lipid A 1-(2-aminoethyl diphosphate)(3-)

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: lipid A 1-(2-aminoethyl diphosphate)(3-)
• 英文别名: [(2R,3S,4R,5R,6R)-6-[[(2R,3S,4R,5R,6R)-6-[[2-azaniumylethoxy(oxido)phosphoryl]oxy-oxidophosphoryl]oxy-3-hydroxy-5-[[(3R)-3-hydroxytetradecanoyl]amino]-4-[(3R)-3-hydroxytetradecanoyl]oxyoxan-2-yl]methoxy]-5-[[(3R)-3-dodecanoyloxytetradecanoyl]amino]-2-(hydroxymethyl)-4-[(3R)-3-tetradecanoyloxytetradecanoyl]oxyoxan-3-yl] phosphate
• 化学式: C96H181N3O28P3-3
• 分子量: 1918.4
• InChiKey: FOCHAVFXCSYXDE-MCJXJNKNSA-K

计算性质

• 辛醇/水分配系数(LogP)：
  22.3
• 重原子数：
  130
• 可旋转键数：
  92
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.94
• 拓扑面积：
  480
• 氢给体数：
  7
• 氢受体数：
  28

反应信息

• 作为反应物：
  描述：

  a 1,2-diacyl-sn-glycero-3-phosphoethanolamine 、 氢(+1)阳离子 、 lipid A 1-(2-aminoethyl diphosphate)(3-) 生成 a 1,2-diacyl-sn-glycerol 、 lipid A 1,4'-bis(2-aminoethyl diphosphate)(3-)
  参考文献：
  名称：

  A link between the assembly of flagella and lipooligosaccharide of the Gram-negative bacterium Campylobacter jejuni

  摘要：

  Campylobacter jejuni是全球急性细菌性腹泻的主要原因，并涉及Guillain-Barré综合症的发展。两种主要的表面特征，外膜脂寡糖和鞭毛，高度可变，并经常成为修饰的目标。这些修饰可能为细菌提供竞争优势。在这项工作中，我们鉴定了一个编码磷酸乙醇胺（pEtN）转移酶（Cj0256）的基因，它在修饰脂寡糖脂肪锚脂质A与鞭毛杆蛋白FlgG方面发挥双重作用。通过中断cj0256在C. jejuni 81-176中的表达，产生了突变体，导致脂质A和FlgG上缺乏pEtN修饰。cj0256突变体对阳离子抗菌肽多粘菌素B的敏感性增加了20倍，运动能力降低。传输电子显微镜观察cj0256突变体表明，约95％的细菌缺乏鞭毛，表明在没有pEtN修饰FlgG的情况下，鞭毛的产生受到阻碍。最有趣的是，这项研究鉴定了一种pEtN转移酶，它显示出对两种胞质外底物的偏好，将膜生物合成和鞭毛组装联系起来。Cj0256是一个大型未被完全表征的蛋白家族的成员，可能在细菌表面结构的装饰中发挥更大的作用。

  DOI：

  10.1073/pnas.0913451107
• 作为产物：
  描述：

  a 1,2-diacyl-sn-glycero-3-phosphoethanolamine 、 氢(+1)阳离子 、 lipid A (E. coli) 生成 a 1,2-diacyl-sn-glycerol 、 lipid A 1-(2-aminoethyl diphosphate)(3-)
  参考文献：
  名称：

  A link between the assembly of flagella and lipooligosaccharide of the Gram-negative bacterium Campylobacter jejuni

  摘要：

  Campylobacter jejuni是全球急性细菌性腹泻的主要原因，并涉及Guillain-Barré综合症的发展。两种主要的表面特征，外膜脂寡糖和鞭毛，高度可变，并经常成为修饰的目标。这些修饰可能为细菌提供竞争优势。在这项工作中，我们鉴定了一个编码磷酸乙醇胺（pEtN）转移酶（Cj0256）的基因，它在修饰脂寡糖脂肪锚脂质A与鞭毛杆蛋白FlgG方面发挥双重作用。通过中断cj0256在C. jejuni 81-176中的表达，产生了突变体，导致脂质A和FlgG上缺乏pEtN修饰。cj0256突变体对阳离子抗菌肽多粘菌素B的敏感性增加了20倍，运动能力降低。传输电子显微镜观察cj0256突变体表明，约95％的细菌缺乏鞭毛，表明在没有pEtN修饰FlgG的情况下，鞭毛的产生受到阻碍。最有趣的是，这项研究鉴定了一种pEtN转移酶，它显示出对两种胞质外底物的偏好，将膜生物合成和鞭毛组装联系起来。Cj0256是一个大型未被完全表征的蛋白家族的成员，可能在细菌表面结构的装饰中发挥更大的作用。

  DOI：

  10.1073/pnas.0913451107

文献信息

• Activation of PmrA inhibits LpxT-dependent phosphorylation of lipid A promoting resistance to antimicrobial peptides
  作者：Carmen M. Herrera、Jessica V. Hankins、M. Stephen Trent

