3-oxo-23,24-bisnorchol-4-en-22-oyl-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: 3-oxo-23,24-bisnorchol-4-en-22-oyl-CoA(4-)
• 英文别名: [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-2-[[[[(3R)-4-[[3-[2-[(2S)-2-[(8S,9S,10R,13S,14S,17R)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]propanoyl]sulfanylethylamino]-3-oxopropyl]amino]-3-hydroxy-2,2-dimethyl-4-oxobutoxy]-oxidophosphoryl]oxy-oxidophosphoryl]oxymethyl]-4-hydroxyoxolan-3-yl] phosphate
• 化学式: C43H62N7O18P3S-4
• 分子量: 1090.0
• InChiKey: CJJBDUCNUMWUJX-ZKTJOKCMSA-J

计算性质

• 辛醇/水分配系数(LogP)：
  -0.9
• 重原子数：
  72
• 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：
  417
• 氢给体数：
  5
• 氢受体数：
  23

反应信息

• 作为反应物：
  描述：

  3-oxo-23,24-bisnorchol-4-en-22-oyl-CoA(4-) 、 (2R)-N-[3-(2-acetylsulfanylethylimino)-3-oxidopropyl]-4-[[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonatooxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]oxy-2-hydroxy-3,3-dimethylbutanimidate 生成 3,22-dioxochol-4-en-24-oyl-CoA(4-) 、 coenzyme A
  参考文献：
  名称：

  FadA5 a Thiolase from Mycobacterium tuberculosis : A Steroid-Binding Pocket Reveals the Potential for Drug Development against Tuberculosis

  摘要：

  With the exception of HIV, tuberculosis (TB) is the leading cause of mortality among infectious diseases. The urgent need to develop new antitubercular drugs is apparent due to the increasing number of drug-resistant Mycobacterium tuberculosis (Mtb) strains. Proteins involved in cholesterol import and metabolism have recently been discovered as potent targets against TB. FadA5, a thiolase from Mtb, is catalyzing the last step of the beta-oxidation reaction of the cholesterol side-chain degradation under release of critical metabolites and was shown to be of importance during the chronic stage of TB infections. To gain structural and mechanistic insight on FadA5, we characterized the enzyme in different stages of the cleavage reaction and with a steroid bound to the binding pocket. Structural comparisons to human thiolases revealed that it should be possible to target FadA5 specifically, and the steroid-bound structure provides a solid basis for the development of inhibitors against FadA5.

  DOI：

  10.1016/j.str.2014.10.010
• 作为产物：
  描述：

  3-Oxo-23,24-bisnorchol-4-en-22-oate 、 adenosine 5'-triphosphate 、 coenzyme A 生成 3-oxo-23,24-bisnorchol-4-en-22-oyl-CoA(4-) 、 adenosine 5'-monophosphate 、 pyrophosphoric acid
  参考文献：
  名称：

  3-酮类固醇 9α-羟化酶 (KshAB) 的活性表明胆固醇侧链和环降解在结核分枝杆菌中同时发生。

  摘要：

  结核分枝杆菌 (Mtb) 是一种重要的全球病原体，含有胆固醇分解代谢途径。尽管胆固醇分解代谢在 Mtb 中的确切作用仍不清楚，但该途径中的 Rieske 单加氧酶，3-酮类固醇 9α-羟化酶 (KshAB)，已被确定为毒力因子。为了研究 KshAB 的生理底物，使用红球菌酰基辅酶 A 合成酶生产两种胆固醇衍生物的辅酶 A 硫酯：3-oxo-23,24-bisnorchol-4-en-22-oic acid（形成 4-BNC -CoA) 和 3-oxo-23,24-bisnorchola-1,4-dien-22-oic 酸（形成 1,4-BNC-CoA）。KshAB 对 CoA 硫酯底物的表观特异性常数 (k(cat)/K(m)) 是相应的 17-酮化合物先前提出的生理底物的 20-30 倍。在存在 1,4-BNC-CoA 的情况下，明显的 K(m)(O(2)) 为 90 + /-10 mu

  DOI：

  10.1074/jbc.m111.289975

文献信息

• Actinobacterial Acyl Coenzyme A Synthetases Involved in Steroid Side-Chain Catabolism
  作者：Israël Casabon、Kendra Swain、Adam M. Crowe、Lindsay D. Eltis、William W. Mohn

  DOI：10.1128/jb.01012-13

  日期：2014.2

  activate the C8 side chain of cholesterol. Both CasGRHA1 and FadD17Mtb are steroid-24-oyl-CoA synthetases. CasG and its orthologs activate the C5 side chain of cholate, while FadD17 and its orthologs appear to activate the C5 side chain of one or more cholesterol metabolites. CasIRHA1 is a steroid-22-oyl-CoA synthetase, representing orthologs that activate metabolites with a C3 side chain, which accumulate

