17-hydroxy-3-oxopregn-4-en-20-carboxy-CoA(4-)

• 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: 17-hydroxy-3-oxopregn-4-en-20-carboxy-CoA(4-)
• 英文别名: [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-2-[[[[(3R)-3-hydroxy-4-[[3-[2-[(2S)-2-[(8R,9S,10R,13S,14S)-17-hydroxy-10,13-dimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1H-cyclopenta[a]phenanthren-17-yl]propanoyl]sulfanylethylamino]-3-oxopropyl]amino]-2,2-dimethyl-4-oxobutoxy]-oxidophosphoryl]oxy-oxidophosphoryl]oxymethyl]oxolan-3-yl] phosphate
• 化学式: C43H62N7O19P3S-4
• 分子量: 1106.0
• InChiKey: UDFHRLPTSACVPG-NSEVOGSXSA-J

计算性质

• 辛醇/水分配系数(LogP)：
  -2
• 重原子数：
  73
• 可旋转键数：
  21
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  438
• 氢给体数：
  6
• 氢受体数：
  24

反应信息

• 作为反应物：
  描述：

  17-hydroxy-3-oxopregn-4-en-20-carboxy-CoA(4-) 生成 雄烯二酮 、 propanoyl-CoA
  参考文献：
  名称：

  Pathway Profiling in Mycobacterium tuberculosis

  摘要：

  Mycobacterium tuberculosis, the bacterium that causes tuberculosis, imports and metabolizes host cholesterol during infection. This ability is important in the chronic phase of infection. Here we investigate the role of the intracellular growth operon (igr), which has previously been identified as having a cholesterol-sensitive phenotype in vitro and which is important for intracellular growth of the mycobacteria. We have employed isotopically labeled low density lipoproteins containing either [1,7,15,22,26-C-14] cholesterol or [1,7,15,22,26-C-13] cholesterol and high resolution LC/MS as tools to profile the cholesterol-derived metabolome of an igr operon-disrupted mutant (Delta igr) of M. tuberculosis. A partially metabolized cholesterol species accumulated in the Delta igr knock-out strain that was absent in the complemented and parental wild-type strains. Structural elucidation by multidimensional H-1 and C-13 NMR spectroscopy revealed the accumulated metabolite to be methyl 1 beta-(2'-propanoate)-3a alpha-H-4 alpha-(3'-propanoic acid)-7a beta-methylhexahydro5-indanone. Heterologously expressed and purified FadE28-FadE29, an acyl-CoA dehydrogenase encoded by the igr operon, catalyzes the dehydrogenation of 2'-propanoyl-CoA ester side chains in substrates with structures analogous to the characterized metabolite. Based on the structure of the isolated metabolite, enzyme activity, and bioinformatic annotations, we assign the primary function of the igr operon to be degradation of the 2'-propanoate side chain. Therefore, the igr operon is necessary to completely metabolize the side chain of cholesterol metabolites.

  DOI：

  10.1074/jbc.m111.313643
• 作为产物：
  描述：

  20-methyl-3-oxopregna-4,17-dien-21-oyl-CoA(4-) 、 水 生成 17-hydroxy-3-oxopregn-4-en-20-carboxy-CoA(4-)
  参考文献：
  名称：

  A Distinct MaoC-like Enoyl-CoA Hydratase Architecture Mediates Cholesterol Catabolism in Mycobacterium tuberculosis

  摘要：

  The Mycobacterium tuberculosis (Mtb) igr operon plays an essential role in Mtb cholesterol metabolism, which is critical for pathogenesis during the latent stage of Mtb infection. Here we report the first structure of a heterotetrameric MaoC-like enoyl-CoA hydratase, ChsH1-ChsH2, which is encoded by two adjacent genes from the igr operon. We demonstrate that ChsH1-ChsH2 catalyzes the hydration of a steroid enoyl-CoA, 3-oxo-4,17-pregnadiene-20-carboxyl-CoA, in the modified beta-oxidation pathway for cholesterol side chain degradation. The ligand-bound and apoenzyme structures of ChsH1-ChsH2(N) reveal an unusual, modified hot-dog fold with a severely truncated central alpha-helix that creates an expanded binding site to accommodate the bulkier steroid ring system. The structures show quaternary structure shifts that accommodate the four rings of the steroid substrate and offer an explanation for why the unusual heterotetrameric assembly is utilized for hydration of this steroid. The unique alpha beta heterodimer architecture utilized by ChsH1-ChsH2 to bind its distinctive substrate highlights an opportunity for the development of new antimycobacterial drugs that target a pathway specific to Mtb.

