3-oxochol-4-en-24-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-oxochol-4-en-24-oyl-CoA(4-)
• 英文别名: [(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-2-[[[[(3R)-4-[[3-[2-[(4R)-4-[(8S,9S,10R,13R,14S,17R)-10,13-dimethyl-3-oxo-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl]pentanoyl]sulfanylethylamino]-3-oxopropyl]amino]-3-hydroxy-2,2-dimethyl-4-oxobutoxy]-oxidophosphoryl]oxy-oxidophosphoryl]oxymethyl]-4-hydroxyoxolan-3-yl] phosphate
• 化学式: C45H66N7O18P3S-4
• 分子量: 1118.0
• InChiKey: VVQGMUPGBRZRFY-ABDXREKHSA-J

计算性质

• 辛醇/水分配系数(LogP)：
  -0.4
• 重原子数：
  74
• 可旋转键数：
  23
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.76
• 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-oxochol-4-en-24-oyl-CoA(4-) 、 A 生成 3-oxochola-4,22-dien-24-oyl-CoA(4-) 、 AH₂
  参考文献：
  名称：

  Shrinking the FadE Proteome of Mycobacterium tuberculosis: Insights into Cholesterol Metabolism through Identification of an α ₂ β ₂ Heterotetrameric Acyl Coenzyme A Dehydrogenase Family

  摘要：

  摘要 病原体 结核分枝杆菌 代谢胆固醇等类固醇的能力以及这些化合物在该病原体的毒力和致病机理中所起的作用日益明显。在这里，我们通过实验和生物信息学分析证明了存在一个结构上不同的酰基辅酶 A（酰基-CoA）脱氢酶（ACAD）亚家族，这些酶是α-CoA（酰基-CoA）脱氢酶和α-CoA（酰基-CoA）脱氢酶。 2 β 2 杂四聚体，有两个活性位点。这些酶由两个相邻的 ACAD ( fadE ）基因编码，受胆固醇调控。FadE26-FadE27 催化 3β-hydroxy-chol-5-en-24-oyl-CoA 的脱氢，3β-hydroxy-chol-5-en-24-oyl-CoA 是 5 碳侧链胆固醇降解中间体的类似物。编码α 2 β 2 杂四聚体 ACAD 结构的基因存在于结核杆菌的多个区域。 结核杆菌 这些基因的子集受四种不同的转录抑制因子或激活因子调控：KstR1（又称 KstR）、KstR2、Mce3R 和 SigE。其他放线菌中也有同源的 ACAD 基因对。 放线菌 以及 蛋白细菌 .它们的结构和基因组位置表明，α 2 β 2 它们的结构和基因组位置表明，α 2 β 2 异构四聚体结构基团是为了能够催化类固醇或多环-CoA 底物的脱氢而进化的，它们在胆固醇代谢的四个子途径中发挥作用。

  DOI：

  10.1128/jb.00502-13
• 作为产物：
  描述：

  3-dehydrolithocholoyl-CoA(4-) 、 nicotinamide adenine dinucleotide 生成 3-oxochol-4-en-24-oyl-CoA(4-) 、 氢(+1)阳离子 、 NADH
  参考文献：
  名称：

  人肠细菌梭状梭状芽胞杆菌ATCC 35704鉴定了编码参与胆汁酸代谢的黄素蛋白的基因。

  摘要：

  背景技术几种梭状芽胞杆菌将多级胆汁酸7α脱羟基途径将宿主一级胆汁酸转化为有毒的二级胆汁酸对于肠道微生物组结构以及宿主生理和疾病具有重要意义。虽然已经鉴定出7α-去羟基化途径的氧化臂中的基因，但该途径的还原臂中的基因仍然不清楚。方法我们确定了候选黄酮蛋白编码基因，该基因预计可代谢类固醇。将该基因克隆并在大肠杆菌中过表达，并进行亲和纯化。通过薄层色谱分离反应底物和产物，并通过液相色谱质谱-离子捕获飞行时间（LCMS-IT-TOF）进行鉴定。进行了氨基酸序列的系统发育分析。结果我们报告鉴定了一种编码黄素蛋白的基因（EDS08212.1），该基因参与了梭状芽孢杆菌ATCC 35704和相关物种的次级胆汁酸代谢。纯化的rEDS08212.1催化了3-脱氢-脱氧胆酸的生成，UPLC-IT-TOF-MS分析表明该产物损失4amu。我们的系统发育在其他胆汁酸7α-脱羟基细菌中鉴定出了该基因。结论这些数据表

  DOI：

  10.1016/j.bbalip.2017.12.001

文献信息

• Characterization of Novel Acyl Coenzyme A Dehydrogenases Involved in Bacterial Steroid Degradation
  作者：Amanda Ruprecht、Jaymie Maddox、Alexander J. Stirling、Nicole Visaggio、Stephen Y. K. Seah

