SULFURYL-TRANSFER--THE HUMAN ESTROGEN SULFOTRANSFERASE

硫酰基转移与磷酰基转移一样，是哺乳动物代谢中重要而普遍的调节机制，但对硫酰基转移的酶学研究却知之甚少。雌激素磺基转移酶（EST）催化PAPS或活化硫酸盐的磺酰基部分转移至各种雌激素（1）。PAPS 2- + E PAP 2- + ES- + H+（1）硫酸化雌激素通过阻止其结合并激活雌激素受体来调节其细胞活性。 EST表达调节月经周期中子宫内膜和乳腺的正常雌激素反应。 最近的研究表明，EST表达和雌激素依赖性生长反应之间存在紧密的因果关系，而雌激素依赖性生长反应是乳腺和子宫内膜肿瘤发生的基础。 磺基转移酶是一个非常高度保守的酶家族，并且重要的磺酰基调控的例子也非常丰富。本提案的主要目标是创造一个国家的最先进的理解化学和酶学的硫酰基转移。 这些新的基本信息将对磺基转移酶领域产生重大影响。 酶学将被带到承担相当大的公众关注的话题：雌激素替代疗法。 倍美力是美国最广泛使用的雌激素替代疗法，每天有1000万妇女注射。 将确定人EST对倍美力中发现的马雌激素的特异性，以评估它们是否在治疗浓度下通过硫酸化进行调节。

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.