(4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate

• 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: (4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate
• 化学式: C24H39O3-
• 分子量: 375.6
• InChiKey: SMEROWZSTRWXGI-HVATVPOCSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  60.4
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate 、 UDP-alpha-D-glucuronate(3-) 生成 1-O-(3alpha-hydroxy-24-oxo-5beta-cholan-24-yl)-beta-D-glucopyranuronate 、 UDP
  参考文献：
  名称：

  The Human UDP-Glucuronosyltransferase UGT2A1 and UGT2A2 Enzymes Are Highly Active in Bile Acid Glucuronidation

  摘要：

  胆汁酸（BA）是脂质、葡萄糖和胆固醇稳态的重要调节剂，但在胆汁淤积的肝脏中会产生细胞毒性。由UDP-葡萄糖醛酸转移酶（UGT）催化的葡萄糖醛酸化是BA解毒过程中一个重要的药理过程。本研究对2A亚家族中研究较少的人UGTs的BA结合活性进行了表征：UGT2A1、2A2和2A3。在杆状病毒感染的昆虫细胞中表达的重组UGT2A对六种主要胆汁酸的葡萄糖醛酸化进行了检测：鹅去氧胆酸（CDCA）、胆酸（CA）、石胆酸（LCA）、脱氧胆酸（DCA）、牛胆酸（HCA）和猪去氧胆酸（HDCA）。UGT2A3对所有测试的BA底物表现出可检测但非常低的活性。UGT2A1在形成LCA-3和LCA-24G、CDCA-24、DCA-24、HCA-24和HDCA-24G方面非常高效，而UGT2A2是形成CA-24G和CDCA-24G的最活跃的酶，并且能够产生HDCA-6G、HDCA-24G、LCA-24G和HCA-24G。UGT2A1的K m

  DOI：

  10.1124/dmd.113.052613
• 作为产物：
  描述：

  (2R)-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonatooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-N-[3-[2-[(4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoyl]sulfanylethylimino]-3-oxidopropyl]-3,3-dimethylbutanimidate 、 3alpha,7beta-Dihydroxy-5beta-cholan-24-oate 生成 (4R)-4-[(3R,5R,8R,9S,10S,13R,14S,17R)-3-hydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate 、 ursodeoxycholoyl-CoA(4-)
  参考文献：
  名称：

  Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7α-dehydroxylating intestinal bacterium

  摘要：

  The human bile acid pool composition is composed of both primary bile acids (cholic acid and chenodeoxycholic acid) and secondary bile acids (deoxycholic acid and lithocholic acid). Secondary bile acids are formed by the 7 alpha-dehydroxylation of primary bile acids carried out by intestinal anaerobic bacteria. We have previously described a multistep biochemical pathway in Clostridium scindens that is responsible for bile acid 7 alpha-dehydroxylation. We have identified a large (12 kb) bile acid inducible (bai) operon in this bacterium that encodes eight genes involved in bile acid 7 alpha-dehydroxylation. However, the function of the baiF gene product in this operon has not been elucidated. In the current study, we cloned and expressed the baiF gene in E. coli and discovered it has bile acid CoA transferase activity. In addition, we discovered a second bai operon encoding three genes. The baiK gene in this operon was expressed in E. coli and found to encode a second bile acid CoA transferase. Both bile acid CoA transferases were determined to be members of the type III family by amino acid sequence comparisons. Both bile acid CoA transferases had broad substrate specificity, except the baiK gene product, which failed to use lithocholyl-CoA as a CoA donor. Primary bile acids are ligated to CoA via an ATP-dependent mechanism during the initial steps of 7 alpha-dehydroxylation. The bile acid CoA transferases conserve the thioester bond energy, saving the cell ATP molecules during bile acid 7 alpha-dehydroxylation. ATP-dependent CoA ligation is likely quickly supplanted by ATP-independent CoA transfer.-Ridlon, J.M., and P. B. Hylemon. Identification and characterization of two bile acid coenzyme A transferases from Clostridium scindens, a bile acid 7 alpha-dehydroxylating intestinal bacterium. J. Lipid Res. 2012. 53: 66-76.

