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Prostaglandin I synthase, Thromboxane A synthase & Prostaglandin E synthase

前列腺素 I 合酶、血栓素 A 合酶

基本信息

批准号：
7820930
负责人：
KE-HE RUAN
金额：
$ 2.5万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2009-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7820930
关键词：
Address Anabolism Binding Biochemical Blood Platelets Blood Vessels Cells Chemicals Chimera organism Circular Dichroism Coupled Coupling Cytochrome P450 Cytoplasmic Tail Detergents Dinoprostone Disease Eicosanoids Elements Endoplasmic Reticulum Energy Transfer Environment Enzymes Epoprostenol Family Fluorescence Fluorescence Resonance Energy Transfer Fluorescence Spectroscopy Funding Goals Human Individual Inflammation Mediators Inflammatory Ion Channel Lead Measurement Mediating Mediator of activation protein Membrane Membrane Proteins Molecular Molecular Models Movement Mutagenesis Myocardial Infarction N-terminal NMR Spectroscopy Nuclear Magnetic Resonance PTGS2 gene Pathologic Processes Pathway interactions Peptide Synthesis Peptides Physiological Production Property Prostacyclin synthase Prostaglandin H2 Prostaglandin-Endoperoxide Synthase Prostaglandins Prostaglandins I Protein Isoforms Proteins Recombinant Proteins Research Research Personnel Resolution Scheme Sequence Homology Side Site Solid Solutions Stream Stroke Structure Structure-Activity Relationship Techniques Testing Thrombosis Thromboxane A2 Thromboxane A2 Receptor Thromboxane-A Synthase Vascular System base crosslink cyclooxygenase 1 design experience insight interest molecular modeling mouse PGE synthase 1 novel therapeutics physical separation programs prostaglandin E synthase research study synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this project is to understand how the native, membrane-bound structures of three eicosanoid-synthesizing enzymes, thromboxane A2 (TXA2) synthase (TXAS), prostaglandin 12(prostacyclin, PGI2) synthase (PGIS), and the inducible microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1) influence their enzyme functions and their functional coupling with upstream enzymes, cyclooxygenase-1 (COX-l) and -2 (COX-2) in the biosynthesis of TXA2 (a key pro-thrombotic mediator causing stroke and heart attack), PGI2 (a key anti-thrombotic mediator against stroke and heart attack) and PGE2 (a key proinflammatory mediator). PGIS, mPGES-1 and TXAS share a common substrate, prostaglandin H2 (PGH2), produced by COX-1 or -2, mainly occurring in the endoplasmic reticulum (ER) membrane. Current studies have revealed that PGIS and mPGES-1 seem to be functionally coupled with COX-2, and TXAS is functionally coupled with COX-lin the ER membrane. The mPGES-1 belongs to a family of enzymes with a different primary structure and membrane topology compared to that of PGIS and TXAS, belonging to the P450 family. This has led us to hypothesize that PGIS, TXAS and mPGES-1 have distinct modes of functional coupling with individual COX isoforms and distinct modes of interaction with PGH2 in the ER membrane. Determination of PGH2 movement (presentation) from the COXs to the downstream enzymes, and their physical proximities in the ER membrane are crucial to elucidate the mechanisms of their different functional coupling. Based on the Pl's previous funding, the new Specific Aims are proposed to: a). Identify and compare the structures and key residues in the membrane anchor domains of TXAS, PGIS and mPGES-1 involved in the PGH2 presentation influencing their biosynthesis of TXA2, PGI2 and PGE2 differently; b). Determine the membrane topology and solution structure of mPGES-1 for comparison with PGIS and TXAS; and c). Elucidate the physical proximities between the COXs and PGIS, TXAS or mPGES- 1 to establish the relationship of the physical separations and their functional couplings. The results will be achieved by using integrated biochemical and biophysical approaches; such as, recombinant proteins and high resolution NMR spectroscopy. These studies will provide insight important to understanding the molecular mechanisms in controlling the biosynthesis of PGI2, TXA2 and PGE2, which mediates vascular and inflammatory diseases, and designs of next generation therapeutic strategies.

描述（由申请人提供）：该项目的总体目标是了解三种类二十烷酸合成酶、血栓素 A2 (TXA2) 合酶 (TXAS)、前列腺素 12（前列环素，PGI2）合酶 (PGIS) 和诱导型微粒体前列腺素 E2 (PGE2) 的天然膜结合结构是如何形成的合成酶-1 (mPGES-1) 影响它们的酶功能及其与上游酶、环氧合酶-1 (COX-1) 和 -2 (COX-2) 在 TXA2（导致中风和心脏病发作的关键促血栓形成介质）、PGI2（针对中风和心脏病发作的关键抗血栓介质）和 PGE2（关键）生物合成中的功能耦合。促炎介质）。 PGIS、mPGES-1 和 TXAS 具有共同的底物前列腺素 H2 (PGH2)，由 COX-1 或 -2 产生，主要存在于内质网 (ER) 膜中。目前的研究表明，PGIS 和 mPGES-1 似乎与 COX-2 功能偶联，TXAS 与内质网膜上的 COX-2 功能偶联。 mPGES-1 属于一个酶家族，与属于 P450 家族的 PGIS 和 TXAS 相比，其一级结构和膜拓扑结构不同。这使我们推测 PGIS、TXAS 和 mPGES-1 与各个 COX 亚型具有不同的功能耦合模式，并且与 ER 膜中的 PGH2 具有不同的相互作用模式。确定 PGH2 从 COX 到下游酶的运动（呈递）以及它们在内质网膜中的物理接近度对于阐明它们不同功能耦合的机制至关重要。根据 PL 之前的资助，新的具体目标建议： a).鉴定并比较参与 PGH2 呈递的 TXAS、PGIS 和 mPGES-1 膜锚定域的结构和关键残基，以不同方式影响 TXA2、PGI2 和 PGE2 的生物合成； b).确定mPGES-1的膜拓扑结构和溶液结构，以便与PGIS和TXAS进行比较；和c)。阐明 COX 与 PGIS、TXAS 或 mPGES-1 之间的物理接近性，以建立物理分离及其功能耦合的关系。该结果将通过使用综合生物化学和生物物理方法来实现；例如重组蛋白和高分辨率核磁共振波谱。这些研究将为理解控制介导血管和炎症疾病的 PGI2、TXA2 和 PGE2 生物合成的分子机制以及设计下一代治疗策略提供重要的见解。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Protective Effects of Up-Regulating Prostacyclin Biosynthesis on Neuron Survival in Hippocampus.

上调前列环素生物合成对海马神经元存活的保护作用。

DOI：
10.1007/s11481-019-09896-5
发表时间：
2020
期刊：
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
影响因子：
0
作者：
Ling,Qing-Lan;Akasaka,Hironari;Chen,Chang;Haile,ColinN;Winoske,Kevin;Ruan,Ke-He
通讯作者：
Ruan,Ke-He

Creating a mouse model resistant to induced ischemic stroke and cardiovascular damage.

创建对诱发缺血性中风和心血管损伤的耐小鼠模型。