BIOCHEMISTRY OF SCHISTOSOME GLUTATHIONE S-TRANSFERASES

据估计，血吸虫病困扰着2亿多人。 全世界。在实用的疫苗问世之前，化疗 将继续是治疗感染的重要因素 个人和用于控制内部传输的程序 人口。尽管目前有几种药物可供选择 对于临床应用，一些药物仅对单一物种有效。 而耐药性的出现也越来越引起人们的关注。 药物寄生虫相关生化机制的阐明 相互作用对于理解分子基础很重要。 既有药效，又有耐药性。 曼氏血吸虫成虫体内含有五种胞浆谷胱甘肽S- 转移酶，其中三种具有相似的性质。此外 催化外源生物的解毒，包括一些药物， 通过与谷胱甘肽(GSH)的结合，这些酶是可望的 具有内源性代谢功能。这项建议是 旨在阐明结构关系和生化 曼氏血吸虫谷胱甘肽S转移酶的功能。各种生化产品 包括重组DNA技术在内的方法将被用于 实现以下目标：1)提纯和表征 催化敌敌畏解毒的谷胱甘肽S转移酶， 2)验证S。 曼氏谷胱甘肽S转移酶是具有催化活性的单体 蛋白质，而不是二聚体；3)描绘了一些内源 这些酶的代谢功能包括催化 白三烯C4的生物合成，防止脂质过氧化， 并作为细胞内配体结合蛋白；以及4) 曼氏血吸虫谷胱甘肽S转移酶基因和基因组的分离与分析 克隆人。

Schistosomiasis is estimated to afflict over 200 million people worldwide. Until a practical vaccine is available, chemotherapy will continue to be important both for treating infected individuals and in programs for controlling transmission within populations. Although several drugs are currently available for clinical use, some are effective against only a single species and the appearance of drug resistance is of increasing concern. Elucidation of biochemical mechanisms involved in drug-parasite interactions is important for understanding the molecular basis of both drug efficacy and resistance. Adult Schistosoma mansoni contain five cytosolic glutathione S- transferases, three of which have similar properties. Besides catalyzing the detoxication of xenobiotics, including some drugs, via conjugation with glutathione (GSH), these enzymes are expected to have endogenous metabolic functions. This proposal is designed to elucidate structural relationships and biochemical Functions of S. mansoni GSH S-transferases. Various biochemical methods, including recombinant DNA techniques, will be used to achieve the following objectives: 1) Purify and characterize the GSH S-transferase that catalyzes the detoxication of dichlorvos, the active form of metrifonate; 2) Test the hypothesis that S. mansoni GSH S-transferases are catalytically active monomeric proteins, rather than dimers; 3) Delineate some endogenous metabolic functions of these enzymes including catalysis of leukotriene C4 biosynthesis, protection against lipid peroxidation, and serving as intracellular ligand binding proteins; and 4) Isolate and analyze S. mansoni GSH S-transferase cDNA and genomic clones.