(S)-propranolol glucuronide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (S)-propranolol glucuronide
• 英文别名: S-PL-Glu；(2S,3S,4S,5R)-3,4,5-trihydroxy-6-[(2S)-1-naphthalen-1-yloxy-3-(propan-2-ylamino)propan-2-yl]oxyoxane-2-carboxylic acid
• 化学式: C₂₂H₂₉NO₈
• 分子量: 435.474
• InChiKey: PCALHJGQCKATMK-XNBWOFMBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.7
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  138
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (S)-1-(异丙基氨基)-3-(萘基氧基)丙-2-醇 、 6-[[[5-(2,4-二氧代嘧啶-1-基)-3,4-二羟基四氢呋喃-2-基]甲氧基-羟基磷酰]氧基-羟基磷酰]氧基-3,4,5-三羟基四氢吡喃-2-羧酸 在 glucuronosyltransferase 910B(115-117) mutant 作用下， 以 水 、 二甲基亚砜 为溶剂， 反应 1.0h， 生成 (S)-propranolol glucuronide
  参考文献：
  名称：

  How Many and Which Amino Acids Are Responsible for the Large Activity Differences between the Highly Homologous UDP-Glucuronosyltransferases (UGT) 1A9 and UGT1A10?

  摘要：

  人UDP-葡萄糖醛酸基转移酶(UGT) 1A9和1A10的氨基酸序列有93%相同，但它们的活性和底物选择性存在很大差异。例如，普萘洛尔葡萄糖醛酸化的区域选择性、多巴酚丁胺葡萄糖醛酸化的区域选择性以及α-和β-雌二醇的葡萄糖醛酸化率在UGT1A9和UGT1A10之间存在很大差异。为了鉴定造成活性差异的残基，我们通过在两个基因的相同位置插入四个独特的限制性位点并构建嵌合体，将两个 UGT 的 N 端一半分成五个可比较的片段，其中 UGT1A9 的片段分别被替换UGT1A10 的相应片段。所得突变体的活性分析，910A [1A10(1–83)/1A9(84–285)]、910B [1A9(1–83)/1A10(84–147)/1A9(148–285)]、910C [ 1A9(1–147)/1A10(148–181)/1A9(182–285)]、910D [1A9(1–181)/1A10(182–235)/1A9(236–285)]和 910E [1A9 (1–235)/1A10(236–285)]表明不止一个残基造成UGT1A9和UGT1A10之间的差异。接下来，我们制备了四个双嵌合体，其中上述 UGT1A9 片段中的两个同时被相应的 UGT1A10 片段替换。然而，没有一个双嵌合体以与 UGT1A10 类似的速率对雌二醇、普萘洛尔或多巴酚丁胺进行葡萄糖醛酸化。另一方面，研究 1-萘酚葡萄糖醛酸化的动力学产生了更集中的结果，表明片段 B (84-147) 内的残基直接影响该底物的 K m 值。进一步的诱变和活性测定表明 UGT1A9 的 Phe117 参与 1-萘酚结合。此外，N 端结构域 C 段内的残基（主要位于位置 152 和 169）似乎有助于提高 UGT1A10 的葡萄糖醛酸化率。

  DOI：

  10.1124/dmd.109.031229

文献信息

• Stereoselective metabolism of propranolol glucuronidation by human UDP-glucuronosyltransferases 2B7 and 1A9
  作者：Lushan Yu、Minrong Qian、Yao Liu、Tongwei Yao、Su Zeng

  DOI：10.1002/chir.20765

  日期：——

  Stereoselective metabolism of propranolol side‐chain glucuronidation was studied for two recombinant human uridine diphosphate glucuronosyltransferases (UGTs), UGT1A9 and UGT2B7. The S‐ and R‐propranolol side‐chain glucuronides produced in the incubation mixtures were assayed simultaneously by RP‐HPLC with fluorescent detector. The excitation and emission wavelengths were set at 310 nm and 339 nm,

