17beta-Estradiol 17-glucosiduronate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 17beta-Estradiol 17-glucosiduronate
• 英文别名: (2S,3S,4S,5R,6R)-3,4,5-trihydroxy-6-[[(8R,9S,13S,14S,17S)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl]oxy]oxane-2-carboxylate
• 化学式: C24H31O8-
• 分子量: 447.5
• InChiKey: MTKNDAQYHASLID-QXYWQCSFSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  32
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  140
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  17beta-Estradiol 17-glucosiduronate 、 PAPS 生成 17beta-estradiol 17-O-(3-sulfo-beta-D-glucuronate) 、 Adenosine 3',5'-bismonophosphate(4-) 、 氢(+1)阳离子
  参考文献：
  名称：

  In Vivo Regulation of Steroid Hormones by the Chst10 Sulfotransferase in Mouse

  摘要：

  Chst10 adds sulfate to glucuronic acid to form a carbohydrate antigen, HNK-1, in glycoproteins and glycolipids. To determine the role of Chst10 in vivo, we generated systemic Chst10-deficient mutant mice. Although Chst10(-/-) mice were born and grew to adulthood with no gross defects, they were subfertile. Uteri from Chst10(-/-) females at the pro-estrus stage were larger than those from wild-type females and exhibited a thick uterine endometrium. Serum estrogen levels in Chst10(-/-) females were higher than those from wild-type females, suggesting impaired down-regulation of estrogen. Because steroid hormones are often conjugated to glucuronic acid, we hypothesized that Chst10 sulfates glucuronidated steroid hormone to regulate steroid hormone in vivo. Enzymatic activity assays and structural analysis of Chst10 products by HPLC and mass spectrometry revealed that Chst10 indeed sulfates glucuronidated estrogen, testosterone, and other steroid hormones. We also identified an HPLC peak corresponding to sulfated and glucuronidated estradiol in serum from wild-type but not from Chst10 null female mice. Estrogen-response element reporter assays revealed that Chst10-modified estrogen likely did not bind to its receptor. These results suggest that subfertility exhibited by female mice following Chst10 loss results from dysregulation of estrogen. Given that Chst10 transfers sulfates to several steroid hormones, Chst10 likely functions in widespread regulation of steroid hormones in vivo.

  DOI：

  10.1074/jbc.m112.433474
• 作为产物：
  描述：

  雌二醇 、 UDP-alpha-D-glucuronate(3-) 生成 17beta-Estradiol 17-glucosiduronate 、 氢(+1)阳离子 、 UDP
  参考文献：
  名称：

  Specificity and Regioselectivity of the Conjugation of Estradiol, Estrone, and Their Catecholestrogen and Methoxyestrogen Metabolites by Human Uridine Diphospho-glucuronosyltransferases Expressed in Endometrium

  摘要：

  酸代谢。

  DOI：

  10.1210/jc.2004-0331

文献信息

• Regiospecificity and Stereospecificity of Human UDP-Glucuronosyltransferases in the Glucuronidation of Estriol, 16-Epiestriol, 17-Epiestriol, and 13-Epiestradiol
  作者：Nina Sneitz、Mikko Vahermo、Johanna Mosorin、Liisa Laakkonen、Donald Poirier、Moshe Finel

