(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

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (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
• 化学式: C45H70N7O18P3S-4
• 分子量: 1122.1
• InChiKey: MHVCMYOMCROIEL-FYYKUXHTSA-J

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  74
• 可旋转键数：
  23
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  421
• 氢给体数：
  6
• 氢受体数：
  23

反应信息

• 作为反应物：
  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
• 作为产物：
  描述：

  adenosine 5'-triphosphate 、 coenzyme A 、 (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 生成 adenosine 5'-monophosphate 、 pyrophosphoric acid 、 (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
  参考文献：
  名称：

  Participation of Two Members of the Very Long-chain Acyl-CoA Synthetase Family in Bile Acid Synthesis and Recycling

  摘要：

  Bile acids are synthesized de novo in the liver from cholesterol and conjugated to glycine or taurine via a complex series of reactions involving multiple organelles. Bile acids secreted into the small intestine are efficiently reabsorbed and reutilized. Activation by thio-esterification to CoA is required at two points in bile acid metabolism. First, 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid, the 27-carbon precursor of cholic acid, must be activated to its CoA derivative before side chain cleavage via peroxisomal beta-oxidation. Second, reutilization of cholate and other C-24 bile acids requires reactivation prior to re-conjugation. We reported previously that homolog 2 of very long-chain acyl-CoA synthetase (VLCS) can activate cholate (Steinberg, S. J., Mihalik, S. J., Kim, D. G., Cuebas, D. A., and Watkins, P. A. (2000) J. Biol. Chem. 275, 15605-15608). We now show that this enzyme also activates chenodeoxycholate, the secondary bile acids deoxycholate and lithocholate, and 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoic acid. In contrast, VLCS activated 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoate, but did not utilize any of the C-24 bile acids as substrates. We hypothesize that the primary function of homolog 2 is in the reactivation and recycling of C-24 bile acids, whereas VLCS participates in the de novo synthesis pathway. Results of in situ hybridization, topographic orientation, and inhibition studies are consistent with the proposed roles of these enzymes in bile acid metabolism.

  DOI：

  10.1074/jbc.m203295200

文献信息

• Structural and functional characterization of BaiA, an enzyme involved in secondary bile acid synthesis in human gut microbe
  作者：Shiva Bhowmik、David H. Jones、Hsien‐Po Chiu、In‐Hee Park、Hsiu‐Ju Chiu、Herbert L. Axelrod、Carol L. Farr、Henry J. Tien、Sanjay Agarwalla、Scott A. Lesley

  DOI：10.1002/prot.24353

  日期：2014.2

  catalyzing its synthesis. Herein, we report apo- and cofactor bound crystal structures of BaiA2, a short chain dehydrogenase/reductase from Clostridium scindens VPI 12708 that represent the first protein structure of this pathway. The structures elucidated the basis of cofactor specificity and mechanism of proton relay. A conformational restriction involving Glu42 located in the cofactor binding site seems

  尽管次级胆汁酸对人类健康和疾病有显着影响，但可用于催化其合成的关键肠道微生物酶的结构和生化信息有限。在此，我们报告了 BaiA2 的脱氢酶和辅因子结合的晶体结构，这是一种来自 Clostridium scindens VPI 12708 的短链脱氢酶/还原酶，代表了该途径的第一个蛋白质结构。这些结构阐明了辅因子特异性的基础和质子中继的机制。涉及位于辅因子结合位点的 Glu42 的构象限制似乎对确定辅因子特异性至关重要。Glu42 有限的柔韧性导致 NADP(H) 的 2'-磷酸基团迫在眉睫的空间位阻和静电位阻。与晶体结构一致，用 BaiA2 和 BaiA1（具有 92% 序列同一性的密切同源物）进行的稳态动力学表征显示 NADP(+) 的特异性常数 (kcat /KM ) 至少比 NAD(+) 低一个数量级。与野生型相比，用 Ala 替代 Glu42 可将 NADP(+) 的特异性提高 10