propofol-glucuronide

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: propofol-glucuronide
• 英文别名: propofol O-glucuronide；(2S,3S,4S,5R)-6-[2,6-di(propan-2-yl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• 化学式: C₁₈H₂₆O₇
• 分子量: 354.4
• InChiKey: JZSJIASBMOIIKI-ODEDACCXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  116
• 氢给体数：
  4
• 氢受体数：
  7

ADMET

代谢

(2S,3S,4S,5R)-6-[2,6-二(丙-2-基)苯氧基]-3,4,5-三羟基氧杂环己烷-2-羧酸是丙泊酚的人类已知代谢物。

(2S,3S,4S,5R)-6-[2,6-Di(propan-2-yl)phenoxy]-3,4,5-trihydroxyoxane-2-carboxylic acid is a known human metabolite of propofol.

来源:NORMAN Suspect List Exchange

反应信息

• 作为产物：
  描述：

  丙泊酚 、 UDP-glucuronic acid 在 human UDP-glucuronosyltransferase 1A₉ 、 magnesium chloride 、 alamethicin 、 糖质酸-1,4-内酯 作用下， 生成 propofol-glucuronide
  参考文献：
  名称：

  Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches

  摘要：

  通过实验使用145种酚类化合物，并通过3D-QSAR方法分析，确定了人UGT1A9的催化选择性。UGT1A9是一种重要的膜结合酶，催化外源性物质的葡糖醛酸化反应。通过动力学分析确定了UGT1A9的催化效率。使用CoMFA和CoMSIA技术分析了定量结构活性关系。通过将葡糖醛酸化位点及其相邻的芳香环重叠，实现了底物结构的最大立体重叠。对于具有多个活性葡糖醛酸化位点的底物，每个位点被视为单独的底物。3D-QSAR分析产生了统计上可靠的模型，具有良好的预测能力（CoMFA：q2=0.548，r2=0.949，r pred 2=0.775；CoMSIA：q2=0.579，r2=0.876，r pred 2=0.700）。通过轮廓系数图阐明了底物中负责选择性差异的结构特征。将轮廓系数图叠加在UGT1A9的同源模型的催化口袋中，能够高度自信地识别UGT1A9的催化口袋。CoMFA/CoMSIA模型可以预测底物的选择性和UGT1A9的体外清除率。我们的发现还提供了理解UGT1A9功能和底物选择性的可能分子基础。

  DOI：

  10.1007/s11095-012-0666-z

文献信息

• Accurate Prediction of Glucuronidation of Structurally Diverse Phenolics by Human UGT1A9 Using Combined Experimental and In Silico Approaches
  作者：Baojian Wu、Xiaoqiang Wang、Shuxing Zhang、Ming Hu

  DOI：10.1007/s11095-012-0666-z

  日期：2012.6

  Catalytic selectivity of human UGT1A9, an important membrane-bound enzyme catalyzing glucuronidation of xenobiotics, was determined experimentally using 145 phenolics and analyzed by 3D-QSAR methods. Catalytic efficiency of UGT1A9 was determined by kinetic profiling. Quantitative structure activity relationships were analyzed using CoMFA and CoMSIA techniques. Molecular alignment of substrate structures was made by superimposing the glucuronidation site and its adjacent aromatic ring to achieve maximal steric overlap. For a substrate with multiple active glucuronidation sites, each site was considered a separate substrate. 3D-QSAR analyses produced statistically reliable models with good predictive power (CoMFA: q2 = 0.548, r2 = 0.949, r pred 2  = 0.775; CoMSIA: q2 = 0.579, r2 = 0.876, r pred 2  = 0.700). Contour coefficient maps were applied to elucidate structural features among substrates that are responsible for selectivity differences. Contour coefficient maps were overlaid in the catalytic pocket of a homology model of UGT1A9, enabling identification of the UGT1A9 catalytic pocket with a high degree of confidence. CoMFA/CoMSIA models can predict substrate selectivity and in vitro clearance of UGT1A9. Our findings also provide a possible molecular basis for understanding UGT1A9 functions and substrate selectivity.

  通过实验使用145种酚类化合物，并通过3D-QSAR方法分析，确定了人UGT1A9的催化选择性。UGT1A9是一种重要的膜结合酶，催化外源性物质的葡糖醛酸化反应。通过动力学分析确定了UGT1A9的催化效率。使用CoMFA和CoMSIA技术分析了定量结构活性关系。通过将葡糖醛酸化位点及其相邻的芳香环重叠，实现了底物结构的最大立体重叠。对于具有多个活性葡糖醛酸化位点的底物，每个位点被视为单独的底物。3D-QSAR分析产生了统计上可靠的模型，具有良好的预测能力（CoMFA：q2=0.548，r2=0.949，r pred 2=0.775；CoMSIA：q2=0.579，r2=0.876，r pred 2=0.700）。通过轮廓系数图阐明了底物中负责选择性差异的结构特征。将轮廓系数图叠加在UGT1A9的同源模型的催化口袋中，能够高度自信地识别UGT1A9的催化口袋。CoMFA/CoMSIA模型可以预测底物的选择性和UGT1A9的体外清除率。我们的发现还提供了理解UGT1A9功能和底物选择性的可能分子基础。
• Identification of Human UGT2B7 as the Major Isoform Involved in the<i>O</i>-Glucuronidation of Chloramphenicol
  作者：Mei Chen、Barbara LeDuc、Stephen Kerr、David Howe、David A. Williams