  细菌类固醇分解代谢是全球碳循环的重要组成部分，在药物合成中有应用。这种分解代谢的途径涉及多种酰基辅酶 A (CoA) 合成酶，它们激活链烷酸酯取代基进行 β-氧化。这些合成酶的功能知之甚少。我们对来自约氏红球菌 RHA1 的胆酸盐分解代谢途径和结核分枝杆菌的胆固醇分解代谢途径的四种不同的酰基辅酶 A 合成酶进行了酶促表征。对预测参与类固醇代谢的 70 种酰基辅酶 A 合成酶进行的系统发育分析表明，所表征的合成酶各自代表在类固醇侧链降解中具有独特功能的直系同源类。合成酶对链烷酸酯取代基的长度具有特异性。FadD19 来自 M。结核分枝杆菌 H37Rv (FadD19Mtb) 转化 3-oxo-4-cholesten-26-oate (kcat/Km = 0.33 × 10(5) ± 0.03 × 10(5) M(-1) s(-1)) 并代表直向同源物激活胆固醇的 C8 侧链。CasGRHA1
• <i>Mycobacterium tuberculosis</i> Utilizes a Unique Heterotetrameric Structure for Dehydrogenation of the Cholesterol Side Chain
  作者：Suzanne T. Thomas、Nicole S. Sampson

  DOI：10.1021/bi4002979

  日期：2013.4.30

  pathogenesis that the metabolism of cholesterol by Mycobacterium tuberculosis plays. Elucidating the pathway by which cholesterol is catabolized is necessary to understand the molecular mechanism by which this pathway contributes to infection. On the basis of early metabolite identification studies in multiple actinomycetes, it has been proposed that cholesterol side chain metabolism requires one or more

  复合证据支持结核分枝杆菌胆固醇代谢在发病机制中的重要作用。阐明胆固醇分解代谢的途径对于了解该途径导致感染的分子机制是必要的。在多种放线菌的早期代谢物鉴定研究的基础上，有人提出胆固醇侧链代谢需要一种或多种酰基辅酶 A 脱氢酶 (ACAD)。在结核分枝杆菌基因组中有 35 个被注释为编码 ACAD 的基因。在这里，我们描述了由Rv3544c和Rv3543c编码的异聚 ACAD ，以前称为fadE28和fadE29， 分别。我们现在将基因Rv3544c和Rv3543c 分别称为chsE1和chsE2，以确认它们在胆固醇侧链脱氢中的验证活性。分析超速离心和液相色谱-紫外实验确定 ChsE1-ChsE2 形成 α 2 β 2异四聚体，ACAD 的新架构。我们的生物信息学分析和诱变研究表明异四聚体 ChsE1-ChsE2 只有两个活性位点。ChsE2 中的 E241 是 ChsE1-ChsE2 催化脱
• 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.
• Unraveling Cholesterol Catabolism in <i>Mycobacterium tuberculosis</i>: ChsE4-ChsE5 α₂β₂ Acyl-CoA Dehydrogenase Initiates β-Oxidation of 3-Oxo-cholest-4-en-26-oyl CoA
  作者：Meng Yang、Rui Lu、Kip E. Guja、Matthew F. Wipperman、Johnna R. St. Clair、Amber C. Bonds、Miguel Garcia-Diaz、Nicole S. Sampson

  DOI：10.1021/id500033m

  日期：2015.2.13

  The metabolism of host cholesterol by Mycobacterium tuberculosis (Mtb) is an important factor for both its virulence and pathogenesis, although how and why cholesterol metabolism is required is not fully understood. Mtb uses a unique set of catabolic enzymes that are homologous to those required for classical beta-oxidation of fatty acids but are specific for steroid-derived substrates. Here, we identify and assign the substrate specificities of two of these enzymes, ChsE4-ChsES (Rv3504-Rv3505) and ChsE3 (Rv3573c), that carry out cholesterol side chain oxidation in Mtb. Steady-state assays demonstrate that ChsE4-ChsES preferentially catalyzes the oxidation of 3-oxo-cholest-4-en-26-oyl CoA in the first cycle of cholesterol side chain beta-oxidation that ultimately yields propionyl-CoA, whereas ChsE3 specifically catalyzes the oxidation of 3-oxo-chol-4-en-24-oyl CoA in the second cycle of beta-oxidation that generates acetyl-CoA. However, ChsE4-ChsES can catalyze the oxidation of 3-oxo-chol-4-en-24-oyl CoA as well as 3-oxo-4-pregnene-20-carboxyl-CoA. The functional redundancy of ChsE4-ChsES explains the in vivo phenotype of the igr knockout strain of Mycobacterium tuberculosis; the loss of ChsEl-ChsE2 can be compensated for by ChsE4-ChsES during the chronic phase of infection. The X-ray crystallographic structure of ChsE4-ChsES was determined to a resolution of 2.0 angstrom and represents the first high-resolution structure of a heterotetrameric acyl-CoA dehydrogenase (ACAD). Unlike typical homotetrameric ACADs that bind four flavin adenine dinucleotide (FAD) cofactors, ChsE4-ChsES binds one FAD at each dimer interface, resulting in only two substrate-binding sites rather than the classical four active sites. A comparison of the ChsE4-ChsES substrate-binding site to those of known mammalian ACADs reveals an enlarged binding cavity that accommodates steroid substrates and highlights novel prospects for designing inhibitors against the committed beta-oxidation step in the first cycle of cholesterol side chain degradation by Mtb.