In the past few years we have discovered an important difference between the metabolism of purines and pyrimidines in schistosomes. It has been known that schistosomes are capable of de novo purine biosynthesis and rely totally on salvage pathways for their purine nucleotide requirements. We found that this is not the case with pyrimidines since both de novo and salvage pathways are operative in these parasites. In addition, several important differences in pyrimidine metabolism between schistosomes and mammals were also discovered. We wish to pursue this work further in an effort to reveal more exploitable biochemical differences between the host and parasite and to develop new chemotherapeutic agents.
Specific Aims are: (1) Detailed studies on pyrimidine metabolism in schistosomes including: (a) A survey of enzyme activities of pyrimidine metabolism in cell free extracts, and (b) A study of the uptake and metabolism of various natural pyrimidine bases and corresponding ribo- and deoxyribosides by whole worms in vitro; (2) The testing of pyrimidine analogues as antischistosomal drugs including: (a) The testing of various pyrimidine analogues as substrates or inhibitors of pyrimidine enzymes in cell free extracts, (b) The evaluation of the effect of enzyme inhibitors (e.g. benzylacyclouridine, 5-azaorotate), on the uptake and metabolism of pyrimidines by whole worms in vitro, (c) The testing of inhibitors as antischistosomal agents in vivo, and (3) The Partial purification and characterization of orotate phosphoribosyltransferase (OPRTase). A strain of S. mansoni originally obtained from Puerto Rico, and the life cycle maintained in this laboratory will be used for in vivo pharmacological studies, and live worms harvested from those mice will be employed in vitro biochemical investigations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Unknown (R22)
Project #
5R22AI022219-03
Application #
3444799
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1985-09-30
Project End
1989-06-30
Budget Start
1987-09-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1987
Total Cost
Indirect Cost
Name
Brown University
Department
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
Naguib, Fardos N M; El Kouni, Mahmoud H (2014) Nucleoside kinases in adult Schistosoma mansoni: phosphorylation of pyrimidine nucleosides. Mol Biochem Parasitol 194:53-5
el Kouni, Mahmoud H (2007) Adenosine metabolism in Toxoplasma gondii: potential targets for chemotherapy. Curr Pharm Des 13:581-97
el Kouni, Mahmoud H (2003) Potential chemotherapeutic targets in the purine metabolism of parasites. Pharmacol Ther 99:283-309
el Kouni, M H (1991) Efficacy of combination therapy with tubercidin and nitrobenzylthioinosine 5'-monophosphate against chronic and advanced stages of schistosomiasis. Biochem Pharmacol 41:815-20
el Kouni, M H; Naguib, F N (1990) Pyrimidine salvage pathways in adult Schistosoma mansoni. Int J Parasitol 20:37-44
el Kouni, M H; Diop, D; O'Shea, P et al. (1989) Prevention of tubercidin host toxicity by nitrobenzylthioinosine 5'-monophosphate for the treatment of schistosomiasis. Antimicrob Agents Chemother 33:824-7
el Kouni, M H; Naguib, F N; Niedzwicki, J G et al. (1988) Uridine phosphorylase from Schistosoma mansoni. J Biol Chem 263:6081-6
el Kouni, M H; Cha, S (1987) Metabolism of adenosine analogues by Schistosoma mansoni and the effect of nucleoside transport inhibitors. Biochem Pharmacol 36:1099-106
el Kouni, M H; Messier, N J; Cha, S (1987) Treatment of schistosomiasis by purine nucleoside analogues in combination with nucleoside transport inhibitors. Biochem Pharmacol 36:3815-21