儿发育过程中合成的肾上腺雄激素和雌激素水平较高，人类在类固醇激素的合成和代谢方面具有相对独特的特点。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，并在硫酸酯酶活性去除硫酸基后为活性类固醇提供储存库。然后类固醇可以在目标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。

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.