Chapter 23. Nucleotide Metabolism in Parasitic Protozoa

Abstract

Publisher Summary A variety of human and animal diseases are caused by parasitic protozoa including malaria, chagas disease (South American trypanosomiasis), african trypanosomiasis, giardiasis, leishmaniasis, coccidiosis, and toxoplasmosis. The nudeotide metabolism of these organisms often differs strikingly from the metabolism of the host mammalian cells. This chapter covers some of the major chemotherapeutic studies carried out on parasitic protozoa recently in the area of purine or pyrimidine nucleotide metabolism. The designation R after a compound number stands for β -D-riboside, RP for the 5' monophosphate and RP 3 , for the 5' triphosphate. This chapter discusses pyraaolopyrimidine analogs, inosine analogs, Formyun B, thiopuinol analogs, inhibition of guanine nucleotide formation, thymidylate synthetase-dihydrofolate reductase, deoxynucleoside phosphotransferase, adenosine deaminase, GMP reductase, and guanine aminohydrolase. Derivatives of pyraaolopyrimidine, including the parent compound albpcrinol, have been intensively studied because they are metabolized in an unusual lay by pathogenic parasitic protozoa of the genera Leishmania and Trypanosoma, which results in antiparasitic activity. The parasite has high levels of hypxanthine guanine phophoribosyl transferase, HCPRTase, which phosphoribosylates the purine analog, and also lacks xanthine oxidase to catalyze oxidation to oxypuinol, which occurs readily in mammalian cells. The succino-AMP synthetase and sucuno-AMP lyase, which normally carry out the conversion of IMP to AMP, have been shown to convert 1-RP to 2-RP if the enzyme from Leishmania donovani or Tranosoma cruzi is used, whereas no conversion occurs with the mammalian enzyme. Guanine nucleotide production in parasitic protoma has been examined as a target in several parasitic protoma. IMP dehydrogenase is responsible for the conversion of inosine monophosphate (IMP) to xanthosine monophosphate (XMP), from which CMP is made. Inhibition of this enzyme using mycophenolic acid decreased guanine nucleotide synthesis in Leishmania tropica promastigotes.