Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
基本信息
- 批准号:7317189
- 负责人:
- 金额:$ 44.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-09-01 至 2011-07-31
- 项目状态:已结题
- 来源:
- 关键词:AbbreviationsAcetatesAcidsAmericanAmino AcidsAnabolismAntibiotic A23187Arachidonic AcidsBe++ elementBerylliumBiochemicalBiologyBolus InfusionBradykininButhionine SulfoximineCatalysisCell CycleCell Differentiation processCellsCommitCoupledCoxibsCultured CellsCysteineCytosolic Phospholipase A2DietDinoprostoneDocosahexaenoic AcidsEMSAEicosapentaenoic AcidEicosatetraenoic AcidsElectrophoretic Mobility Shift AssayElementsEmbryoEndoglycosidasesEngineeringEnvironmentEpoprostenolEstersEuropeanEventExhibitsFatty AcidsFibroblastsFigs - dietaryFish OilsFlurbiprofenGTP-Binding ProteinsGene ExpressionGenesGlycerophospholipidsGoalsHTATIP geneHealth BenefitHormonesHousekeepingHumanHydrogen PeroxideIn VitroIonophoresKidneyKineticsKnock-in MouseKnockout MiceLearningLinkLinoleic AcidsMammalian CellMeasuresMolecularMusNIH 3T3 CellsNon-Steroidal Anti-Inflammatory AgentsOmega-6 Fatty AcidsOutcome StudyPGF genePLA2G4A genePPIXPathway interactionsPatternPenicillinsPeroxidasePeroxidasesPersonal SatisfactionPhasePhenotypePhospholipase A2PhospholipidsPlacental Growth FactorPlatelet-Derived Growth FactorProgress ReportsPropertyProstaglandin D2Prostaglandin EndoperoxidesProstaglandin H2Prostaglandin-Endoperoxide SynthaseProstaglandinsProstaglandins DProstaglandins EProstaglandins FProtein IsoformsProtein OverexpressionProtoporphyrinsReactionReduced GlutathioneRegulationResearchResearch PersonnelRoleSeriesSiteStimulusStreptomycinSystemTestingTetradecanoylphorbol AcetateThromboxane ReceptorThromboxanesTimebasecell typeconceptcyclooxygenase 1cyclooxygenase 2designfeedinghuman PLA2G4A proteinhuman WFDC2 proteinhuman prostaglandin D2 receptorimmunocytochemistryin vivokifunensinemead acidmouse PGE synthase 1phorbol-12-myristateprogesterone 11-hemisuccinate-(2-iodohistamine)programsprostaglandin G2prostaglandin I3prostaglandin R2 D-isomeraseprotein degradationreceptorresearch studyurinary
项目摘要
DESCRIPTION (provided by applicant): The long-term goal of our studies is to understand how prostaglandin (PG) synthesis is regulated. There are two PGH synthases (PGHS-1 and -2) each able to catalyze the committed step in PG formation-oxygenation of the omega 6 fatty acid arachidonic acid (AA) or the co3 fatty acid eicosapentaenoic acid. PGHSs, also known as cyclooxygenases (COXs), are products of different genes; typically, PGHS-1 is expressed constitutively, while PGHS-2 is expressed transiently. Each PGHS isoform subserves different biologies, and a central question is how this can occur. PGHS-1 displays negative substrate cooperativity. We posit that this restricts PGHS-1 to operating only at high AA concentrations when a bolus of PGs is required for a pulsatile, housekeeping event-something that could happen at any time during the cell cycle. Unlike PGHS-1, PGHS-2 can function at all substrate concentrations. We suggest that its normal function is to provide a slow, continuous synthesis of PGs during a 1-2 h period preceding cell differentiation or replication when AA levels are low and PGHS-2 is briefly present. In short, we hypothesize that regulation of PGHS-1 activity is kinetic while control of PGHS-2 activity resides in its expression. These ideas can explain how when the isoforms are co-expressed in cells, PGHS-2 can be active while PGHS-1 is latent. The kinetic properties of PGHS-1 permit its functioning in vitro only when AA or EPA levels reach > 1-2 uM. It is probably rare that cellular EPA levels become this high; moreover, EPA is a very poor substrate for PGHS-1. So we suggest that except at unusually high EPA/AA ratios, EPA does not function as a substrate for PGHS-1 in vivo. Some beneficial effects of dietary fish oil could relate to the inactivity of PGHS-1 with EPA. Specific Aim #1 will test our concepts about the differences in the abilities of PGHS-1 and PGHS-2 to oxygenate low vs. high concentrations of endogenous AA vs. EPA in cells. Fibroblasts expressing PGHS-1 or PGHS-2 and having different EPA/AA ratios in their phospholipids will be cultured. PGE2 and PGEj, synthesis will be measured with cells stimulated to mobilize low vs. high levels of endogenous substrates. To determine if PGHS-1 can oxygenate EPA in vivo, PGHS-2 null mice will be fed fish oil and urinary, EPA-derived PGs will be quantified. Specific Aim #2 will examine an unexplored aspect of the control of PGHS-2 expression-protein degradation. Compared to PGHS-1 degradation, PGHS-2 degradation is rapid (tj/2 ~ 2 h). We have identified a 27 amino acid instability element (27-IE) near the C-terminus of PGHS-2 that targets it to the ER-associated degradation system. We will define structural features of the 27-IE involved in its function and will phenotype a newly engineered PGHS-2 knock-in mouse having a non-functional 27-IE.