  DOI：10.1128/jb.02420-14

  日期：2015.4.15

  The acyl coenzyme A (acyl-CoA) dehydrogenases (ACADs) FadE34 and CasC, encoded by the cholesterol and cholate gene clusters of Mycobacterium tuberculosis and Rhodococcus jostii RHA1, respectively, were successfully purified. Both enzymes differ from previously characterized ACADs in that they contain two fused acyl-CoA dehydrogenase domains in a single polypeptide. Site-specific mutagenesis showed that only the C-terminal ACAD domain contains the catalytic glutamate base required for enzyme activity, while the N-terminal ACAD domain contains an arginine required for ionic interactions with the pyrophosphate of the flavin adenine dinucleotide (FAD) cofactor. Therefore, the two ACAD domains must associate to form a single active site. FadE34 and CasC were not active toward the 3-carbon side chain steroid metabolite 3-oxo-23,24-bisnorchol-4-en-22-oyl-CoA (4BNC-CoA) but were active toward steroid CoA esters containing 5-carbon side chains. CasC has similar specificity constants for cholyl-CoA, deoxycholyl-CoA, and 3β-hydroxy-5-cholen-24-oyl-CoA, while FadE34 has a preference for the last compound, which has a ring structure similar to that of cholesterol metabolites. Knockout of the casC gene in R. jostii RHA1 resulted in a reduced growth on cholate as a sole carbon source and accumulation of a 5-carbon side chain cholate metabolite. FadE34 and CasC represent unique members of ACADs with primary structures and substrate specificities that are distinct from those of previously characterized ACADs.

  IMPORTANCE We report here the identification and characterization of acyl-CoA dehydrogenases (ACADs) involved in the metabolism of 5-carbon side chains of cholesterol and cholate. The two homologous enzymes FadE34 and CasC, from M. tuberculosis and Rhodococcus jostii RHA1, respectively, contain two ACAD domains per polypeptide, and we show that these two domains interact to form a single active site. FadE34 and CasC are therefore representatives of a new class of ACADs with unique primary and quaternary structures. The bacterial steroid degradation pathway is important for the removal of steroid waste in the environment and for survival of the pathogen M. tuberculosis within host macrophages. FadE34 is a potential target for development of new antibiotics against tuberculosis.

  摘要 由结核分枝杆菌胆固醇和胆酸基因簇编码的酰基辅酶 A（酰基-CoA）脱氢酶（ACADs）FadE34 和 CasC 结核分枝杆菌 和 结核分枝杆菌 RHA1 编码的 FadE34 和 CasC 已成功纯化。这两种酶与之前表征的 ACAD 不同，它们在单个多肽中含有两个融合的酰基-CoA 脱氢酶结构域。位点特异性诱变显示，只有 C 端 ACAD 结构域含有酶活性所需的催化谷氨酸碱基，而 N 端 ACAD 结构域含有与黄素腺嘌呤二核苷酸（FAD）辅助因子的焦磷酸离子相互作用所需的精氨酸。因此，两个 ACAD 结构域必须结合在一起才能形成一个活性位点。FadE34 和 CasC 对 3 碳侧链类固醇代谢物 3-氧代-23,24-双去甲胆-4-烯-22-酰基-CoA（4BNC-CoA）没有活性，但对含有 5 碳侧链的类固醇 CoA 酯有活性。CasC 对胆酰-CoA、脱氧胆酰-CoA 和 3β-羟基-5-胆烯-24-酰基-CoA 具有相似的特异性常数，而 FadE34 则偏好最后一种化合物，其环状结构与胆固醇代谢物相似。敲除 casC 基因的 R. jostii RHA1 中的 casC 基因敲除会导致以胆酸盐为唯一碳源的生长减弱，并导致 5 碳侧链胆酸盐代谢物的积累。FadE34 和 CasC 是 ACADs 的独特成员，它们的主要结构和底物特异性与之前表征的 ACADs 不同。 重要意义 我们在此报告了参与胆固醇和胆酸盐 5 碳侧链代谢的酰基-CoA 脱氢酶（ACADs）的鉴定和特征描述。来自结核杆菌的两种同源酶 FadE34 和 CasC 结核杆菌 和 Rhodococcus jostii 我们的研究表明，这两个结构域相互作用形成了一个单一的活性位点。因此，FadE34 和 CasC 是具有独特一级和四级结构的新型 ACAD 的代表。细菌类固醇降解途径对清除环境中的类固醇废物和病原体的生存非常重要 结核杆菌 在宿主巨噬细胞内生存的重要途径。FadE34 是开发抗结核新抗生素的潜在靶点。
• 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.
• Identification of a gene encoding a flavoprotein involved in bile acid metabolism by the human gut bacterium Clostridium scindens ATCC 35704
  作者：Spencer C. Harris、Saravanan Devendran、João M.P. Alves、Sean M. Mythen、Phillip B. Hylemon、Jason M. Ridlon