  DOI：

  10.1194/jlr.m020313

文献信息

• The Enzymes, Regulation, and Genetics of Bile Acid Synthesis
  作者：David W. Russell

  DOI：10.1146/annurev.biochem.72.121801.161712

  日期：2003.6

  ▪ Abstract  The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals. Synthesis provides a direct means of converting cholesterol, which is both hydrophobic and insoluble, into a water-soluble and readily excreted molecule, the bile acid. The biosynthetic steps that accomplish this transformation also confer detergent properties to the bile acid, which are exploited by the body to facilitate the secretion of cholesterol from the liver. This role in the elimination of cholesterol is counterbalanced by the ability of bile acids to solubilize dietary cholesterol and essential nutrients and to promote their delivery to the liver. The synthesis of a full complement of bile acids requires 17 enzymes. The expression of selected enzymes in the pathway is tightly regulated by nuclear hormone receptors and other transcription factors, which ensure a constant supply of bile acids in an ever changing metabolic environment. Inherited mutations that impair bile acid synthesis cause a spectrum of human disease; this ranges from liver failure in early childhood to progressive neuropathy in adults.

  ▪ 摘要：在哺乳动物体内，胆汁酸的合成和排泄构成了胆固醇分解的主要途径。合成提供了一种将既疏水又不溶于水的胆固醇直接转化为水溶性且容易排泄的分子——胆汁酸的直接方法。完成这种转化的生物合成步骤也赋予了胆汁酸的清洁剂特性，这些特性被机体利用来促进从肝脏排泄胆固醇。这种在胆固醇排泄中的作用被胆汁酸溶解膳食胆固醇和必需营养素以及促进它们传递到肝脏的能力所平衡。合成完整的胆汁酸需要17种酶。途径中的选择性酶的表达受到核激素受体和其他转录因子的严格调控，这些因子确保在不断变化的代谢环境中始终有足够的胆汁酸供应。遗传突变会影响胆汁酸的合成，导致一系列人类疾病，从儿童早期的肝衰竭到成年人的渐进性神经病变。
• A biosynthetic pathway for a prominent class of microbiota-derived bile acids
  作者：A Sloan Devlin、Michael A Fischbach

  DOI：10.1038/nchembio.1864

  日期：2015.9

  A bioinformatic and phylogenetic search identifies five enzymes involved in the conversion of DCA to isoDCA in the bacterial bile acid biosynthetic pathway. An investigation of the biological roles of bile acids defines a mutualism between the producer R. gnavus and the nonproducer Bacteroides. The gut bile acid pool is millimolar in concentration, varies widely in composition among individuals and is linked to metabolic disease and cancer. Although these molecules are derived almost exclusively from the microbiota, remarkably little is known about which bacterial species and genes are responsible for their biosynthesis. Here we report a biosynthetic pathway for the second most abundant class in the gut, 3β-hydroxy(iso)-bile acids, whose levels exceed 300 μM in some humans and are absent in others. We show, for the first time, that iso–bile acids are produced by Ruminococcus gnavus, a far more abundant commensal than previously known producers, and that the iso–bile acid pathway detoxifies deoxycholic acid and thus favors the growth of the keystone genus Bacteroides. By revealing the biosynthetic genes for an abundant class of bile acids, our work sets the stage for predicting and rationally altering the composition of the bile acid pool.

  通过生物信息学和系统发生学搜索，确定了在细菌胆汁酸生物合成途径中参与将二氯苯甲醚（DCA）转化为异二氯苯甲醚（isoDCA）的五种酶。对胆汁酸生物学作用的研究确定了生产者 R. gnavus 和非生产者 Bacteroides 之间的互作关系。 肠道胆汁酸池的浓度为毫摩尔，个体之间的组成差异很大，并且与代谢疾病和癌症有关。虽然这些分子几乎全部来自微生物群，但人们对负责其生物合成的细菌种类和基因知之甚少。在这里，我们报告了肠道中含量第二高的3δ²-羟基（异）-胆酸的生物合成途径，在一些人体内，3δ²-羟基（异）-胆酸的含量超过300 ¼M，而在另一些人体内则没有。我们首次发现gnavus反刍球菌能产生异胆酸，它是一种比以前已知的生产者更丰富的共生菌，异胆酸途径能解毒脱氧胆酸，从而有利于关键菌属Bacteroides的生长。通过揭示一类丰富胆汁酸的生物合成基因，我们的工作为预测和合理改变胆汁酸库的组成奠定了基础。
• The lithocholic acid 6<i>β</i>-hydroxylase cytochrome <i>P</i>-450, CYP 3A10, is an active catalyst of steroid-hormone 6<i>β</i>-hydroxylation
  作者：T K H Chang、J Teixeira、G Gil、D J Waxman

