(3R,5S,7R,8R,9S,10S,13R,14S,17R)-10,13-二甲基-17-[(2R)-6-甲基庚烷-2-基]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3,7-二醇 | 3862-26-8

• 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
• 中文名称: (3R,5S,7R,8R,9S,10S,13R,14S,17R)-10,13-二甲基-17-[(2R)-6-甲基庚烷-2-基]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3,7-二醇
• 英文名称: 5β-cholestane-3α,7α-diol
• 英文别名: 5β-Cholestan-3α,7α-diol；5beta-Cholestane-3alpha,7alpha-diol；(3R,5S,7R,8R,9S,10S,13R,14S,17R)-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthrene-3,7-diol
• CAS: 3862-26-8
• 化学式: C₂₇H₄₈O₂
• 分子量: 404.677
• InChiKey: APYVEUGLZHAHDJ-TVRYRFOISA-N

物化性质

• 熔点：
  84-86 °C
• 沸点：
  503.4±33.0 °C(Predicted)
• 密度：
  1.003±0.06 g/cm3(Predicted)
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  40.5
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R,5S,7R,8R,9S,10S,13R,14S,17R)-10,13-二甲基-17-[(2R)-6-甲基庚烷-2-基]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3,7-二醇 在 盐酸 、 乙醇 作用下， 生成 7α-acetoxy-5β-cholestan-3α-ol
  参考文献：
  名称：

  Yamasaki et al., Yonago Acta Medica, 1959, vol. 4, p. 37

  摘要：

  DOI：
• 作为产物：
  描述：

  异戊酸 、 鹅去氧胆酸 、 sodium methylate 在 甲醇 作用下， 生成 (3R,5S,7R,8R,9S,10S,13R,14S,17R)-10,13-二甲基-17-[(2R)-6-甲基庚烷-2-基]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-十四氢-1H-环戊二烯并[a]菲-3,7-二醇
  参考文献：
  名称：

  Bergstroem; Krabisch, Acta Chemica Scandinavica (1947), 1957, vol. 11, p. 1067

  摘要：

  DOI：

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。
• Purification and characterization of a vitamin D3 25-hydroxylase from pig liver microsomes
  作者：E Axén、T Bergman、K Wikvall

  DOI：10.1042/bj2870725

  日期：1992.11.1

  A cytochrome P-450 which catalyses 25-hydroxylation of vitamin D3 has been purified to apparent homogeneity from pig liver microsomes. The specific content of cytochrome P-450 was 12 nmol.mg of protein-1, and the preparation showed a single band with an apparent M(r) of 50,500 upon SDS/PAGE. A monoclonal antibody raised against the vitamin D3 25-hydroxylase reacted strongly with the purified 25-hydroxylating cytochrome P-450 from pig kidney microsomes [Bergman & Postlind (1990) Biochem. J. 270, 345-350]. The liver enzyme showed structural and functional properties very similar to those of the kidney enzyme. The two enzymes differed with respect to only one of the first 16 N-terminal amino acids. The vitamin D3 25-hydroxylase in pig liver microsomes exhibited a turnover and an apparent Km for 25-hydroxylation of vitamin D3 which were of the same order of magnitude as those of a well-characterized male-specific 25-hydroxylating cytochrome P-450 in rat liver microsomes. The two enzymes differed structurally. The pig liver enzyme was, in contrast to the rat liver enzyme, not sex-specific, and did not catalyse 16 alpha-hydroxylation of testosterone. These properties of the 25-hydroxylase in rat liver microsomes have led to questions on the role of microsomal 25-hydroxylation of vitamin D3. It is concluded that studies on microsomal 25-hydroxylation with the rat may be misleading. The results of the present study show that the pig appears to be a representative species for evaluation of vitamin D3 hydroxylases in other mammals, including man.

