Leishmania donovani utilizes D-lactate pathway for pyruvate production under hypophosphatemic conditions

Methylglyoxal (MG), a toxic metabolite of the glycolysis pathway, is converted to D-lactate in the Leishmania parasite. Our previous study shows the importance of inorganic phosphate (Pi) in MG synthesis and its intracellular accumulation. No microscopic signs of adverse effects were observed in the Leishmania parasite at high MG concentrations. We hypothesize that under hypophosphatemic (Pi-deficient) conditions, D-lactate is converted to pyruvate with the help of a functionally uncharacterized lactate dehydrogenase (LDH) like protein in the Leishmania parasite. Under the Pi-deficient state, the glycolytic pathway was skewed towards the MG production from glyceraldehyde-3-phosphate. Increased glyoxalase (GLO)-I and II, LDH-like protein, and pyruvate concentrations were found under hypophosphatemic conditions. Antimony (Sb) is toxic to the Leishmania parasite by disrupting thiol homeostasis. Sb was shown to increase MG concentrations by inhibiting the GLO pathway, and to decrease LDH-like protein and pyruvate levels. We conclude that under hypophosphatemic conditions, the glycolysis pathway is compromised, and to fulfill energy requirements, the Leishmania donovani parasite converts D-lactate into pyruvate to replenish its energy levels.