Schistosomiasis is estimated to afflict over 200 million people worldwide. Until a practical vaccine is available, chemotherapy will continue to be important both for treating infected individuals and in programs for controlling transmission within populations. Although several drugs are currently available for clinical use, some are effective against only a single species and the appearance of drug resistance is of increasing concern. Elucidation of biochemical mechanisms involved in drug-parasite interactions is important for understanding the molecular basis of both drug efficacy and resistance. Adult Schistosoma mansoni contain five cytosolic glutathione S- transferases, three of which have similar properties. Besides catalyzing the detoxication of xenobiotics, including some drugs, via conjugation with glutathione (GSH), these enzymes are expected to have endogenous metabolic functions. This proposal is designed to elucidate structural relationships and biochemical Functions of S. mansoni GSH S-transferases. Various biochemical methods, including recombinant DNA techniques, will be used to achieve the following objectives: 1) Purify and characterize the GSH S-transferase that catalyzes the detoxication of dichlorvos, the active form of metrifonate; 2) Test the hypothesis that S. mansoni GSH S-transferases are catalytically active monomeric proteins, rather than dimers; 3) Delineate some endogenous metabolic functions of these enzymes including catalysis of leukotriene C4 biosynthesis, protection against lipid peroxidation, and serving as intracellular ligand binding proteins; and 4) Isolate and analyze S. mansoni GSH S-transferase cDNA and genomic clones.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Unknown (R22)
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Tropical Medicine and Parasitology Study Section (TMP)
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University of Wisconsin Madison
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Milhon, J L; Albert, T J; Vande Waa, E A et al. (2000) SmMAK16, the Schistosoma mansoni homologue of MAK16 from yeast, targets protein transport to the nucleolus. Mol Biochem Parasitol 108:225-36
Thiboldeaux, R L; Lindroth, R L; Tracy, J W (1998) Effects of juglone (5-hydroxy-1,4-naphthoquinone) on midgut morphology and glutathione status in Saturniid moth larvae. Comp Biochem Physiol C Pharmacol Toxicol Endocrinol 120:481-7
Milhon, J L; Thiboldeaux, R L; Glowac, K et al. (1997) Schistosoma japonicum GSH S-transferase Sj26 is not the molecular target of praziquantel action. Exp Parasitol 87:268-74
Milhon, J L; Tracy, J W (1995) Updated codon usage in Schistosoma. Exp Parasitol 80:353-6
Vande Waa, E A; Campbell, C K; O'Leary, K A et al. (1993) Induction of Schistosoma mansoni glutathione S-transferase by xenobiotics. Arch Biochem Biophys 303:15-21
O'Leary, K A; Hathaway, K M; Tracy, J W (1992) Schistosoma mansoni: single-step purification and characterization of glutathione S-transferase isoenzyme 4. Exp Parasitol 75:47-55
Tracy, J W; O'Leary, K A (1991) Analysis of glutathione S-transferase-catalyzed S-alkylglutathione formation by high-performance liquid chromatography. Anal Biochem 193:1-5
O'Leary, K A; Tracy, J W (1991) Schistosoma mansoni: glutathione S-transferase-catalyzed detoxication of dichlorvos. Exp Parasitol 72:355-61
Siegel, D A; Tracy, J W (1989) Schistosoma mansoni: influence of the female parasite on glutathione biosynthesis in the male. Exp Parasitol 69:116-24
Holy, J M; O'Leary, K A; Oaks, J A et al. (1989) Immunocytochemical localization of the major glutathione S-transferases in adult Schistosoma mansoni. J Parasitol 75:181-90

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