Pi inhibits intracellular accumulation of methylglyoxal in promastigote form of L. donovani.

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 (Sb(III)) 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, Sb(III) 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.