  DOI：10.1016/j.bbalip.2017.12.001

  日期：2018.3

  secondary bile acid metabolism by Clostridium scindens ATCC 35704 and related species. Purified rEDS08212.1 catalyzed formation of a product from 3-dehydro-deoxycholic acid that UPLC-IT-TOF-MS analysis suggests loses 4amu. Our phylogeny identified this gene in other bile acid 7α-dehydroxylating bacteria. CONCLUSIONS These data suggest formation of a product, 3-dehydro-4,6-deoxycholic acid, a recognized

  背景技术几种梭状芽胞杆菌将多级胆汁酸7α脱羟基途径将宿主一级胆汁酸转化为有毒的二级胆汁酸对于肠道微生物组结构以及宿主生理和疾病具有重要意义。虽然已经鉴定出7α-去羟基化途径的氧化臂中的基因，但该途径的还原臂中的基因仍然不清楚。方法我们确定了候选黄酮蛋白编码基因，该基因预计可代谢类固醇。将该基因克隆并在大肠杆菌中过表达，并进行亲和纯化。通过薄层色谱分离反应底物和产物，并通过液相色谱质谱-离子捕获飞行时间（LCMS-IT-TOF）进行鉴定。进行了氨基酸序列的系统发育分析。结果我们报告鉴定了一种编码黄素蛋白的基因（EDS08212.1），该基因参与了梭状芽孢杆菌ATCC 35704和相关物种的次级胆汁酸代谢。纯化的rEDS08212.1催化了3-脱氢-脱氧胆酸的生成，UPLC-IT-TOF-MS分析表明该产物损失4amu。我们的系统发育在其他胆汁酸7α-脱羟基细菌中鉴定出了该基因。结论这些数据表
• Shrinking the FadE Proteome of Mycobacterium tuberculosis: Insights into Cholesterol Metabolism through Identification of an α ₂ β ₂ Heterotetrameric Acyl Coenzyme A Dehydrogenase Family
  作者：Matthew F. Wipperman、Meng Yang、Suzanne T. Thomas、Nicole S. Sampson

  DOI：10.1128/jb.00502-13

  日期：2013.10

  The ability of the pathogen Mycobacterium tuberculosis to metabolize steroids like cholesterol and the roles that these compounds play in the virulence and pathogenesis of this organism are increasingly evident. Here, we demonstrate through experiments and bioinformatic analysis the existence of an architecturally distinct subfamily of acyl coenzyme A (acyl-CoA) dehydrogenase (ACAD) enzymes that are α ₂ β ₂ heterotetramers with two active sites. These enzymes are encoded by two adjacent ACAD ( fadE ) genes that are regulated by cholesterol. FadE26-FadE27 catalyzes the dehydrogenation of 3β-hydroxy-chol-5-en-24-oyl-CoA, an analog of the 5-carbon side chain cholesterol degradation intermediate. Genes encoding the α ₂ β ₂ heterotetrameric ACAD structures are present in multiple regions of the M. tuberculosis genome, and subsets of these genes are regulated by four different transcriptional repressors or activators: KstR1 (also known as KstR), KstR2, Mce3R, and SigE. Homologous ACAD gene pairs are found in other Actinobacteria , as well as Proteobacteria . Their structures and genomic locations suggest that the α ₂ β ₂ heterotetrameric structural motif has evolved to enable catalysis of dehydrogenation of steroid- or polycyclic-CoA substrates and that they function in four subpathways of cholesterol metabolism.

  摘要 病原体 结核分枝杆菌 代谢胆固醇等类固醇的能力以及这些化合物在该病原体的毒力和致病机理中所起的作用日益明显。在这里，我们通过实验和生物信息学分析证明了存在一个结构上不同的酰基辅酶 A（酰基-CoA）脱氢酶（ACAD）亚家族，这些酶是α-CoA（酰基-CoA）脱氢酶和α-CoA（酰基-CoA）脱氢酶。 2 β 2 杂四聚体，有两个活性位点。这些酶由两个相邻的 ACAD ( fadE ）基因编码，受胆固醇调控。FadE26-FadE27 催化 3β-hydroxy-chol-5-en-24-oyl-CoA 的脱氢，3β-hydroxy-chol-5-en-24-oyl-CoA 是 5 碳侧链胆固醇降解中间体的类似物。编码α 2 β 2 杂四聚体 ACAD 结构的基因存在于结核杆菌的多个区域。 结核杆菌 这些基因的子集受四种不同的转录抑制因子或激活因子调控：KstR1（又称 KstR）、KstR2、Mce3R 和 SigE。其他放线菌中也有同源的 ACAD 基因对。 放线菌 以及 蛋白细菌 .它们的结构和基因组位置表明，α 2 β 2 它们的结构和基因组位置表明，α 2 β 2 异构四聚体结构基团是为了能够催化类固醇或多环-CoA 底物的脱氢而进化的，它们在胆固醇代谢的四个子途径中发挥作用。