Biochemical genetic analysis of formycin B action in Leishmania donovani

N. Robinson, K. Kaur, K. Emmett, D. M. Iovannisci, B. Ullman

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13 Scopus citations

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 languageEnglish (US)
Pages (from-to)7637-7643
Number of pages7
JournalJournal of Biological Chemistry
Volume259
Issue number12
StatePublished - Aug 23 1984

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Robinson, N., Kaur, K., Emmett, K., Iovannisci, D. M., & Ullman, B. (1984). Biochemical genetic analysis of formycin B action in Leishmania donovani. Journal of Biological Chemistry, 259(12), 7637-7643.