The adult parasitic helminths presents a unique chemotherapeutic problem. Unlike other pathogens, in which metabolic events associated with proliferation can be disrupted, the helminths are more sensitive to agents that alter energetic or energy-related events, neurotransmission or neuromuscular activity. Thus, as part of a three-pronged chemotherapeutic strategy, it is essential to understand and evaluate the energetic mechanisms of the helminths because such evaluations assist in the determination of vulnerable sites for specific chemotherapeutic attack and present a reasonable approach to the development and assay of agents displaying chemotherapeutic efficacy. The proposed research focuses on the energetic impact of two mitochondrial systems, i.e., the inner membrane-associated NADPH:NAD and NADH:NAD transhydrogenations, on the helminths and an evaluation of the key mitochondrial electron transport complex of the helminths employing adult H. diminuta as the model. A vast number of the adult helminths are predominantly anaerobic energetically and accumulate succinate (or products derived from succinate) as the result of carbohydrate catabolism. Succinate is formed by the essential, anaerobic, mitochondrial electron transport mechanism of the helminths. The studies proposed address the energetic significance of the transhydrogenations and characteristics of the mitochondrial complex associated with anaerobic energy generation. The proposed studies will permit a novel evaluation of the NAPDH:NAD system in terms of protonmotive function, transmembrane configuration, potential energy conservation and composition, the potential of the NADH:NAD system to act in vectorial transmembrane hydride translocation, and the possible association of the transhydrogenations with a """"""""Complex I"""""""" of helminth mitochondria.
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