The life cycle of African trypanosomes is characterized by mitochondrial biogenesis as the parasites differentiate from the bloodstream to pro- cyclic trypomastigotes. The bloodstream organisms are characterized by the presence of an alternative oxidase to the usual cytochrome oxidase. This trypanosome alternative oxidase (TAO) is cyanide-resistant but inhibited 100% by salicylhydroxamic acid, a known inhibitor of alternative oxidases in plants and fungi. Pro-cyclic trypomastigotes similar to those found in the mid-gut of the tsetse fly, have 75% cyanide- sensitive respiration and 25% SHAM sensitive suggesting a retention of the TAO during differentiation. This enzyme system is critically important to the bloodstream parasite as it is responsible for the aerobic respiration of the bloodstream trypanosomes and its inhibition would damage the parasite's chances for survival. It plays an essential role in the re-oxidation of NADH in the trypanosome. We have recently cloned, sequenced, and expressed the TAO genes from Trypanosoma brucei brucei.
The specific aims of this proposal are: 1. To elucidate the protein structure of TAO; 2. To elucidate key properties responsible for the function of the TAO; and 3. To evaluate how essential the TAO is to the trypanosome and its potential as a drug target. 4. To evaluate new compounds a potential inhibitors of TAO and their effectiveness as trypanocidal drugs. The goal of the proposed research is to characterize the TAO in trypanosomes at the molecular and biochemical levels so as to have information valuable for studies leading to the use of this enzyme as a target for trypanocidal drugs.
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