SUICIDE INACTIVATION OF LTA4 HYDROLASE AND THROMBOXANE SYNTHASE

LTA4 水解酶和血栓烷合酶的自杀失活

• 批准号: 3844414
• 负责人: FRANK A FITZPATRICK
• 金额: --
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3844414
• 关键词: eicosanoids; enzyme mechanism; fatty acid biosynthesis; guinea pigs; hydrolase; immunochemistry; laboratory rabbit; lung disorder; molecular biology; pneumonia; stoichiometry; thromboxanes

Eicosanoids are biologically active lipids derived from cellular oxidative metabolism of arachidonic acid. These substances are autacoid mediators which initiate, aggravate, or sustain respiratory and cardiac disorders. Recent investigations indicate that 'suicide' inactivation of certain key enzymes occurs during eicosanoid biosynthesis. Suicide inactivation, by modulating the accumulation and disposition of pivotal substrates, influences both quantitative and qualitative aspects of eicosanoid formation. For example, termination of leukotriene B4 biosynthesis by suicide inactivation of LTA4 hydrolase may promote conversion of LTA4 into other leukotrienes; it may promote non-enzymatic reactions of LTA4, such as hydrolysis or nucleophilic addition to macromolecules; or it may promote secretion of LTA4 by one cell type for metabolism by a separate cell type (transcellular biosynthesis). An analogous example exists for thromboxane A4 biosynthesis. Suicide inactivation of thromboxane synthase terminates thromboxane biosynthesis and promotes alternate fates for its pivotal substrate, prostaglandin endoperoxide (PGH2). These include conversion into other prostaglandins by non-enzymatic processes, or by transcellular biosynthesis. We propose to investigate: i) the chemical nature of the suicide inactivation process ii) its biochemical and cellular consequences with particular reference to the accumulation and disposition of LTA4 and PGH2 iii) the selectivity, reversibility, and potential to use suicide inactivation as a "marker" for unrestrained eicosanoid biosynthesis. We selected LTA4 hydrolase and thromboxane A2 synthase as enzymatic models because they regulate critical branch points during eicosanoid biosynthesis. The former influences leukotriene formation and the latter influences prostaglandin and thromboxane formation. In addition, their products, leukotriene B4 and thromboxane A2, have potent effects on pulmonary vasoconstriction and blood cell activation. This is a new research program based on the hypothesis that suicide substrate inactivation of enzymes in the arachidonic acid cascade is a cellular mechanism to alter temporally, qualitatively, and quantitatively the biosynthesis of eicosanoids. We aim to develop a more accurate model to account for the role of eicosanoids in chronic, rather than acute, pulmonary disorders.

二十烷基类化合物是细胞氧化产生的生物活性脂类。 花生四烯酸的代谢。这些物质是金盏花环类物质。 引发、加重或维持呼吸系统和心脏疾病。 最近的调查表明，某些键的‘自杀’失活 酶发生在二十烷类化合物的生物合成过程中。自杀灭活，由 调节关键底物的积累和配置， 影响二十烷类化合物的定量和定性方面 队形。例如，通过终止白三烯B4的生物合成 自杀式失活LTA4水解酶可能促进LTA4转化为 其他白三烯；它可能促进LTA4的非酶反应，如 大分子的水解性或亲核性加成；或者它可能促进 一种细胞类型分泌LTA4以供另一种细胞类型代谢 (跨细胞生物合成)。血栓烷也有类似的例子。 A4生物合成。血栓素合成酶的自杀失活终止 血栓素的生物合成和促进其关键的另类命运 底物前列腺素内源性过氧化产物(PGH2)。其中包括转换 通过非酶过程或跨细胞途径转化为其他前列腺素 生物合成。 我们建议调查：i)自杀的化学性质 失活过程II)其生化和细胞后果 特别提到LTA4和PGH2的积累和处置 三)自杀的选择性、可逆转性和潜力 失活是不受限制的二十烷类化合物生物合成的“标志”。我们 选择LTA4水解酶和血栓素A2合成酶作为酶模型 因为它们调节二十烷类药物期间的关键分支点 生物合成。前者影响白三烯的形成，后者影响白三烯的形成。 影响前列腺素和血栓素的形成。此外，他们的 白三烯B4和血栓素A2的产物对 肺血管收缩和血细胞激活。 这是一个新的研究项目，基于自杀的假设 花生四烯酸级联反应中酶的底物失活是一种 时间上、质量上和数量上改变的细胞机制 二十烷类化合物的生物合成。我们的目标是开发一种更准确的模型 来解释二十烷类化合物在慢性而不是急性 肺部疾病。