It is proposed to continue biochemical studies of parasitic helminths which have been inaugurated over the previous 14 years of this proposal (AI-09483). Particular emphasis will continue to be placed on the intestinal roundworm, Ascaris suum, the filariids, Brugia pahangi, Litomosoides carinii and Dipetalonema viteae; the cestodes Hymenolepis diminuta and Spirometra mansonoides; and the trematode Faciole hepatica. A number of striking differences have become apparent between the host and parasite metabolisms. These differences have been shown to exist at the level of overall metabolic pathways, including energy yielding reactions, as well as at the more subtle level of enzyme kinetics, structure and intracellular distribution of enzymes. Such differences are vulnerable to chemotherapeutic attack. Detailed metabolic studies of the parasitic helminths will continue in an effort to attain a more precise appreciation of the comparative aspects of host and parasite biochemistry which, in turn, is essential for a more basic understanding of host-parasite and parasite-drug interactions. Specific areas of investigation will include: a) The mechanism of formation of succinate and volatile fatty acids by adult Ascaris. b) Comparative studies of energy generating reactions in the mitochondria of Ascaris and other helminths. These are quite different from the corresponding reactions of mammalian systems, and include substrate level phosphorylation from the decarboxylation of succinate to propionate, as well as the electron transport system associated generation of ATP from the fumarate reductase reaction. C) The metabolism of the Ascaris reproductive system, whish differs considerably from that of the nematode muscle, will be examined. Interrelationships between the muscle and reproductive metabolisms will be studied. d) Studies will be inaugurated concerning the function of highly cristaeted mitochondria in the apparently homolactate fermenting filariid parasites. This will include amino acid and fatty acid oxidizing capabilities. e) Additional vulnerable sites for anthelmintic activity and the modes of action of anthelmintics upon metabolic reactions in the parasite will be considered. f) New techniques of electrophysiology and neuropharmacology of D. viteae are being developed employing microelectrodes placed in individual somatic muscle cells. g) The invasive technique of 31P Nuclear Magnetic Resonance will be employed to examine metabolism and drug action in intact Ascaris and Fasciola hepatica.