  研究了普萘洛尔侧链葡糖醛酸糖苷的立体选择性代谢对两种重组人尿苷二磷酸葡糖醛酸糖基转移酶（UGTs）UGT1A9和UGT2B7的影响。孵育混合物中产生的S-和R-普萘洛尔侧链葡糖醛酸苷通过带荧光检测器的RP-HPLC同时测定。激发和发射波长分别设置为310 nm和339 nm。UGT1A9喜欢催化š -对映体，以[R -对映体和固有清除率（CL INT）的比率小号-对映体，以ř外消旋心得安和单个对映体的对映体分别是其的3.8倍和6.5倍。UGT2B7，但是，催化略少š比-对映体[R -对映体和CL INT的比率小号-对映体，以[R -对映体为0.8倍。高浓度外消旋普萘洛尔（> 0.57 mmol / l）和单个对映异构体（> 0.69 mmol / l）对UGT2B7的葡糖醛酸化表现出底物抑制作用，但在消旋普萘洛尔中仅S-对映体（> 0.44 mmol / l）表现出底物抑制作用用于UGT1A9。底物抑制常数（K
• How Many and Which Amino Acids Are Responsible for the Large Activity Differences between the Highly Homologous UDP-Glucuronosyltransferases (UGT) 1A9 and UGT1A10?
  作者：Katriina Itäaho、Liisa Laakkonen、Moshe Finel

  DOI：10.1124/dmd.109.031229

  日期：2010.4

  The amino acid sequences of the human UDP-glucuronosyltransferases (UGTs) 1A9 and 1A10 are 93% identical, yet there are large differences in their activity and substrate selectivity. For example, the regioselectivity in propranolol glucuronidation, the regioselectivity in dobutamine glucuronidation, and the glucuronidation rate of α- and β-estradiol differ greatly between UGT1A9 and UGT1A10. To identify the residue responsible for the activity differences, we divided the N-terminal half of the two UGTs into five comparable segments by inserting four unique restriction sites at identical positions in both genes and constructing chimeras in which segments of UGT1A9 were individually replaced by the corresponding segments from UGT1A10. Activity analyses of the resulting mutants, 910A [1A10(1–83)/1A9(84–285)], 910B [1A9(1–83)/1A10(84–147)/1A9(148–285)], 910C [1A9(1–147)/1A10(148–181)/1A9(182–285)], 910D [1A9(1–181)/1A10(182–235)/1A9(236–285)], and 910E [1A9(1–235)/1A10(236–285)] indicated that more than one residue is responsible for the differences between UGT1A9 and UGT1A10. We next prepared four double chimeras, in which two of the above UGT1A9 segments were replaced simultaneously by the corresponding UGT1A10 segments. However, none of the double chimeras glucuronidated either estradiol, propranolol, or dobutamine at rates that resembled those of UGT1A10. On the other hand, studying the kinetics of 1-naphthol glucuronidation yielded more focused results, indicating that residues within segment B (84–147) contribute directly to the K m value for this substrate. Further mutagenesis and activity assays suggested that Phe117 of UGT1A9 participates in 1-naphthol binding. In addition, it appears that residues within segment C of the N-terminal domain, mainly at positions 152 and 169, contribute to the higher glucuronidation rates of UGT1A10.

  人UDP-葡萄糖醛酸基转移酶(UGT) 1A9和1A10的氨基酸序列有93%相同，但它们的活性和底物选择性存在很大差异。例如，普萘洛尔葡萄糖醛酸化的区域选择性、多巴酚丁胺葡萄糖醛酸化的区域选择性以及α-和β-雌二醇的葡萄糖醛酸化率在UGT1A9和UGT1A10之间存在很大差异。为了鉴定造成活性差异的残基，我们通过在两个基因的相同位置插入四个独特的限制性位点并构建嵌合体，将两个 UGT 的 N 端一半分成五个可比较的片段，其中 UGT1A9 的片段分别被替换UGT1A10 的相应片段。所得突变体的活性分析，910A [1A10(1–83)/1A9(84–285)]、910B [1A9(1–83)/1A10(84–147)/1A9(148–285)]、910C [ 1A9(1–147)/1A10(148–181)/1A9(182–285)]、910D [1A9(1–181)/1A10(182–235)/1A9(236–285)]和 910E [1A9 (1–235)/1A10(236–285)]表明不止一个残基造成UGT1A9和UGT1A10之间的差异。接下来，我们制备了四个双嵌合体，其中上述 UGT1A9 片段中的两个同时被相应的 UGT1A10 片段替换。然而，没有一个双嵌合体以与 UGT1A10 类似的速率对雌二醇、普萘洛尔或多巴酚丁胺进行葡萄糖醛酸化。另一方面，研究 1-萘酚葡萄糖醛酸化的动力学产生了更集中的结果，表明片段 B (84-147) 内的残基直接影响该底物的 K m 值。进一步的诱变和活性测定表明 UGT1A9 的 Phe117 参与 1-萘酚结合。此外，N 端结构域 C 段内的残基（主要位于位置 152 和 169）似乎有助于提高 UGT1A10 的葡萄糖醛酸化率。