  DOI：10.1124/dmd.112.049072

  日期：2013.3

  The glucuronidation of estriol, 16-epiestriol, and 17-epiestriol by the human UDP-glucuronosyltransferases (UGTs) of subfamilies 1A, 2A, and 2B was examined. UGT1A10 is highly active in the conjugation of the 3-OH in all these estriols, whereas UGT2B7 is the most active UGT toward one of the ring D hydroxyls, the 16-OH in estriol and 16-epiestriol, but the 17-OH in 17-epiestriol. Kinetic analyses indicated that the 17-OH configuration plays a major role in the affinity of UGT2B7 for estrogens. The glucuronidation of the different estriols by the human liver and intestine microsomes reflects the activity of UGT1A10 and UGT2B7 in combination with the tissues’ difference in UGT1A10 expression. The UGT1A10 mutant 1A10-F93G exhibited much higher V max values than UGT1A10 in estriol and 17-epiestriol glucuronidation, but a significantly lower value in 16-epiestriol glucuronidation. To this study on estriol glucuronidation we have added experiments with 13-epiestradiol, a synthetic estradiol in which the spatial arrangement of the methyl on C18 and the hydroxyl on C17 is significantly different than in other estrogens. In comparison with estradiol glucuronidation, the C13 configuration change decreases the turnover of UGTs that conjugate the 3-OH, but increases it in UGTs that primarily conjugate the 17-OH. Unexpectedly, UGT2B17 exhibited similar conjugation rates of both the 17-OH and 3-OH of 13-espiestradiol. The combined results reveal the strong preference of UGT1A10 for the 3-OH of physiologic estrogens and the equivalently strong preference of UGT2B7 and UGT2B17 for the hydroxyls on ring D of such steroid hormones.

  检查了亚家族 1A、2A 和 2B 的人 UDP-葡萄糖醛酸基转移酶 (UGT) 对雌三醇、16-表三醇和 17-表三醇的葡萄糖醛酸化。 UGT1A10 在所有这些雌三醇中的 3-OH 缀合中具有高度活性，而 UGT2B7 是对 D 环羟基之一（雌三醇和 16-表三醇中的 16-OH）最活跃的 UGT，但 17 中的 17-OH -表三醇。动力学分析表明，17-OH构型在UGT2B7与雌激素的亲和力中起主要作用。人肝和肠微粒体对不同雌三醇的葡萄糖醛酸化反映了UGT1A10和UGT2B7的活性以及组织中UGT1A10表达的差异。 UGT1A10突变体1A10-F93G在雌三醇和17-表三醇葡萄糖醛酸化中表现出比UGT1A10高得多的V max 值，但在16-表三醇葡萄糖醛酸化中表现出显着较低的值。在这项关于雌三醇葡萄糖醛酸化的研究中，我们添加了 13-表雌二醇的实验，这是一种合成雌二醇，其中 C18 上的甲基和 C17 上的羟基的空间排列与其他雌激素显着不同。与雌二醇葡萄糖醛酸化相比，C13构型变化降低了缀合3-OH的UGT的周转率，但增加了主要缀合17-OH的UGT的周转率。出乎意料的是，UGT2B17 表现出与 13-espiestradiol 的 17-OH 和 3-OH 相似的缀合率。综合结果揭示了UGT1A10对生理雌激素的3-OH的强烈偏好，以及UGT2B7和UGT2B17对此类类固醇激素的环D上的羟基的同样强烈的偏好。
• The Configuration of the 17-Hydroxy Group Variably Influences the Glucuronidation of β-Estradiol and Epiestradiol by Human UDP-Glucuronosyltransferases
  作者：Katriina Itäaho、Peter I. Mackenzie、Shin-ichi Ikushiro、John O. Miners、Moshe Finel

