Purine salvage in Leishmania: complex or simple by design?

Abstract

Purine nucleotides function in a variety of vital cellular and metabolic processes including energy production, cell signaling, synthesis of vitamin-derived cofactors and nucleic acids, and as determinants of cell fate. Unlike their mammalian and insect hosts, Leishmania cannot synthesize the purine ring de novo and are absolutely dependent upon them to meet their purine requirements. The obligatory nature of purine salvage in these parasites, therefore, offers an attractive paradigm for drug targeting, and consequently, the delineation of the pathway has been under scientific investigation for over 30 years. Here we review recent developments that reveal how purines flux in Leishmania and offer a potential ‘Achilles’ heel’ for future validation.

Comprehensive Proteomics Analysis of Glycosomes fromLeishmania donovani

“…Purines and pyrimidines are an important pool of biomolecules as these molecules acts as co-factors, precursors of nucleic acids, secondary messengers, and the energy currency of cells. A de novo purine biosynthesis pathway is absent in Leishmania and the parasite depends on its host for its purine requirements and also possess enzymes for the purine salvage pathway (Boitz et al, 2012). In comparison to purine salvage pathway, Leishmania parasites are prototrophs for pyrimdine and also express the pyrimidine salvage enzymes.…”

“…In comparison to purine salvage pathway, Leishmania parasites are prototrophs for pyrimdine and also express the pyrimidine salvage enzymes. In Leishmania and other related parasites, enzymes in purine and pyrimidine metabolism are compartmentalized inside glycosomes (Carter et al, 2008) and most of these enzymes have either the PTS-1 or PTS-2 motif (Boitz et al, 2012). …”

Mycophenolic Acid and Its Derivatives as Potential Chemotherapeutic Agents Targeting Inosine Monophosphate Dehydrogenase in Trypanosoma congolense

“…This enzyme is very important in the Trypanosoma spp. because it lacks a de novo purine synthesis pathway, which makes the purine nucleotide synthesis in these parasites solely dependent on a salvage pathway in the glycosomes (5)(6)(7). IMPDH converts IMP into XMP through this pathway, which is a rate-limiting step in the metabolism of guanine nucleotides (8).…”

Selection of Molecular Targets for Drug Development Against Trypanosomatids

“…Trypanosomatid parasites are totally defi cient in the de novo biosynthesis of purines, and rely on the scavenging from the host (Boitz et al 2012 ). Research on purine transport (nucleobase/nucleoside) has focused on the use of purine antimetabolites or specifi c inhibition of the host nucleoside transporters (de Koning et al 2005 ).…”