MITOCHONDRIAL ELECTRON TRANSPORT IN AFRICAN TRYPANOSOMES

快速分化的非洲致病病毒的能量生产 锥虫完全依赖于糖酵解。这通常是 取决于一种不寻常的线粒体电子传输系统以及什么时候 这并不是基于一种不寻常的甘油生产方法。在……里面 细长血流锥虫的电子传递系统 只包含两种酶，甘油-3-磷酸脱氢酶和 锥虫交替氧化酶(TAO)。《TAO》与《唐诗》的产生 甘油是两个代谢步骤，不是宿主所共有的，但对 寄生虫。因此，这些步骤是 化疗。甘油的生产被认为是通过逆转 但对TAO除了其基因外，我们知之甚少 与一些高等植物、真菌和 藻类。为此，我们计划对TAO及其抑制剂进行研究。 所获得的信息预计将允许明确的生化 要利用的宿主和寄生虫之间的差异导致 高度选择性的治疗。 将以布氏锥虫为模型实现两次初选 目标。首先是分离、表征，最后是 重建电子传输系统。第二种方法是评估一个 作为候选药物使用的抑制剂数量有限。 甘油-3-磷酸脱氢酶和TAO组分 电子传递链将从线粒体中释放出来 布鲁氏支原体血液细胞膜。他们将被分开并 然后，一个正常运作的系统将从孤立的 组件。将研究氧化物酶的作用机制。 链的组件被禁止，所得到的信息是 用于最终设计改进的抑制剂。 一种有希望成为实用的TAO抑制剂的线索已经开发出来： N-正-烷基3，4-二羟基苯甲酰胺。治愈率很高 其中之一，N-正丁基-3，4-二羟基苯甲酰胺。这种化合物会 将进一步评估，几种密切相关的化合物将被 被检查作为化疗药物的效用。

Energy production in the rapidly dividing forms of pathogenic African trypanosomes is totally dependent upon glycolysis. This normally depends on an unusual mitochondrial electron transport system and when this is not operating on an unusual method of glycerol production. In the long slender bloodstream trypanosome tbe electron transport system contains only two enzymes, glycerol-3-phosphate dehydrogenase and the trypanosome alternative oxidase (TAO). The TAO and the production of glycerol are two metabolic steps not shared by the host but essential to the parasite. These steps are, therefore, ideal targets for chemotherapy. The production of glycerol is thought to be by a reversal of glycerol kinase but little is known of the TAO other than its similarity to the alternative oxidase of some higher plants, fungi and algae. For this reason, we plan a study of the TAO and its inhibitors. The information gained is expected to allow clear biochemical differences between host and parasite to be exploited leading to a highly selective therapy. Trypanosoma brucei brucei will be used as a model to achieve two primary objectives. The first is to isolate, characterize, and finally reconstitute the electron transport system. The second is to evaluate a limited number of inhibitors for utility as drug candidates. The glycerol-3-phosphate dehydrogenase and the TAO components of the electron transport chain will be released from the mitochondrial membranes of T. b. brucei bloodstream cells. They will be separated and then a functioning system will be reconstituted from the isolated components. A study will be made of the mechanism whereby the oxidase component of the chain is inhibited, the resulting information being used in the eventual design of improved inhibitors. A promising lead for a practical inhibitor of the TAO has developed: the N-n-alkyl 3,4dihydroxybenzamides. A high cure rate has been achieved with one of these, N-n-butyl 3,4dihydroxybenzamide. This compound will be evaluated further and several closely related compounds will be examined for utility as chemotherapeutic agents.