Carbohydrate Metabolism in Trypanosomatids: New Insights Revealing Novel Complexity, Diversity and Species-unique Features

The human pathogenic trypanosomatid species collectively called the "TriTryp parasites" - Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. - have complex life cycles, with each of these parasitic protists residing in a different niche during their successive developmental stages where they encounter diverse nutrients. Consequently, they adapt their metabolic network accordingly. Yet, throughout the life cycles, carbohydrate metabolism - involving the glycolytic, gluconeogenic and pentose-phosphate pathways - always plays a central role in the biology of these parasites, whether the available carbon and free energy sources are saccharides, amino acids or lipids. In this paper, we provide an updated review of the carbohydrate metabolism of the TriTryps, highlighting new data about this metabolic network, the interconnection of its pathways and the compartmentalisation of its enzymes within glycosomes, cytosol and mitochondrion. Differences in the expression of the branches of the metabolic network between the successive life-cycle stages of each of these parasitic trypanosomatids are discussed, as well as differences between them. Recent structural and kinetic studies have revealed unique regulatory mechanisms for some of the network's key enzymes with important species-specific variations. Furthermore, reports of multiple post-translational modifications of trypanosomal glycolytic enzymes suggest that additional mechanisms for stage- and/or environmental cues that regulate activity are operational in the parasites. The detailed comparison of the carbohydrate metabolism of the TriTryps has thus revealed multiple differences and a greater complexity, including for the reduced metabolic network in bloodstream-form T. brucei, than previously appreciated. Although these parasites are related, share many cytological and metabolic features and are grouped within a single taxonomic family, the differences highlighted in this review reflect their separate evolutionary tracks from a common ancestor to the extant organisms. These differences are indicative of their adaptation to the different insect vectors and niches occupied in their mammalian hosts.