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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI015597-12
Application #
2060240
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1979-01-01
Project End
1997-04-30
Budget Start
1994-05-01
Budget End
1995-04-30
Support Year
12
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Bowling Green State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
617407325
City
Bowling Green
State
OH
Country
United States
Zip Code
43403
Holowiecki, Andrew; Fioravanti, Carmen F (2015) NADH?NAD? Transhydrogenation in Adult Ascaris suum Mitochondria. J Parasitol 101:358-63
Vandock, Kurt P; Mitchell, Martin J; Fioravanti, Carmen F (2012) Effects of plant flavonoids on Manduca sexta (tobacco hornworm) fifth larval instar midgut and fat body mitochondrial transhydrogenase. Arch Insect Biochem Physiol 80:15-25
Fioravanti, C F; Vandock, K P (2010) Transhydrogenase and the anaerobic mitochondrial metabolism of adult Hymenolepis diminuta. Parasitology 137:395-410
Vandock, Kurt P; Drummond, Christopher A; Smith, Stan L et al. (2010) Midgut and fatbody mitochondrial transhydrogenase activities during larval-pupal development of the tobacco hornworm, Manduca sexta. J Insect Physiol 56:774-9
Mercer-Haines, Nancy; Fioravanti, Carmen F (2008) Hymenolepis diminuta: mitochondrial transhydrogenase as an additional site for anaerobic phosphorylation. Exp Parasitol 119:24-9
Vandock, Kurt P; Smith, Stan L; Fioravanti, Carmen F (2008) Midgut mitochondrial transhydrogenase in wandering stage larvae of the tobacco hornworm, Manduca sexta. Arch Insect Biochem Physiol 69:118-26
Park, J P; Fioravanti, C F (2006) Catalysis of NADH-->NADP+ transhydrogenation by adult Hymenolepis diminuta mitochondria. Parasitol Res 98:200-6
Mercer, N A; McKelvey, J R; Fioravanti, C F (1999) Hymenolepis diminuta: catalysis of transmembrane proton translocation by mitochondrial NADPH-->NAD transhydrogenase. Exp Parasitol 91:52-8
Fioravanti, C F; Walker, D J; Sandhu, P S (1998) Metabolic transition in the development of Hymenolepis diminuta (Cestoda). Parasitol Res 84:777-82
Walker, D J; Burkhart, W; Fioravanti, C F (1997) Hymenolepis diminuta: mitochondrial NADH --> NAD transhydrogenation and the lipoamide dehydrogenase system. Exp Parasitol 85:158-67

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