Action of Lipolytic Enzymes

脂肪分解酶的作用

基本信息

  • 批准号:
    10544745
  • 负责人:
  • 金额:
    $ 40.29万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-01-01 至 2025-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT The overall goal of this grant in recent years has been to describe in molecular detail the mechanism of action of physiologically important human forms of phospholipase A2 (PLA2). During the course of these studies, we have discovered that the activity of this superfamily of enzymes depends critically on the interaction of two large macromolecules (the protein and the large lipid aggregate), where the orientation of the enzyme with respect to the plane of the lipid-water interface can have a dramatic effect on activity. The nature of this interaction has been challenging to explore, but we have now shown that association of the membrane or micelle interface with the enzyme causes an allosteric activation through a resulting conformational change. This renewal application will extend our current studies on the pure recombinant human cytosolic Group IVA cPLA2, secretory Group V sPLA2, Ca2+-independent Group VIA iPLA2, and lipoprotein-associated PLA2/PAF (platelet-activating factor) acetyl hydrolase Group VIIA LpPLA2. During the renewal period, we will focus on three new directions. First, we will explore the further role of additional allosteric sites on iPLA2 (for ATP and calmodulin) and cPLA2 (for PIP2) for enzyme regulation and as drug targets. Second, we will expand and apply what we learned with phospholipases to triglyceride lipases starting with PNPLA3, which contains a patatin-like domain and is homologous to the catalytic domain of iPLA2. PNPLA3 is of great interest because GWAS studies have shown that a natural mutation (I148M) enriched in the Hispanic population leads to an increase in nonalcoholic steatohepatitis (NASH), the advanced form of nonalcoholic fatty liver disease (NAFLD). Our lipidomics analysis shows that the pure recombinant human mutant PNPLA3 has decreased triglyceride hydrolase activity and our MD studies show that the catalytic site has adopted to a triacylglyceride substrate rather than the phospholipid substrate in iPLA2. Third, we will explore the functioning and physiological role of the various intracellular phospholipase A2s in relevant intact cells, where the actual specificity will depend on the proximity and availability of optimal phospholipid molecular species. Although we have developed a novel lipidomics assay of PLA2 specificity and function in vitro, one barrier to progress in this field is the lack of methods for determining PLA2 activity in living cells. To address this issue, we have developed a new platform for measuring PLA2 specificity and inhibition ex vivo in macrophage cells in culture. This work has and will generate important widely applicable novel information on how physiologically important phospholipases and triacylglycerol lipases interact with the lipid-water interfaces of membranes, micelles and lipid droplets to compete physiologically in selecting their substrates. This work should enable us to fully explain and integrate at a structural level the resulting specificity of multiple members of the PLA2 superfamily acting in vitro with the specific molecular species of phospholipids hydrolyzed and the specific fatty acids released as well as correlating with ex vivo specificity.
项目总结/文摘

项目成果

期刊论文数量(0)
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EDWARD A DENNIS其他文献

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{{ truncateString('EDWARD A DENNIS', 18)}}的其他基金

Action of Lipolytic Enzymes
脂肪分解酶的作用
  • 批准号:
    10323245
  • 财政年份:
    2021
  • 资助金额:
    $ 40.29万
  • 项目类别:
Action of Lipolytic Enzymes
脂肪分解酶的作用
  • 批准号:
    10582007
  • 财政年份:
    2021
  • 资助金额:
    $ 40.29万
  • 项目类别:
Bioactive Metabolites Modulate Immune-Related Adverse Events in Cancer Immunotherapy
生物活性代谢物调节癌症免疫治疗中与免疫相关的不良事件
  • 批准号:
    10654674
  • 财政年份:
    2021
  • 资助金额:
    $ 40.29万
  • 项目类别:
LIPIDOMICS BASED DIAGNOSTICS FOR NONALCOHOLIC STEATOHEPATITIS
基于脂质组学的非酒精性脂肪性肝炎诊断
  • 批准号:
    9313262
  • 财政年份:
    2015
  • 资助金额:
    $ 40.29万
  • 项目类别:
LIPIDOMICS BASED DIAGNOSTICS FOR NONALCOHOLIC STEATOHEPATITIS
基于脂质组学的非酒精性脂肪性肝炎诊断
  • 批准号:
    8940970
  • 财政年份:
    2015
  • 资助金额:
    $ 40.29万
  • 项目类别:
LIPIDOMICS BASED DIAGNOSTICS FOR NONALCOHOLIC STEATOHEPATITIS
基于脂质组学的非酒精性脂肪性肝炎诊断
  • 批准号:
    9132243
  • 财政年份:
    2015
  • 资助金额:
    $ 40.29万
  • 项目类别:
Metabolomics Core
代谢组学核心
  • 批准号:
    8689908
  • 财政年份:
    2014
  • 资助金额:
    $ 40.29万
  • 项目类别:
Impact of Lipidomics Conference Series
脂质组学会议系列的影响
  • 批准号:
    8993903
  • 财政年份:
    2014
  • 资助金额:
    $ 40.29万
  • 项目类别:
Impact of Lipidomics Conference Series
脂质组学会议系列的影响
  • 批准号:
    8804273
  • 财政年份:
    2014
  • 资助金额:
    $ 40.29万
  • 项目类别:
VISUALIZING LOCALIZATION & TRANSLOCATION OF THREE TYPES OF PHOSPHOLIPASE A2
可视化本地化
  • 批准号:
    7358028
  • 财政年份:
    2006
  • 资助金额:
    $ 40.29万
  • 项目类别:

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