title: A putative role for inosine 5' monophosphate dehydrogenase (IMPDH) in Leishmania amazonensis programmed cell death.
abstract: Leishmania amazonensis undergoes apoptosis-like programmed cell death (PCD) under heat shock conditions. We identified a potential role for inosine 5' monophosphate dehydrogenase (IMPDH) in L. amazonensis PCD. Trypanosomatids do not have a "de novo" purine synthesis pathway, relying on the salvage pathway for survival. IMPDH, a key enzyme in the purine nucleotide pathway, is related to cell growth and apoptosis. Since guanine nucleotide depletion triggers cell cycle arrest and apoptosis in several organisms we analyzed the correlation between IMPDH and apoptosis-like death in L. amazonensis. The L. amazonensis IMPDH inhibition effect on PCD was evaluated through gene expression analysis, mitochondrial depolarization and detection of Annexin-V labeled parasites. We demonstrated a down-regulation of impdh expression under heat shock treatment, which mimics the natural mammalian host infection. Also, IMPDH inhibitors ribavirin and mycophenolic acid (MPA) prevented cell growth and generated an apoptosis-like phenotype in sub-populations of L. amazonensis promastigotes. Our results are in accordance with previous results showing that a subpopulation of parasites undergoes apoptosis-like cell death in the nutrient poor environment of the vector gut. Here, we suggest the involvement of purine metabolism in previously observed apoptosis-like cell death during Leishmania infection.
authors.affiliation: Laboratório de Biologia Molecular de Parasitas e Vetores, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil. Electronic address: pitaluga@ioc.fiocruz.br.
authors.forename: A N
authors.initials: AN
authors.lastname: Pitaluga
authors.affiliation: Divisão de Medicina Experimental, Instituto Nacional de Câncer, Rio de Janeiro, Brazil.
authors.forename: M E C
authors.initials: ME
authors.lastname: Moreira
authors.affiliation: Laboratório de Biologia Molecular de Parasitas e Vetores, Instituto Oswaldo Cruz/FIOCRUZ, Rio de Janeiro, Brazil.
authors.forename: Y M
authors.initials: YM
authors.lastname: Traub-Csekö
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015971:Gene Expression Regulation, Enzymologic; D018869:Heat-Shock Response / Q000502:physiology; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors / Q000502:physiology*; D007894:Leishmania mexicana / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008807:Mice, Inbred BALB C; D009173:Mycophenolic Acid / Q000494:pharmacology; D009705:Nucleosides / Q000494:pharmacology; D011685:Purine Nucleotides / Q000378:metabolism; D016053:RNA, Protozoan / Q000302:isolation & purification; D012254:Ribavirin / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D009705:Nucleosides; D011685:Purine Nucleotides; D016053:RNA, Protozoan; C076145:3-(1-deoxyribofuranosyl)benzamide; D012254:Ribavirin; D007168:IMP Dehydrogenase; D009173:Mycophenolic Acid; C033706:tiazofurin
keywords: Apoptosis-like programmed cell death; IMPDH; Leishmania amazonensis; Mycophenolic acid (MPA); Ribavirin