Genetic dissection of nucleoside transport in Leishmiania dotnov alni indicates that the insect vector form of these parasites possesses two biochemically distinct nucleoside transport systems. The first transports inosine, guanosine, and formycin B, and the second transports pyrimidine nucleosides and the adenosine analogs, formycin A and tubercidin. Adenosine is transported by both systems. A mutant, FBD5, isolated by virtue of its resistance to growth inhibition by 5 ,uM formycin B, cannot efficiently transport inosine, guanosine, or formycin B. This cell line is also cross-resistant to growth inhibition by a spectrum of cytotoxic analogs of inosine and guanosine. A second parasite mutant, TUBA5, isolated for its resistance to 20 puM tubercidin, cannot take up from the culture medium radiolabeled tubercidin, formycin A, uridine, cytidine, or thymidine. Both the FBD5 and the TUBA5 cell lines have about a 50% reduced capacity to take up adenosine, indicating that adenosine is transported by both systems. A tubercidin-resistant clonal derivative of FBD5, FBD5-TUB, has acquired the combined biochemical phenotype of each single mutant. The wild-type and mutant cell lines transport purine bases and uracil with equal efficiency. Mutational analysis of the relative growth sensitivities to cytotoxic nucleoside analogs and the selective capacities to take up exogenous radiolabeled nucleosides from the culture medium have enabled us to define genetically the multiplicity and substrate specificities of the nucleoside transport systems in L. donovani promastigotes.The parasitic protozoa are the causative agents for a plethora of infectious diseases. Most of the major metabolic pathways in parasites are thought to be similar to those found in mammalian systems with one major exception. All the parasitic protozoa examined to date are incapable of de novo synthesis of the purine ring and are therefore auxotrophic for purines (14). Cultured forms of parasites are dependent on an exogenous source of purines for survival and growth, whereas intracellular parasites scavenge purines from their hosts. To meet their purine requirement, the parasites have evolved a series of unique purine salvage enzymes and cell surface functions for which no mammalian counterpart exists. Because nucleoside or nucleobase analogs are selectively metabolized by this unique purine salvage system, they are growth inhibitory and cytotoxic to parasitic protozoa but not to mammalian cells. For instance, allopurinol (4-hydroxypyrazolo[3,4,-d]pyrimnidine) (1, 15), allopurinol riboside (1, 19), thiopurinol (4-thiopyrazolo[3,4-d] pyrimidine) (15), thiopurinol riboside (15), and formycin B (7-hydroxy-3-,-D-ribofuranosyl-pyrazolo[4,3-d]pyrimidine)
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