  DOI：10.1124/dmd.108.022731

  日期：2008.11

  The glucuronidation of 17β-estradiol (β-estradiol) and 17α-estradiol (epiestradiol) was studied to elucidate how the orientation of the 17-OH group affects conjugation at the 3-OH or the 17-OH of either diastereomer. Recombinant human UDP-glucuronosyltransferases (UGTs) UGT1A1, UGT1A3, UGT1A7, UGT1A8, and UGT1A10 conjugated one or both diastereomers, mainly at the 3-OH. The activity of UGT1A4 was low and unique because it was directed merely toward the 17-OH of both aglycones. UGT1A10 exhibited particularly high estradiol glucuronidation activity, the rate and affinity of which were significantly higher in the case of β-estradiol than with epiestradiol. UGT1A9 did not catalyze estradiol glucuronidation, but UGT1A9-catalyzed scopoletin glucuronidation was competitively inhibited by β-estradiol. UGT2B4, UGT2B7, and UGT2B17 exclusively conjugated the estradiols at the 17-OH position in a highly stereoselective fashion. UGT2B4 was specific for epiestradiol; UGT2B7 glucuronidated both diastereomers, with high affinity for epiestradiol, whereas UGT2B17 only glucuronidated β-estradiol. UGT2B15 glucuronidated both estradiols at the 3-OH, with a strong preference for epiestradiol. Human UGT2A1 and UGT2A2 glucuronidated both diastereoisomers at both hydroxyl groups. Microsomal studies revealed that human liver mainly yielded epiestradiol 17- O -glucuronide, and human intestine primarily yielded β-estradiol 3- O -glucuronide, whereas rat liver preferentially formed β-estradiol 17- O -glucuronide. Of the three recombinant rat UGTs that were examined in this study, rUGT2B1 was specific for the 17-OH of β-estradiol, rUGT2B2 did not catalyze estradiol glucuronidation, whereas rUGT2B3 exhibited high activity toward the 17-OH in both diastereoisomers. The results show that although many UGTs can catalyze estradiol glucuronidation, there are marked differences in their kinetics, regioselectivity, and stereoselectivity.

  研究了 17β-estradiol （β-雌二醇）和 17α-estradiol （表雌二醇）的葡萄糖醛酸化作用，以阐明 17-OH 基团的取向如何影响非对映异构体 3-OH 或 17-OH 的共轭作用。重组人 UDP-葡萄糖醛酸转移酶（UGTs）UGT1A1、UGT1A3、UGT1A7、UGT1A8 和 UGT1A10 主要在 3-OH 处与一种或两种非对映异构体共轭。UGT1A4 的活性很低，而且很独特，因为它只针对两种苷元的 17-OH。UGT1A10 对雌二醇的葡萄糖醛酸化活性特别高，β-雌二醇的葡萄糖醛酸化速率和亲和力明显高于表雌二醇。UGT1A9 不催化雌二醇葡糖醛酸化，但 UGT1A9 催化的莨菪亭葡糖醛酸化被β-雌二醇竞争性抑制。UGT2B4、UGT2B7 和 UGT2B17 独家以高度立体选择性的方式在 17-OH 位上共轭雌二醇。UGT2B4 对表雌二醇具有特异性；UGT2B7 可葡糖醛酸化两种非对映异构体，对表雌二醇具有高亲和力，而 UGT2B17 只葡糖醛酸化 β-雌二醇。UGT2B15 对两种雌二醇的 3-OH 都进行葡萄糖醛酸化，但对表雌二醇有强烈的偏好。人 UGT2A1 和 UGT2A2 在两个羟基上葡萄糖醛酸化两种非对映异构体。微粒体研究显示，人类肝脏主要产生表雌二醇 17- O -葡萄糖醛酸，人类肠道主要产生 β- 雌二醇 3- O -葡萄糖醛酸，而大鼠肝脏更倾向于形成 β- 雌二醇 17- O -葡萄糖醛酸。在本研究检测的三种重组大鼠 UGTs 中，rUGT2B1 对 β-雌二醇的 17-OH 具有特异性，rUGT2B2 不催化雌二醇葡萄糖醛酸化，而 rUGT2B3 对两种非对映异构体中的 17-OH 均表现出较高的活性。结果表明，尽管许多 UGTs 都能催化雌二醇葡萄糖醛酸化反应，但它们的动力学、区域选择性和立体选择性存在明显差异。
• Specificity and Regioselectivity of the Conjugation of Estradiol, Estrone, and Their Catecholestrogen and Methoxyestrogen Metabolites by Human Uridine Diphospho-glucuronosyltransferases Expressed in Endometrium
  作者：Johanie Lépine、Olivier Bernard、Marie Plante、Bernard Têtu、Georges Pelletier、Fernand Labrie、Alain Bélanger、Chantal Guillemette