  DOI：

  10.1021/cb500232h

文献信息

• Pathway Profiling in Mycobacterium tuberculosis
  作者：Suzanne T. Thomas、Brian C. VanderVen、David R. Sherman、David G. Russell、Nicole S. Sampson

  DOI：10.1074/jbc.m111.313643

  日期：2011.12

  Mycobacterium tuberculosis, the bacterium that causes tuberculosis, imports and metabolizes host cholesterol during infection. This ability is important in the chronic phase of infection. Here we investigate the role of the intracellular growth operon (igr), which has previously been identified as having a cholesterol-sensitive phenotype in vitro and which is important for intracellular growth of the mycobacteria. We have employed isotopically labeled low density lipoproteins containing either [1,7,15,22,26-C-14] cholesterol or [1,7,15,22,26-C-13] cholesterol and high resolution LC/MS as tools to profile the cholesterol-derived metabolome of an igr operon-disrupted mutant (Delta igr) of M. tuberculosis. A partially metabolized cholesterol species accumulated in the Delta igr knock-out strain that was absent in the complemented and parental wild-type strains. Structural elucidation by multidimensional H-1 and C-13 NMR spectroscopy revealed the accumulated metabolite to be methyl 1 beta-(2'-propanoate)-3a alpha-H-4 alpha-(3'-propanoic acid)-7a beta-methylhexahydro5-indanone. Heterologously expressed and purified FadE28-FadE29, an acyl-CoA dehydrogenase encoded by the igr operon, catalyzes the dehydrogenation of 2'-propanoyl-CoA ester side chains in substrates with structures analogous to the characterized metabolite. Based on the structure of the isolated metabolite, enzyme activity, and bioinformatic annotations, we assign the primary function of the igr operon to be degradation of the 2'-propanoate side chain. Therefore, the igr operon is necessary to completely metabolize the side chain of cholesterol metabolites.
• A Distinct MaoC-like Enoyl-CoA Hydratase Architecture Mediates Cholesterol Catabolism in <i>Mycobacterium tuberculosis</i>
  作者：Meng Yang、Kip E. Guja、Suzanne T. Thomas、Miguel Garcia-Diaz、Nicole S. Sampson

  DOI：10.1021/cb500232h

  日期：2014.11.21

  The Mycobacterium tuberculosis (Mtb) igr operon plays an essential role in Mtb cholesterol metabolism, which is critical for pathogenesis during the latent stage of Mtb infection. Here we report the first structure of a heterotetrameric MaoC-like enoyl-CoA hydratase, ChsH1-ChsH2, which is encoded by two adjacent genes from the igr operon. We demonstrate that ChsH1-ChsH2 catalyzes the hydration of a steroid enoyl-CoA, 3-oxo-4,17-pregnadiene-20-carboxyl-CoA, in the modified beta-oxidation pathway for cholesterol side chain degradation. The ligand-bound and apoenzyme structures of ChsH1-ChsH2(N) reveal an unusual, modified hot-dog fold with a severely truncated central alpha-helix that creates an expanded binding site to accommodate the bulkier steroid ring system. The structures show quaternary structure shifts that accommodate the four rings of the steroid substrate and offer an explanation for why the unusual heterotetrameric assembly is utilized for hydration of this steroid. The unique alpha beta heterodimer architecture utilized by ChsH1-ChsH2 to bind its distinctive substrate highlights an opportunity for the development of new antimycobacterial drugs that target a pathway specific to Mtb.