Central carbon metabolism ofLeishmaniaparasites

Abstract

Leishmania spp. are sandfly-transmitted protozoa parasites that cause a spectrum of diseases in humans. Many enzymes involved in Leishmania central carbon metabolism differ from their equivalents in the mammalian host and are potential drug targets. In this review we summarize recent advances in our understanding of Leishmania central carbon metabolism, focusing on pathways of carbon utilization that are required for growth and pathogenesis in the mammalian host. While Leishmania central carbon metabolism shares many features in common with other pathogenic trypanosomatids, significant differences are also apparent. Leishmania parasites are also unusual in constitutively expressing most core metabolic pathways throughout their life cycle, a feature that may allow these parasites to exploit a range of different carbon sources (primarily sugars and amino acids) rapidly in both the insect vector and vertebrate host. Indeed, recent gene deletion studies suggest that mammal-infective stages are dependent on multiple carbon sources in vivo. The application of metabolomic approaches, outlined here, are likely to be important in defining aspects of central carbon metabolism that are essential at different stages of mammalian host infection.

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

“…A similar growth arrest can be induced by treating L. mexicana promastigotes with inhibitors of the respiratory chain (cyanide and antimycin) suggesting that oxidation of glucose in the TCA cycle is important for energy generation (20). However, respiratory chain inhibitors can also inhibit the operation of the TCA cycle 4 raising the possibility that growth inhibition may be a consequence of loss of TCA cycle anabolic functions, rather than decreased energy production. A major anabolic role for the TCA cycle was initially suggested by the finding that most of the C4 dicarboxylic acids generated by succinate fermentation are used to replenish TCA cycle intermediates.…”

“…There are no vaccines against any of these diseases, and current drug therapies are both limited and, in many cases, are being undermined by widespread resistance (2). Although the genomes of several Leishmania species have now been sequenced and key aspects of metabolism intensively studied, major gaps exist in our understanding of central carbon metabolism in these divergent eukaryotes (3,4). Given the importance of intermediary metabolism for parasite growth and protection against host microbicidal processes, detailed dissection of Leishmania carbon metabolism may reveal new therapeutic targets (4 -6).…”

Immunocytochemistry of Proteases in the Study of Leishmania Physiology and Host-Parasite Interaction

“…The glycolytic enzymes of Leishmania exhibited large phylogenetic distance with the mammalian hosts and, for this reasons, specific inhibitors have been designed for the most important regulator enzyme, the glyceraldehyde-3-phosphate dehydrogenase. These compounds inhibited growth of L. (L.) mexicana by blocking the energy production, since glycolysis is the most important source of energy for these parasites (Saunders et al, 2010). Furthermore, the biogenesis of these organelles occurs via peroxins self-interactions and the reduction of peroxin expression or their self-interaction inhibition induced the Leishmania death (Michels et al, 2006).…”

Increased Glycolytic ATP Synthesis Is Associated with Tafenoquine Resistance inLeishmania major

“…The first option can be ruled out in light of the fact that the ATP levels after treatment with sodium azide and deoxyglucose, which inhibits both mitochondrial synthesis and glycolysis, are significantly diminished. This indicates that R4 parasites cannot make use of other carbon sources, such as ␤-oxidation of fatty acids or the catabolism of certain amino acids (22). Experiments are under way to determine which glycolytic enzymes are upregulated and could therefore be used as molecular markers of TFQ resistance in Leishmania.…”