  DOI：10.1111/j.1365-2958.2010.07150.x

  日期：——

  P>During its transport to the bacterial surface, the phosphate groups of the lipid A anchor of Escherichia coli and Salmonella lipopolysaccharide are modified by membrane enzymes including ArnT, EptA and LpxT. ArnT and EptA catalyse the periplasmic addition of the positively charged substituents 4-amino-4-deoxy-L-arabinose and phosphoethanolamine respectively. These modifications are controlled by the PmrA transcriptional regulator and confer resistance to cationic antimicrobial peptides, including polymyxin. LpxT, however, catalyses the phosphorylation of lipid A at the 1-position forming 1-diphosphate lipid A increasing the negative charge of the bacterial surface. Here, we report that PmrA is involved in the regulation of LpxT. Interestingly, this regulation does not occur at the level of transcription, but rather following the assembly of LpxT into the inner membrane. PmrA-dependent inhibition of LpxT is required for phosphoethanolamine decoration of lipid A, which is shown here to be critical for E. coli to resist the bactericidal activity of polymyxin. Furthermore, although Salmonella lipid A is more prevalently modified with l-4-aminoarabinose, we demonstrate that loss of Salmonella lpxT greatly increases EptA modification. The current work is an example of the complexities associated with the structural remodelling of Gram-negative lipopolysaccharides promoting bacterial survival.
• Cloning, expression, purification and crystallization of an endotoxin-biosynthesis enzyme from<i>Neisseria meningitidis</i>
  作者：Anandhi Anandan、Susannah Piek、Charlene M. Kahler、Alice Vrielink

  DOI：10.1107/s1744309112042236

  日期：2012.12.1

  The enzyme phosphoethanolamine transferase A is involved in the addition of phosphoethanolamine moieties to lipid A in Neisseria meningitidis. The enzyme is composed of an N-terminal transmembrane domain and a C-terminal soluble domain that is present in the periplasm of the bacteria. A membrane-deletion construct of the enzyme was designed and expressed in Escherichia coli. Well ordered crystals that diffracted to 1.7 angstrom resolution were obtained by carrying out a limited trypsin digestion of the protein to remove a predicted N-terminal disordered portion. The crystals belonged to space group P2(1), with unit-cell parameters a = 44.3, b = 71.6, c = 49.9 angstrom, beta = 109.2 degrees, and contained one molecule in the asymmetric unit.
• Periplasmic Cleavage and Modification of the 1-Phosphate Group of Helicobacter pylori Lipid A
  作者：An X. Tran、Mark J. Karbarz、Xiaoyuan Wang、Christian R.H. Raetz、Sara C. McGrath、Robert J. Cotter、M. Stephen Trent

  DOI：10.1074/jbc.m406480200

  日期：2004.12

  Pathogenic bacteria modify the lipid A portion of their lipopolysaccharide to help evade the host innate immune response. Modification of the negatively charged phosphate groups of lipid A aids in resistance to cationic antimicrobial peptides targeting the bacterial cell surface. The lipid A of Helicobacter pylori contains a phosphoethanolamine (pEtN) unit directly linked to the 1-position of the disaccharide backbone. This is in contrast to the pEtN units found in other pathogenic Gram-negative bacteria, which are attached to the lipid A phosphate group to form a pyrophosphate linkage. This study describes two enzymes involved in the periplasmic modification of the 1-phosphate group of H. pylori lipid A. By using an in vitro assay system, we demonstrate the presence of lipid A 1-phosphatase activity in membranes of H. pylori. In an attempt to identify genes encoding possible lipid A phosphatases, we cloned four putative orthologs of Escherichia coli pgpB, the phosphatidylglycerol-phosphate phosphatase, from H. pylori 26695. One of these orthologs, Hp0021, is the structural gene for the lipid A 1-phosphatase and is required for removal of the 1-phosphate group from mature lipid A in an in vitro assay system. Heterologous expression of Hp0021 in E. coli resulted in the highly selective removal of the 1-phosphate group from E. coli lipid A, as demonstrated by mass spectrometry. We also identified the structural gene for the H. pylori lipid A pEtN transferase (Hp0022). Mass spectrometric analysis of the lipid A isolated from E. coli expressing Hp0021 and Hp0022 shows the addition of a single pEtN group at the 1-position, confirming that Hp0022 is responsible for the addition of a pEtN unit at the 1-position in H. pylori lipid A. In summary, we demonstrate that modification of the 1-phosphate group of H. pylori lipid A requires two enzymatic steps.
• The Structure of the Neisserial Lipooligosaccharide Phosphoethanolamine Transferase A (LptA) Required for Resistance to Polymyxin
  作者：Christopher Wanty、Anandhi Anandan、Susannah Piek、James Walshe、Jhuma Ganguly、Russell W. Carlson、Keith A. Stubbs、Charlene M. Kahler、Alice Vrielink

  DOI：10.1016/j.jmb.2013.06.029

  日期：2013.9

  Gram-negative bacteria possess an outer membrane envelope consisting of an outer leaflet of lipopolysaccharides, also called endotoxins, which protect the pathogen from antimicrobial peptides and have multifaceted roles in virulence. Lipopolysaccharide consists of a glycan moiety attached to lipid A, embedded in the outer membrane. Modification of the lipid A headgroups by phosphoethanolamine (PEA) or 4-amino-arabinose residues increases resistance to the cationic cyclic polypeptide antibiotic, polymyxin. Lipid A PEA transferases are members of the YhjW/YjdB/YijP superfamily and usually consist of a transmembrane domain anchoring the enzyme to the periplasmic face of the cytoplasmic membrane attached to a soluble catalytic domain. The crystal structure of the soluble domain of the protein of the lipid A PEA transferase from Neisseria meningitidis has been determined crystallographically and refined to 1.4 angstrom resolution. The structure reveals a core hydrolase fold similar to that of alkaline phosphatase. Loop regions in the structure differ, presumably to enable interaction with the membrane-localized substrates and to provide substrate specificity. A phosphorylated form of the putative nucleophile, Thr280, is observed. Metal ions present in the active site are coordinated to Thr280 and to residues conserved among the family of transferases. The structure reveals the protein components needed for the transferase chemistry; however, substrate-binding regions are not evident and are likely to reside in the transmembrane domain of the protein. (C) 2013 Elsevier Ltd. All rights reserved.