SULFURYL-TRANSFER--THE HUMAN ESTROGEN SULFOTRANSFERASE

硫酰转移与磷酸化转移一样，是哺乳动物重要而普遍的代谢调节机制；然而，对硫酰转移的酶学知之甚少。雌激素硫转移酶（EST）催化硫基部分从PAPS或活化硫酸盐转移到多种雌激素(1)。PAPS2- + E PAP2- + ES- + H+(1)硫酸雌激素通过阻止其与雌激素受体的结合和激活来调节其细胞活性。EST的表达调节月经周期中子宫内膜和乳房的正常雌激素反应。最近的研究表明，EST表达与雌激素依赖性生长反应之间存在紧密而偶然的联系，而雌激素依赖性生长反应是乳房和子宫内膜肿瘤发生的基础。硫基转移酶是一个高度保守的酶家族，具有重要的硫基调控作用。本建议的主要目标是建立对硫基转移的化学和酶学的最新理解。这一新的基础性信息将对硫转移酶领域产生重大影响。酶学将带来承担相当公众关注的话题：雌激素替代疗法。普雷马林是美国最常用的雌激素替代疗法，每天有1000万女性注射。人类EST对马雌激素的特异性将被确定，以评估它们是否在治疗浓度下通过硫酸化调节。

Sulfuryl-transfer, much like phosphoryl-transfer, is an important and prevalent regulatory mechanism in mammalian metabolism; yet, little is known about the enzymology of sulfuryl-transfer. Estrogen sulfotransferase (EST) catalyzes transfer of the sulfuryl-moiety from PAPS, or activated sulfate, to a variety of estrogens (1). PAPS2- + E PAP2- + ES- + H+ (1) Sulfating estrogen regulates its cellular activity by preventing it from binding to and activating the estrogen receptor. EST expression regulates the normal estrogen response of the endometrium and breast during the menstrual cycle. Recent studies suggest a tight, casual link between EST expression and the estrogen-dependent growth response that underlies tumorgenesis in both breast and endometrium. The sulfotransferase are a very highly conserved enzyme family, and examples of the importance of sulfuryl-regulation and abundant. The primary goal of this proposal is to create a state-of-the-art understanding of the chemistry and enzymology of sulfuyl- transfer. This new and fundamental information will have a significant impact on the sulfotransferase field. The enzymology will be brought to bear on a topic of considerable public concern: estrogen replacement therapy. Premarin, the most widely prescribed estrogen replacement therapeutic in the United States, is injested by 10 million women daily. The specificity of human EST toward the equine estrogens found in Premarin will be determined to assess whether they are regulated via sulfation at therapeutic concentrations.