Common pathways and outliers in glucose catabolism across Trypanosomatidae

Glucose catabolism in trypanosomatids differs significantly from that in most other eukaryotes. Here, the first few enzymes of the pathway are all located inside glycosomes, that is, the peroxisome-like microbodies uniquely present in the Kinetoplastida and Diplonemida of the Euglenozoa. Glycosomal AMP/ADP/ATP and NAD(H)⁺ pools cannot freely equilibrate with their corresponding cytosolic pools, and any ATP and NAD⁺ consumed within the organelles have to be regenerated inside to maintain the redox balance and glycolytic flux. Analyses of the reported end-products of both aerobic and anaerobic glucose catabolism experiments in various trypanosomatids have revealed that the ability to maintain the intra-glycosomal ATP/ADP energy balance and NAD⁺/NADH redox balance is essentially limited to three pathways. 1) Under aerobic conditions, glycosomal NADH is preferably reoxidized indirectly by molecular oxygen via a dihydroxyacetone phosphate/glycerol-3-phosphate shuttle which links to the mitochondrial respiratory chain, where either an alternative oxidase or a cytochrome oxidase functions as terminal oxidases. 2) Under oxygen starvation or limited activity of enzymes of the DHAP/G3P shuttle, glycosomal NADH is reoxidized by a redirection of part of the cytosolic PEP towards the glycosome, where it is reduced to succinate. 3) A succinate/fumarate/malate cycle permits an exchange of succinate and malate between the glycosome/cytosol and the mitochondrion via a mitochondrial dicarboxylate carrier, whereby succinate is oxidized to fumarate by the mitochondrial succinate dehydrogenase (complex II). In parallel, trypanosomatids have evolved various pathways to form sufficient ATP to satisfy their energy requirements. Some trypanosomatids survive true anaerobiosis through pyruvate dismutation or fermentation of propionic acid.