描述(由申请人提供):我们研究的长期目标是了解前列腺素(PG)合成是如何调节的。有两种 PGH 合酶(PGHS-1 和 -2),每种都能够催化 omega 6 脂肪酸花生四烯酸 (AA) 或 co3 脂肪酸二十碳五烯酸氧化的 PG 形成中的关键步骤。 PGHS,也称为环氧合酶(COX),是不同基因的产物;通常,PGHS-1 是组成型表达,而 PGHS-2 是瞬时表达。每种 PGHS 异构体都有不同的生物学功能,一个中心问题是这是如何发生的。 PGHS-1 显示负底物协同性。我们推测,这限制了 PGHS-1 仅在高 AA 浓度下工作,此时需要大量 PG 来进行脉动的内务事件(细胞周期中的任何时间都可能发生这种情况)。与 PGHS-1 不同,PGHS-2 可以在所有底物浓度下发挥作用。我们认为其正常功能是在细胞分化或复制之前的 1-2 小时内,当 AA 水平较低且 PGHS-2 短暂存在时,提供缓慢、连续的 PG 合成。简而言之,我们假设 PGHS-1 活性的调节是动态的,而 PGHS-2 活性的控制在于其表达。这些想法可以解释当异构体在细胞中共表达时,PGHS-2 可以活跃而 PGHS-1 是潜伏的。仅当 AA 或 EPA 水平达到 > 1-2 uM 时,PGHS-1 的动力学特性才允许其在体外发挥作用。细胞 EPA 水平达到如此高的情况可能很少见。此外,EPA 是 PGHS-1 的一种非常差的底物。因此,我们建议,除非 EPA/AA 比例异常高,否则 EPA 在体内不起 PGHS-1 底物的作用。膳食鱼油的一些有益作用可能与 PGHS-1 与 EPA 的不活性有关。具体目标 #1 将测试我们关于 PGHS-1 和 PGHS-2 氧化细胞内低浓度和高浓度内源 AA 和 EPA 的能力差异的概念。将培养表达PGHS-1或PGHS-2并且其磷脂中具有不同EPA/AA比率的成纤维细胞。 PGE2 和 PGEj 的合成将通过刺激细胞动员低水平与高水平的内源底物来测量。为了确定 PGHS-1 是否可以在体内氧化 EPA,将给 PGHS-2 缺失小鼠喂食鱼油,并对尿中 EPA 衍生的 PG 进行定量。具体目标#2 将检查 PGHS-2 表达蛋白质降解控制的一个未探索的方面。与PGHS-1降解相比,PGHS-2降解迅速(tj/2~2 h)。我们在 PGHS-2 C 末端附近鉴定了一个由 27 个氨基酸组成的不稳定元件 (27-IE),该元件将其靶向 ER 相关降解系统。我们将定义与其功能相关的 27-IE 的结构特征,并对具有非功能性 27-IE 的新工程 PGHS-2 敲入小鼠进行表型分析。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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William L Smith其他文献
Race and Ethnicity
种族和民族
- DOI:
10.4135/9781483391144.n309 - 发表时间:
1995 - 期刊:
- 影响因子:3.2
- 作者:
William L Smith - 通讯作者:
William L Smith
Arctic Radiation-IceBridge Sea and Ice Experiment: The Arctic Radiant Energy System during the Critical Seasonal Ice Transition
北极辐射-冰桥海冰实验:关键季节冰转变期间的北极辐射能源系统
- DOI:
10.1175/bams-d-14-00277.1 - 发表时间:
2017-07-28 - 期刊:
- 影响因子:8
- 作者:
William L Smith;C. Hansen;A. Bucholtz;Bruce Anderson;M. Beckley;Joseph G. Corbett;R. Cullather;K. Hines;M. Hofton;S. Kato;D. Lubin;Richard H. Moore;Michal Segal Rosenhaimer;J. Redemann;S. Schmidt;Ryan C. Scott;Shi Song;J. Barrick;J. B. Blair;D. Bromwich;C. Brooks;Gao Chen;H. Cornejo;C. Corr;S. Ham;A. S. Kittelman;S. Knappmiller;S. LeBlanc;Norman G. Loeb;Colin R. Miller;L. Nguyen;R. Palikonda;D. Rabine;Elizabeth A. Reid;J. Richter;P. Pilewskie;Y. Shinozuka;D. Spangenberg;P. Stackhouse;P. Taylor;K. Thornhill;David van Gilst;E. Winstead - 通讯作者:
E. Winstead
William L Smith的其他文献
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{{ truncateString('William L Smith', 18)}}的其他基金
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化作用
- 批准号:
7932688 - 财政年份:2009
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
- 批准号:
8185845 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化作用
- 批准号:
8658102 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
- 批准号:
7664259 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
- 批准号:
6677554 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化作用
- 批准号:
7109363 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
- 批准号:
6792121 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
- 批准号:
6936502 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化作用
- 批准号:
8469864 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
Catalysis by Prostaglandin Endoperoxide H Synthases
前列腺素内过氧化物 H 合成酶的催化
- 批准号:
8323415 - 财政年份:2003
- 资助金额:
$ 44.02万 - 项目类别:
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