  DOI：10.1042/bj2910429

  日期：1993.4.15

  mRNA. Since it has not been established whether the specificities of bile acid hydroxylase P450s, such as CYP 3A10, are restricted to their anionic bile acid substrates, we investigated the role of CYP 3A10 in the metabolism of a series of neutral steroid hormones using cDNA directed-expression in COS cells. The steroid hormones examined, testosterone, androstenedione and progesterone, were each metabolized

  CYP 3A10是一种仓鼠肝细胞色素P-450（P450），其编码石胆酸6β-羟化酶，该酶在胆汁静止性胆汁酸胆汁酸胆汁酸酯的解毒中起重要作用。Western印迹分析表明，CYP 3A10蛋白在仓鼠肝微粒体中表达是男性特异性的，这一发现与早期对CYP 3A10 mRNA的分析一致。由于尚未确定胆汁酸羟化酶P450的特异性（例如CYP 3A10）是否仅限于其阴离子胆汁酸底物，因此我们使用cDNA指导研究了CYP 3A10在一系列中性甾体激素代谢中的作用。在COS细胞中的表达。所检测的甾体激素，睾丸激素，雄烯二酮和孕酮均通过表达的CYP 3A10代谢，在所有这三种情况下，具有6个β-羟基化的化合物均具有主要活性。当从与NADPH：P450还原酶cDNA共转染的COS细胞中制备微粒体时，CYP 3A10依赖性类固醇的羟基化作用显着增加。在这种情况下，表达的P450积极催化睾丸激素的6β-羟基化（每毫克COS细胞微粒体蛋白每分钟288
• Structural and Chemical Profiling of the Human Cytosolic Sulfotransferases
  作者：Abdellah Allali-Hassani、Patricia W Pan、Ludmila Dombrovski、Rafael Najmanovich、Wolfram Tempel、Aiping Dong、Peter Loppnau、Fernando Martin、Janet Thonton、Aled M Edwards、Alexey Bochkarev、Alexander N Plotnikov、Masoud Vedadi、Cheryl H Arrowsmith

  DOI：10.1371/journal.pbio.0050097

  日期：——

  The human cytosolic sulfotransfases (hSULTs) comprise a family of 12 phase II enzymes involved in the metabolism of drugs and hormones, the bioactivation of carcinogens, and the detoxification of xenobiotics. Knowledge of the structural and mechanistic basis of substrate specificity and activity is crucial for understanding steroid and hormone metabolism, drug sensitivity, pharmacogenomics, and response to environmental toxins. We have determined the crystal structures of five hSULTs for which structural information was lacking, and screened nine of the 12 hSULTs for binding and activity toward a panel of potential substrates and inhibitors, revealing unique “chemical fingerprints” for each protein. The family-wide analysis of the screening and structural data provides a comprehensive, high-level view of the determinants of substrate binding, the mechanisms of inhibition by substrates and environmental toxins, and the functions of the orphan family members SULT1C3 and SULT4A1. Evidence is provided for structural “priming” of the enzyme active site by cofactor binding, which influences the spectrum of small molecules that can bind to each enzyme. The data help explain substrate promiscuity in this family and, at the same time, reveal new similarities between hSULT family members that were previously unrecognized by sequence or structure comparison alone.

  人体细胞质磺基转移酶（hSULTs）由12种II期酶组成，参与药物和激素代谢、致癌物质的生物活化以及异生物的解毒。了解底物特异性和活性的结构和机理基础对于理解类固醇和激素代谢、药物敏感性、药物基因组学以及对环境毒素的反应至关重要。我们确定了五种hSULTs的晶体结构，这些结构信息此前一直缺失，并对12种hSULTs中的9种进行了筛选，以确定其对一组潜在底物和抑制剂的结合和活性，揭示了每种蛋白质独特的“化学指纹”。通过筛选和结构数据的家族分析，我们全面、深入地了解了底物结合的决定因素、底物和环境毒素的抑制机理，以及孤儿家族成员SULT1C3和SULT4A1的功能。实验证据表明，辅因子结合对酶活性位点的结构“启动”有影响，从而影响可与每种酶结合的小分子谱。这些数据有助于解释该家族中底物的杂合性，同时揭示了hSULT家族成员之间新的相似性，而此前仅通过序列或结构比较无法识别这些相似性。
• Hylemon P.B.; Melone P.D.; Franklund C.V., J Lipid Res, 1991, 0022-2275, 89-96
  作者：Hylemon P.B.、Melone P.D.、Franklund C.V.、Lund E.、Bjorkhem I.

  DOI：——

  日期：——