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: 3880260
• 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/3880260
• 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.

类二十烷酸是一种生物活性脂质，来源于细胞氧化