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.
