Abstract
Formycin B is cytotoxic toward Leishmania and is a potential chemotherapeutic agent for leishmaniasis. In order to determine the mechanism of action of formycin B, we have isolated and characterized clonal populations of formycin B-resistant Leishmania donovani. These formycin B-resistant clones are also cross-resistant to formycin A and allopurinol riboside-mediated growth inhibition. Incubation of the formycin B-resistant cells with [3H]formycin B indicates that, unlike wild type cells, the resistant populations cannot accumulate phosphorylated metabolites of exogenous [3H]formycin B. This is due to a defective transport system for formycin B in the resistant cells. However, wild type and mutant cells incorporate [3H]formycin A equally efficiently into [3H]formycin A-containing nucleotides and into RNA. These data suggest that formycin B cytotoxicity in Leishmania is not mediated by its incorporation as the adenosine analog into RNA. A plausible alternative hypothesis is proposed for the mechanism of action of the pyrazolo(4,3-d)pyrimidine C-nucleosides based upon depletion of an essential intracellular metabolite.
Original language | English (US) |
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Pages (from-to) | 7637-7643 |
Number of pages | 7 |
Journal | Journal of Biological Chemistry |
Volume | 259 |
Issue number | 12 |
State | Published - 1984 |
ASJC Scopus subject areas
- Biochemistry
- Molecular Biology
- Cell Biology