  DOI：10.1124/dmd.109.029900

  日期：2010.3

  Chloramphenicol (CP), a broad spectrum antibiotic, is eliminated in humans by glucuronidation. The primary UGT enzymes responsible for CP O -glucuronidation remain unidentified. We have previously identified the 3- O -CP (major) and 1- O -CP (minor) glucuronides by β-glucuronidase hydrolysis, liquid chromatography-tandem mass spectrometry, and 1D/2D H NMR. Reaction phenotyping for the glucuronidation of CP with 12 expressed human liver UGT isoforms has identified UGT2B7 as having the highest activity for 3- O - and 1- O -CP glucuronidation with minor contributions from UGT1A6 and UGT1A9. The kinetics of CP 3- O -glucuronidation by pooled human liver microsomes (HLMs) exhibited biphasic Michaelis-Menten kinetics with the apparent high-affinity K m1 and low-affinity K m2 values of 46.0 and 1027 μM, whereas expressed UGT2B7 exhibited Michaelis-Menten kinetics with the apparent K m value of 109.1 μM. The formation of 1- O -CP glucuronide by pooled HLM and expressed UGT2B7 exhibited substrate inhibition kinetics with apparent K m values of 408.2 and 115.0 μM, respectively. Azidothymidine (AZT) and hyodeoxycholic acid (substrates of UGT2B7) inhibited 3- O - and 1- O -CP glucuronidation in pooled HLMs. In 10 donor HLM preparations, both CP 3- O - and CP 1- O -glucuronidation showed a significant correlation with AZT glucuronidation (UGT2B7) ( r s = 0.85 and r s = 0.83, respectively) at 30 μM CP, whereas no significant correlation was observed between CP 3- O -glucuronidation and serotonin glucuronidation (UGT1A6) or propofol glucuronidation (UGT1A9) at this CP concentration. These results suggest that UGT2B7 is the primary human hepatic UDP-glucuronosyltransferase isoform catalyzing 3- O - and 1- O -CP glucuronidation with minor contributions from UGT1A6 and UGT1A9.

  氯霉素(CP)是一种广谱抗生素,在人体内通过葡糖醛酸化途径被清除。负责CP O-葡糖醛酸化的主要UGT酶仍然未被识别。我们之前通过β-葡糖醛酸苷酶水解、液相色谱-串联质谱和1D/2D 1H NMR鉴定了3-O-CP(主要)和1-O-CP(次要)葡糖醛酸苷。对12种表达的人肝UGT同工酶的CP葡糖醛酸化反应表型进行鉴定,发现UGT2B7对3-O-和1-O-CP葡糖醛酸化活性最高,UGT1A6和UGT1A9有较小贡献。人肝微粒体(HLMs)中CP 3-O-葡糖醛酸化动力学呈双相米氏动力学,高亲和力Km1值和低亲和力Km2值分别为46.0μM和1027μM,而表达的UGT2B7呈现单相米氏动力学,Km值为109.1μM。人肝微粒体和表达的UGT2B7的1-O-CP葡糖醛酸苷形成呈现底物抑制动力学,Km值分别为408.2μM和115.0μM。叠氮胸苷(AZT)和猪胆酸(UGT2B7的底物)抑制了人肝微粒体中的3-O-和1-O-CP葡糖醛酸化。在10个供体的人肝微粒体中,30μM CP时,CP 3-O-和CP 1-O-葡糖醛酸化与AZT葡糖醛酸化(UGT2B7)显著相关(rs=0.85和rs=0.83),而CP 3-O-葡糖醛酸化与5-羟色胺葡糖醛酸化(UGT1A6)或丙泊酚葡糖醛酸化(UGT1A9)在此CP浓度下无显著相关性。这些结果表明,UGT2B7是催化3-O-和1-O-CP葡糖醛酸化的主要人肝UDP-葡糖醛酸基转移酶同工酶,UGT1A6和UGT1A9有较小贡献。
• Yang, Jing; Zhang, Beibei; Qin, Zi Fei, International Journal of Clinical and Experimental Medicine, 2019, vol. 12, # 5, p. 4960 - 4971
  作者：Yang, Jing、Zhang, Beibei、Qin, Zi Fei、Zhang, Xiao Jian

  DOI：——

  日期：——
• Validated assay for the evaluation of multiple glucuronidation activities in human liver microsomes via liquid chromatography-tandem mass spectrometry
  作者：Rong Shi、Yuanyuan Yang、Jie Zhong、Tianming Wang、Yueming Ma

  DOI：10.1039/c4ra10687c

  日期：——

  A faster and more accurate LC-MS/MS method was established for the activity determination of multiple UGT isoforms in HLMs.

  在人类肝微粒体中，建立了一种更快、更准确的LC-MS/MS方法，用于确定多种UGT同工酶的活性。