| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 2829707 | Molecular and Biochemical Parasitology | 2016 | 7 Pages |
•This knowledge of methylglyoxal metabolism can be exploited to treat parasitic diseases.•Understanding the detoxification of MG can restore antimony sensitivity.•Detoxification of MG is done via two methods excretion and glyoxalase pathway.•Parasite prefers excretion as major mode of detoxification over glyoxalase pathway.•Pi inhibits production and promotes excretion of MG, thus no cellular accumulation.
Similar to their mammalian counterpart, protozoan parasites including Leishmania donovani detoxify methylglyoxal (MG), 1 a toxic ubiquitous product generated in glycolysis pathway. However, it differs in one or more way(s) from the humans. It is known that MG is eliminated either through glyoxalase (GLO)2 pathway and/or excreted across the cell membrane. This toxic metabolic by-product is known to be detoxified predominantly by the GLO pathway and excretion across the cell membrane is never considered to be a significant pathway for its detoxification. We have tried to modulate these pathways under various physiological conditions to find ways that may lead to accumulation of MG in L. donovani. Besides targeting the GLO pathway, we intend to understand the mechanism of MG release across the cell membrane and possible ways to inhibit its exclusion from parasites. In our study, it was found that inorganic phosphate (Pi) 3 in the presence of glucose inhibits the production of MG as well as promotes the expulsion of MG from the cell. Moreover, the trivalent form of antimony (SbIII) inhibits GLO pathway and thus detoxification of MG. Inhibition of Pi transport, which is a Na+/H+ dependent process, restores the Pi mediated abrogation of MG production. Thus, SbIII along with inhibitors of Pi transporter may be a therapeutic advancement for treatment of antimony resistant cases of human visceral leishmaniasis. However, it requires further validation using specific inhibitor(s) of Pi transporter.
Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (166 K)Download as PowerPoint slide