  一种细胞色素P-450酶催化维生素D3的25-羟化已经从猪肝微粒体中纯化到表观同质性。细胞色素P-450的特异性含量为12 nmol.mg蛋白质^-1，该制备在SDS/PAGE上显示一个明显的M(r)为50,500的单一条带。一种针对维生素D3 25-羟化酶制备的单克隆抗体与从猪肾微粒体中纯化的25-羟化细胞色素P-450强烈反应[Bergman & Postlind（1990）Biochem. J. 270, 345-350]。肝酶显示出与肾酶非常相似的结构和功能特性。这两种酶仅在前16个N末端氨基酸中的一个方面不同。猪肝微粒体中的维生素D3 25-羟化酶表现出与大鼠肝微粒体中一个经过充分表征的男性特异性25-羟化细胞色素P-450相同数量级的25-羟化维生素D3的周转和表观Km。这两种酶在结构上有所不同。与大鼠肝酶相比，猪肝酶不是性别特异性的，也不催化睾酮的16α-羟化。大鼠肝微粒体中25-羟化维生素D3的这些特性引发了对微粒体25-羟化在维生素D3代谢中作用的质疑。结论是，在大鼠上进行的微粒体25-羟化研究可能是误导性的。本研究的结果表明，猪似乎是其他哺乳动物，包括人类，评估维生素D3羟化酶的代表性物种。
• Characterization of pig kidney microsomal cytochrome <i>P</i>-450 catalysing 25-hydroxylation of vitamin D3 and C27 steroids
  作者：T Bergman、H Postlind

  DOI：10.1042/bj2700345

  日期：1990.9.1

  The cytochrome P-450 enzyme which catalyses 25-hydroxylation of vitamin D3 (cytochrome P-450(25] from pig kidney microsomes [Postlind & Wikvall (1988) Biochem. J. 253, 549-552] has been further purified. The specific content of cytochrome P-450 was 15.0 nmol.mg of protein-1, and the protein showed a single spot with an apparent isoelectric point of 7.4 and an Mr of 50,500 upon two-dimensional isoelectric-focusing/SDS/PAGE. The 25-hydroxylase activity towards vitamin D3 was 124 pmol.min-1.nmol of cytochrome P-450-1 and towards 1 alpha-hydroxyvitamin D3 it was 1375 pmol.min-1.nmol-1. The preparation also catalysed the 25-hydroxylation of 5 beta-cholestane-3 alpha,7 alpha-diol at a rate of 1000 pmol.min-1.nmol of cytochrome P-450-1 and omega-1 hydroxylation of lauric acid at a rate of 200 pmol.min-1.nmol of cytochrome P-450-1. A monoclonal antibody raised against the 25-hydroxylating cytochrome P-450, designated mAb 25E5, was prepared. After coupling to Sepharose, the antibody was able to bind to cytochrome P-450(25) from kidney as well as from pig liver microsomes, and to immunoprecipitate the activity for 25-hydroxylation of vitamin D3 and 5 beta-cholestane-3 alpha,7 alpha-diol when assayed in a reconstituted system. The hydroxylase activity towards lauric acid was not inhibited by the antibody. By SDS/PAGE and immunoblotting with mAb 25E5, cytochrome P-450(25) was detected in both pig kidney and pig liver microsomes. These results indicate a similar or the same species of cytochrome P-450 in pig kidney and liver microsomes catalysing 25-hydroxylation of vitamin D3 and C27 steroids. The N-terminal amino acid sequence of the purified cytochrome P-450(25) from pig kidney microsomes differed from those of hitherto isolated mammalian cytochromes P-450.

