LEISHMANIA METABOLISM: NEW THERAPEUTIC APPROACH TO INFECTION UNCOVERED

         Scientists from the Bio21 Institute at the University of Melbourne have come up with a novel technique for understanding infectious parasites and bacteria using labeled carbon atoms (¹³C). In a paper published in the Journal of Biological Chemistry, they followed the intracellular and secretion metabolites of the labeled carbon atoms using gas chromatography mass spectrometry and ¹³C NMR. Specifically, the scientists investigated the metabolic mechanism of Leishmania parasites as they “proliferate within nutritionally complex niches in their sandfly vector and mammalian hosts”. Leishmania parasites possess the ability to infect many animals and therefore treatment and vaccine development has been made difficult.

         Leishmania results in a wide spectrum of diseases in humans that range from “self-limiting cutaneous infections to disseminating infections that can lead to severe morbidity and death,” infecting more than 12 million people with 50,000 deaths annually.  The study lead by Dr. Malcolm McConville attempts to narrow the gaps in understanding the carbon metabolism of Leishmania, with the eventual intention to develop insight into possible new therapeutic pathways.

         The glycosome is an important localization point for many enzymes involved in the glycolytic pathway of Leishmania. Specifically, glycosomal succinate fermentation was responsible for the regeneration of ATP and NAD+ that was consumed in the upper glycolytic pathway, which is facilitated by enzymes sequestered within glycosomes. The tricarboxylic acid cycle (TCA cycle) was found to catabolize most of the C4 dicarboxylic acids generated during succinate fermentation. TCA cycle anaplerosis (intermediate reactions) was thus needed to sustain glutamate production in Leishmania.

         These results encouraged researchers to experimentally inhibit mitochondrial metabolic pathways within Leishmania, keeping in mind the implications as a potential avenue for therapy. Using Sodium fluoroacetate they were able to inhibit mitochondrial aconitase and they witnessed the rapid depletion of intracellular glutamate pools and growth arrest. Exogenous application of a high concentration of glutamate was found to alleviate the witnessed growth arrest. They concluded a tight coupling between glycosomal and mitochondrial metabolism pathway in Leishmania promastigotes. Furthermore, they suggest that somewhat surprisingly, the TCA cycle in Leishmania has crucial anabolic functions not witnessed in some other trypanosomatid parasites. The carbon labeling technique for understanding carbon metabolic pathways in parasites may have valuable potential in drug development and the discovery of unexpected parasitic metabolic processes.

REFERENCE: McConville et al. Isotopomer Profiling of Leishmania mexicana Promastigotes Reveals Important Roles for Succinate Fermentation and Aspartate Uptake in Tricarboxylic Acid Cycle (TCA) Anaplerosis, Glutamate Synthesis, and Growth. Journal of Biological Chemistry. 2011: 31(286) 27706-27717.