Biochemical genetic analysis of formycin B action in Leishmania donovani.
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.
D000493:Allopurinol / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004351:Drug Resistance; D005573:Formycins / Q000494:pharmacology*; D007891:Leishmania / Q000187:drug effects / Q000235:genetics*; D011687:Purines / Q000494:pharmacology; D012313:RNA / Q000378:metabolism; D012263:Ribonucleosides / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D005573:Formycins; D011687:Purines; D012263:Ribonucleosides; C034561:formycin B; D012313:RNA; D000493:Allopurinol; C034550:formycin; C021958:allopurinol riboside