  细胞色素P-450酶催化维生素D3的25-羟化（来自猪肾微粒体的细胞色素P-450（25）[Postlind＆Wikvall（1988）Biochem.J.253,549-552]已被进一步纯化。细胞色素P-450的特异含量为15.0 nmol.mg-1蛋白质，并且该蛋白质在二维等电聚焦/SDS/PAGE上显示出一个明显的等电点为7.4，分子量为50,500的单一斑点。对于维生素D3的25-羟化酶活性为124 pmol.min-1.nmol细胞色素P-450-1，对于1α-羟基维生素D3的酶活性为1375 pmol.min-1.nmol-1。该制剂还催化了5β-胆甾烷-3α,7α-二醇的25-羟化，速率为1000 pmol.min-1.nmol细胞色素P-450-1，以及月桂酸的ω-1羟化，速率为200 pmol.min-1.nmol细胞色素P-450-1。制备了一种针对25-羟化细胞色素P-450的单克隆抗体，称为mAb 25E5。将抗体偶联到Sepharose后，抗体能够结合到肾脏以及猪肝微粒体的细胞色素P-450（25），并在重构系统中免疫沉淀维生素D3和5β-胆甾烷-3α,7α-二醇的25-羟化活性。抗体未抑制对月桂酸的羟化活性。通过SDS/PAGE和mAb 25E5的免疫印迹，检测到细胞色素P-450（25）存在于猪肾和猪肝微粒体中。这些结果表明，在猪肾和肝微粒体中存在相似或相同的细胞色素P-450物种，可催化维生素D3和C27类固醇的25-羟化。从猪肾微粒体中纯化的细胞色素P-450（25）的N末端氨基酸序列与迄今为止分离的哺乳动物细胞色素P-450的氨基酸序列不同。
• Gene structure of pig sterol 12α-hydroxylase (CYP8B1) and expression in fetal liver: comparison with expression of taurochenodeoxycholic acid 6α-hydroxylase (CYP4A21)
  作者：Kerstin Lundell、Kjell Wikvall

  DOI：10.1016/j.bbalip.2003.09.002

  日期：2003.11

  Cholic acid is the major trihydroxy bile acid formed in most mammals. The domestic pig (Sus scrofa) is an exception. The bile of adult pig is devoid of cholic acid whereas hyocholic acid is found in amounts equal to that of cholic acid in humans. The pathway leading to formation of hyocholic acid is believed to be species-specific and to have evolved in the pig to compensate for a nonexistent or deficient cholic acid biosynthesis. However, a high level of cholic acid has recently been found in the bile of fetal pig. Here we describe that a gene encoding the key enzyme in cholic acid biosynthesis, the sterol 12alpha-hydroxylase (CYP8B1), is in fact present in the pig genome. The deduced amino acid sequence shows 81% identity to the human and rabbit orthologues. CYP8B1 mRNA is expressed at significant levels in fetal pig liver. Both CYP8B1 and the key enzyme in hyocholic acid formation, taurochenodeoxycholic acid 6alpha-hydroxylase (CYP4A21), were found to be expressed in pig liver in a developmental-dependent but opposite fashion. (C) 2003 Elsevier B.V. All rights reserved.
• α1-Fetoprotein Transcription Factor Is Required for the Expression of Sterol 12α-Hydroxylase, the Specific Enzyme for Cholic Acid Synthesis
  作者：Antonio del Castillo-Olivares、Gregorio Gil

  DOI：10.1074/jbc.m000996200

  日期：2000.6

  Cholesterol conversion to bile acids occurs via the "classic" (neutral) or the "alternative" (acidic) bile acid biosynthesis pathways. Sterol 12 alpha-hydroxylase/CYP8b1 is the specific enzyme required for cholic acid synthesis. The levels of this enzyme determine the ratio of cholic acid to chenodeoxycholic acid and thus the hydrophobicity of the circulating bile acid pool. Expression of the 12 alpha-hydroxylase gene is tightly down-regulated by hydrophobic bile acids. In this study, we report the characterization of two DNA elements that are required for both the 12 alpha-hydroxylase promoter activity and bile acid-mediated regulation. Mutation of these elements suppresses 12 alpha-hydroxylase promoter activity. Mutations of any other part of the promoter do not alter substantially the promoter activity or alter regulation by bile acids relative to the wild type promoter. These two DNA elements bind alpha(1)-fetoprotein transcription factor (FTF), a member of the nuclear receptor family. We also show that overexpression of FTF in a non-liver cell line activates the sterol 12 alpha-hydroxylase promoter. These studies demonstrate the crucial role of FTF for the expression and regulation of a critical gene in the bile acid biosynthetic pathways.