A BROMOENOL LACTONE SUICIDE SUBSTRATE INACTIVATES GROUP VIA PHOSPHOLIPASE A2

溴烯醇内酯自杀底物通过磷脂酶 A2 灭活基团

基本信息

  • 批准号:
    7721511
  • 负责人:
  • 金额:
    $ 0.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-02-01 至 2009-01-31
  • 项目状态:
    已结题

项目摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Phospholipases A2 (PLA2) comprise a superfamily of enzymes that hydrolyze phospholipids to a free fatty acid, e.g., arachidonate, and a 2-lysophospholipid. Dissecting their individual functions has relied in large part on pharmacological inhibitors that discriminate among PLA2. Group VIA PLA2 (iPLA2) has a GTSTG serine lipase consensus sequence, and studies with a bromoenol lactone (BEL) suicide substrate inhibitor have been taken to suggest that iPLA2 participates in a wide variety of biological processes. Such conclusions presume inhibitor specificity. Inhibition by BEL requires its hydrolysis by and results in uncharacterized covalent modification(s) of iPLA2. We performed mass spectrometric analyses of proteolytic digests of BEL-treated iPLA2 to identify modifications associated with loss of activity. The GTSTG active site and large flanking regions of sequence are not modified by BEL treatment, but most iPLA2 Cys residues are alkylated at various BEL concentrations to form a thioether linkage to a BEL keto acid hydrolysis product. Synthetic Cys-containing peptides are alkylated when incubated with iPLA2 and BEL, which reflects iPLA2-catalyzed BEL hydrolysis to a diffusible bromomethyl keto acid product that reacts with distant thiols. The BEL concentration dependence of Cys651 alkylation closely parallels that of loss of iPLA2 activity. No amino acid residues other than Cys were found to be modified, suggesting that Cys alkylation is the covalent modification of iPLA2 responsible for loss of activity, and the alkylating species appears to be a diffusible hydrolysis product of BEL rather than a tethered acyl-enzyme intermediate.
该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金, 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说,它不一定是研究者的机构。 磷脂酶 A2 (PLA2) 包含将磷脂水解为游离脂肪酸(例如花生四烯酸)和 2-溶血磷脂的酶超家族。剖析它们各自的功能在很大程度上依赖于区分 PLA2 的药理学抑制剂。 VIA PLA2 组 (iPLA2) 具有 GTSTG 丝氨酸脂肪酶共有序列,对溴烯醇内酯 (BEL) 自杀底物抑制剂的研究表明 iPLA2 参与多种生物过程。这些结论假定了抑制剂的特异性。 BEL 的抑制需要被 iPLA2 水解并导致 iPLA2 发生未表征的共价修饰。我们对 BEL 处理的 iPLA2 的蛋白水解消化物进行了质谱分析,以确定与活性丧失相关的修饰。 GTSTG 活性位点和序列的大侧翼区域不会通过 BEL 处理进行修饰,但大多数 iPLA2 Cys 残基在不同的 BEL 浓度下被烷基化,形成与 BEL 酮酸水解产物的硫醚键。当与 iPLA2 和 BEL 一起孵育时,合成的含 Cys 肽会被烷基化,这反映了 iPLA2 催化的 BEL 水解为可扩散的溴甲基酮酸产物,该产物与远处的硫醇反应。 Cys651 烷基化的 BEL 浓度依赖性与 iPLA2 活性丧失的 BEL 浓度依赖性非常相似。除Cys外,没有发现其他氨基酸残基被修饰,这表明Cys烷基化是iPLA2的共价修饰,导致活性丧失,并且烷基化物质似乎是BEL的可扩散水解产物,而不是束缚的酰基酶中间体。

项目成果

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HAOWEI SONG其他文献

HAOWEI SONG的其他文献

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{{ truncateString('HAOWEI SONG', 18)}}的其他基金

ALGORITHMS FOR AUTOMATIC PROCESSING OF DATA FROM MASS SPECTROMETRIC ANALYSES
自动处理质谱分析数据的算法
  • 批准号:
    8361390
  • 财政年份:
    2011
  • 资助金额:
    $ 0.44万
  • 项目类别:
EVIDENCE FOR PROTEOLYTIC PROCESSING AND STIMULATED ORGANELLE REDISTRIBUTION
蛋白水解加工和刺激细胞器重新分布的证据
  • 批准号:
    8168828
  • 财政年份:
    2010
  • 资助金额:
    $ 0.44万
  • 项目类别:
ALGORITHMS FOR AUTOMATIC PROCESSING OF DATA FROM MASS SPECTROMETRIC ANALYSES
自动处理质谱分析数据的算法
  • 批准号:
    8168786
  • 财政年份:
    2010
  • 资助金额:
    $ 0.44万
  • 项目类别:
MODULATION OF THE REGULATORY ACTIVITY OF BACTERIAL TWO-COMPONENT SYSTEMS BY SLY
SLY 对细菌二组分系统调节活性的调节
  • 批准号:
    8168776
  • 财政年份:
    2010
  • 资助金额:
    $ 0.44万
  • 项目类别:
MODULATION OF THE REGULATORY ACTIVITY OF BACTERIAL TWO-COMPONENT SYSTEMS BY SLY
SLY 对细菌二组分系统调节活性的调节
  • 批准号:
    7954025
  • 财政年份:
    2009
  • 资助金额:
    $ 0.44万
  • 项目类别:
ALGORITHM FOR PROCESSING RAW MASS SPECTROMETRIC DATA TO IDENTIFY AND QUANTITATE
处理原始质谱数据以进行识别和定量的算法
  • 批准号:
    7953990
  • 财政年份:
    2009
  • 资助金额:
    $ 0.44万
  • 项目类别:
ALGORITHMS FOR AUTOMATIC PROCESSING OF DATA FROM MASS SPECTROMETRIC ANALYSES
自动处理质谱分析数据的算法
  • 批准号:
    7954035
  • 财政年份:
    2009
  • 资助金额:
    $ 0.44万
  • 项目类别:
EFFECTS OF BIOLOGICAL OXIDANTS ON THE CATALYTIC ACTIVITY AND STRUCTURE OF GROUP
生物氧化剂对催化活性和基团结构的影响
  • 批准号:
    7721510
  • 财政年份:
    2008
  • 资助金额:
    $ 0.44万
  • 项目类别:
N-TERMINAL PROCESSING OF IPLA2B AND OF POT CLEAVAGE SITES OF APP CONSTRUCTS
IPLA2B 和 APP 构建体的 Pot 裂解位点的 N 端处理
  • 批准号:
    7355244
  • 财政年份:
    2006
  • 资助金额:
    $ 0.44万
  • 项目类别:
BROMOENOL LACTONE SUICIDE SUBSTR INACTIVATES IPLA2B BY GENERATING A DIFF
溴烯醇内酯自杀底物通过产生差异使 IPLA2B 失活
  • 批准号:
    7355273
  • 财政年份:
    2006
  • 资助金额:
    $ 0.44万
  • 项目类别:

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