The parasitic helminths continue to represent serious global concerns that impact significantly both on human and veterinary medicine. Considered within the framework of effective chemotherapy, these pathogens present a unique problem. It is now clear that in marked contrast to corresponding viral, bacterial, mycotic and protozoan disease-causing systems, the helminths present an unmatched level of complexity because chemotherapeutic elimination of helminth infections is generally not amenable to agents that would solely disrupt proliferation. Indeed, where determined, a large number of agents that display chemotherapeutic efficacy do so by disrupting energy-generating and related sequences, neurotransmission or neuromuscular events. Thus, in the development of any multi-faceted approach to the effective chemotherapy of the parasitic helminths, it is essential to understand and evaluate the energetic mechanisms of these systems. Such evaluations are required 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. A vast number of the helminth parasites are predominantly anaerobic and accumulate succinate, or products derived from succinate, as the result of carbohydrate dissimilation. Succinate is formed by the required, anaerobic, mitochondrial electron transport mechanism of the helminths. The research proposed addresses a totally novel aspect of the biochemistry of parasitic helminths, viz., the metabolic impact of proton translocation/membrane energization as this relates to the characteristically anaerobic, mitochondrial energetics of the helminths. Data accumulated, employing the adult cestode, Hymenolepis diminuta as the model, indicate that mitochondrial, inner membrane-associated NADPH:NAD transhydrogenase engages not only in hydride transfer but in transmembrane proton translocation. Therefore, characterization of this enzyme and the development of a proton-translocating, NADPH:NAD transhydrogenase-containing liposome system are proposed. The H. diminuta electron transport mechanism also will be studied in terms of characterization/isolation of NADH dehydrogenase, """"""""Complex I"""""""" (NADH-rhodoquinone reductase) and Mg++-dependent ATPase. Furthermore, a study of the possible occurrence of an NADPH:NAD system in the adult nematode, Ascaris suum, will aid considerably in the elucidation of functional significance. Lastly, comparative studies of the A. suum """"""""Complex 1"""""""" and electron transport system, in light of the H. diminuta model, will contribute significantly to an understanding of the molecular make up of mitochondrial electron transport in the helminths.
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