  DOI：10.1210/jc.2004-0331

  日期：2004.10.1

  Uridine diphospho-glucuronosyltransferases (UGTs) inactivate and facilitate the excretion of estrogens to glucuronides (-G), the most abundant circulating estrogen conjugates. The identity of the conjugated estrogens formed by all known overexpressed UGTs (n = 16) was analyzed by comparison with retention time and mass fragmentation of authentic standards by HPLC tandem mass spectrometry methods. Six UGTs, namely 1A1, 1A3, 1A8, 1A9, 1A10, and 2B7, were found to glucuronidate estradiol (E2) and estrone (E1), their hydroxyls (OH), and their methoxy derivatives (MeO). Addition of glucuronic acid was catalyzed by specific UGTs at positions 2, 3, and 4 of the estrogens, whereas only E2 was conjugated at position 17 by UGT2B7. Kinetic parameters indicate that the conjugation of E2 at position 3 was predominantly catalyzed by 1A1, 1A3, and 1A8 and by 1A8 for E1. Conjugation of 2-OHE1/E2 and 2- and 4-MeOE1/E2 was selective at position 3, mostly catalyzed by 1A1 and 1A8. Of all UGTs, UGT2B7 demonstrated the highest catalytic activities for estrogens and at least 10- to 50-fold higher activity for the conjugation of genotoxic 4-hydroxycatecholestrogens at position 4, compared with the conjugation of E2, E1, and 2-hydroxycatecholestrogens. Its presence was further shown in the endometrium by RT-PCR and immunohistochemistry, localizing in the same cells expressing CYP1B1, involved locally in the formation of 4-hydroxycatecholestrogens. Data show that several UGT enzymes detected in the endometrium are involved in the glucuronidation of E2 and its 2-OH, 4-OH, and 2-MeO metabolites that exert various biological effects in the tissue.

  酸代谢。
• In Vivo Regulation of Steroid Hormones by the Chst10 Sulfotransferase in Mouse
  作者：Misa Suzuki-Anekoji、Atsushi Suzuki、Sz-Wei Wu、Kiyohiko Angata、Keith K. Murai、Kazuhiro Sugihara、Tomoya O. Akama、Kay-Hooi Khoo、Jun Nakayama、Michiko N. Fukuda、Minoru Fukuda

  DOI：10.1074/jbc.m112.433474

  日期：2013.2

  Chst10 adds sulfate to glucuronic acid to form a carbohydrate antigen, HNK-1, in glycoproteins and glycolipids. To determine the role of Chst10 in vivo, we generated systemic Chst10-deficient mutant mice. Although Chst10(-/-) mice were born and grew to adulthood with no gross defects, they were subfertile. Uteri from Chst10(-/-) females at the pro-estrus stage were larger than those from wild-type females and exhibited a thick uterine endometrium. Serum estrogen levels in Chst10(-/-) females were higher than those from wild-type females, suggesting impaired down-regulation of estrogen. Because steroid hormones are often conjugated to glucuronic acid, we hypothesized that Chst10 sulfates glucuronidated steroid hormone to regulate steroid hormone in vivo. Enzymatic activity assays and structural analysis of Chst10 products by HPLC and mass spectrometry revealed that Chst10 indeed sulfates glucuronidated estrogen, testosterone, and other steroid hormones. We also identified an HPLC peak corresponding to sulfated and glucuronidated estradiol in serum from wild-type but not from Chst10 null female mice. Estrogen-response element reporter assays revealed that Chst10-modified estrogen likely did not bind to its receptor. These results suggest that subfertility exhibited by female mice following Chst10 loss results from dysregulation of estrogen. Given that Chst10 transfers sulfates to several steroid hormones, Chst10 likely functions in widespread regulation of steroid hormones in vivo.