(4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异香豆素
• 英文名称: (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate
• 英文别名: (E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate
• 化学式: C17H19O6-
• 分子量: 319.3
• InChiKey: HPNSFSBZBAHARI-RUDMXATFSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  95.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate 、 UDP-alpha-D-glucuronate(3-) 生成 mycophenolic acid O-acyl-glucuronide(1-) 、 UDP
  参考文献：
  名称：

  鉴定涉及霉酚酸II期代谢的UDP-葡萄糖醛酸转移酶同工型。

  摘要：

  麦考酚酸（MPA）是免疫抑制剂麦考酚酸酯的活性代谢产物，主要通过葡萄糖醛酸化作用进行代谢。参与该途径的UDP-葡萄糖醛酸转移酶（UGT）的性质仍在争论中。本研究旨在明确鉴定参与生产MPA-苯基-葡糖醛酸苷（MPAG）和MPA-酰基葡糖醛酸苷（AcMPAG）的UGT亚型。开发了一种液相色谱-串联质谱法，可以鉴定和测定麦考酚酸的代谢产物。在霉酚酸酯治疗下，在将麦考酚酸与人肝（HLM），肾脏（HKM）或肠微粒体（HIM）孵育后，在肾移植患者的尿液和血浆样品中对代谢产物进行了表征。使用诱导的大鼠肝微粒体，异源表达的UGT（超体）以及对HLM，HKM和HIM的化学选择性抑制，研究了参与MPAG或AcMPAG生产的UGT亚型。三种微粒体制剂产生了MPAG，AcMPAG和两种霉酚酸酯糖苷。在测试的10种UGT异构体中，UGT 1A9最有效用于MPAG合成，K（m）为0.16 mM，接近于HLM的观测值（0

  DOI：

  10.1124/dmd.104.001651
• 作为产物：
  描述：

  水 、 mycophenolic acid O-acyl-glucuronide(1-) 生成 D-glucuronate 、 氢(+1)阳离子 、 (4E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoate
  参考文献：
  名称：

  Human α/β Hydrolase Domain Containing 10 (ABHD10) Is Responsible Enzyme for Deglucuronidation of Mycophenolic Acid Acyl-glucuronide in Liver

  摘要：

  Mycophenolic acid (MPA), the active metabolite of the immunosuppressant mycophenolate mofetil (MMF), is primarily metabolized by glucuronidation to a phenolic glucuronide (MPAG) and an acyl glucuronide (AcMPAG). It is known that AcMPAG, which may be an immunotoxic metabolite, is deglucuronidated in human liver. However, it has been reported that recombinant beta-glucuronidase does not catalyze this reaction. AcMPAG deglucuronidation activity was detected in both human liver cytosol (HLC) and microsomes (HLM). In this study, the enzyme responsible for AcMPAG deglucuronidation was identified by purification from HLC with column chromatographic purification steps. The purified enzyme was identified as alpha/beta hydrolase domain containing 10 (ABHD10) by amino acid sequence analysis. Recombinant ABHD10 expressed in Sf9 cells efficiently deglucuronidated AcMPAG with a K-m value of 100.7 +/- 10.2 mu M, which was similar to those in HLM, HLC, and human liver homogenates (HLH). Immunoblot analysis revealed ABHD10 protein expression in both HLC and HLM. The AcMPAG deglucuronidation by recombinant ABHD10, HLC, and HLH were potently inhibited by AgNO3, CdCl2, CuCl2, PMSF, bis-p-nitrophenylphosphate, and DTNB. The CLint value of AcMPAG formation from MPA, which was catalyzed by human UGT2B7, in HLH was increased by 1.8-fold in the presence of PMSF. Thus, human ABHD10 would affect the formation of AcMPAG, the immunotoxic metabolite.

  DOI：

  10.1074/jbc.m111.271288

文献信息

• Compartmentalized biosynthesis of mycophenolic acid
  作者：Wei Zhang、Lei Du、Zepeng Qu、Xingwang Zhang、Fengwei Li、Zhong Li、Feifei Qi、Xiao Wang、Yuanyuan Jiang、Ping Men、Jingran Sun、Shaona Cao、Ce Geng、Fengxia Qi、Xiaobo Wan、Changning Liu、Shengying Li

  DOI：10.1073/pnas.1821932116

  日期：2019.7.2

  Mycophenolic acid (MPA) from filamentous fungi is the first natural product antibiotic to be isolated and crystallized, and a first-line immunosuppressive drug for organ transplantations and autoimmune diseases. However, some key biosynthetic mechanisms of such an old and important molecule have remained unclear. Here, we elucidate the MPA biosynthetic pathway that features both compartmentalized enzymatic

  来自丝状真菌的霉酚酸（MPA）是第一种被分离和结晶的天然产物抗生素，也是用于器官移植和自身免疫性疾病的一线免疫抑制药物。然而，这种古老而重要的分子的一些关键生物合成机制仍不清楚。在这里，我们阐明了MPA生物合成途径，该途径既具有区分开的酶促步骤，又具有基于目标基因失活，异源表达宿主的供料实验，酶功能表征和动力学分析以及蛋白质微观观察的生物合成和β-氧化分解代谢机制之间的独特合作。亚细胞定位。除了将加氧酶MpaB'鉴定为负责法呢基侧链氧化裂解的长期寻找的关键酶外，我们揭示了MPA生物合成酶分区的有趣模式，包括胞质聚酮化合物合酶MpaC'和O-甲基转移酶MpaG'，高尔基体相关异戊二烯基转移酶MpaA'，内质网结合加氧酶MpaB'和P450水解酶融合酶MpaDE'和过氧化物酶体酰基辅酶A（CoA）水解酶MpaH'。这些分隔的酶与过氧化物酶体β-氧化机制共同优雅地介导了整个途径。除了表征MPA生