BIOCHEMISTRY OF SCHISTOSOME GLUTATHIONE S-TRANSFERASES

据估计，血吸虫病折磨着2亿多人， 国际吧 在研制出实用的疫苗之前， 将继续对治疗感染 个人和用于控制传输的程序 人口。 尽管目前有几种药物 在临床应用中，有些药物仅对单一物种有效， 并且耐药性的出现越来越受到关注。 药物-寄生虫感染的生化机制 相互作用对于理解 药物功效和耐药性。 曼氏血吸虫成虫胞浆中含有5种谷胱甘肽S- 其中三种具有相似的性质。 除了 催化异生物质的解毒，包括一些药物， 通过与谷胱甘肽（GSH）结合，这些酶有望 具有内源性代谢功能。 这项建议是 旨在阐明结构关系和生物化学 S的功能。mansoni GSH S-转移酶。 各种生化 方法，包括重组DNA技术，将用于 实现以下目标：1）纯化和表征 谷胱甘肽S-转移酶催化敌敌畏的解毒作用， 验证了S. mansoni GSH S-转移酶是催化活性单体 蛋白质，而不是二聚体; 3）描绘一些内源性 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;和4） 分离并分析S.曼氏谷胱甘肽S-转移酶cDNA和基因组 克隆

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.