SUICIDE INACTIVATION OF LTA4 HYDROLASE AND THROMBOXANE SYNTHASE

类二十烷酸是源自细胞氧化的生物活性脂质， 花生四烯酸的代谢。 这些物质是自体激素介质 其引发、加重或维持呼吸和心脏疾病。 最近的研究表明，“自杀”失活的某些关键 酶在类花生酸生物合成期间发生。 自杀失活， 调节关键底物的积累和分布， 影响类花生酸的定量和定性方面 阵 例如，通过抑制白细胞介素B4的生物合成， LTA 4水解酶自杀性失活可促进LTA 4转化为 其他白三烯;它可能促进LTA 4的非酶促反应，如 水解或亲核加成到大分子上;或者它可以促进 由一种细胞类型分泌LTA 4，用于由另一种细胞类型代谢 （transcellular biosynthesis）。 血栓烷也有类似的例子 A4生物合成。 血栓素合酶的自杀失活终止 血栓素生物合成，并促进其关键的交替命运， 底物前列腺素内过氧化物（PGH 2）。 其中包括转换 通过非酶促过程或通过跨细胞 生物合成 我们建议调查：i）自杀的化学性质 灭活过程ii）其生物化学和细胞后果， 特别提及LTA 4和PGH 2的积累和处置 iii）选择性、可逆性和使用硅化物的可能性 作为不受限制的类二十烷酸生物合成的“标记”的失活。 我们 选择LTA 4水解酶和血栓烷A2合酶作为酶模型 因为它们调节类花生酸形成过程中的关键分支点 生物合成 前者影响白三烯的形成，而后者影响 影响前列腺素和血栓素的形成。 另外他们 产品，白三烯B4和血栓素A2，有强大的影响， 肺血管收缩和血细胞活化。 这是一个新的研究项目， 花生四烯酸级联反应中酶的底物失活是一种 细胞机制改变时间，定性和定量 类花生酸的生物合成。 我们的目标是建立一个更精确的模型 为了解释类二十烷酸在慢性，而不是急性， 肺部疾病

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.