Trypanosomiasis

All living organisms make ATP as an energy carrier. This is produced mainly by the oxidation of carbohydrates using glycolysis and the tricarboxylic acid (TCA) cycle (figure 6). Because free living organisms (like us) do not have an abundance of food, we rely on the much more efficient TCA cycle for most of our ATP production. The trypanosome meets very different environments at different stages of its life cycle. In the mammalian blood stream there is an abundance of oxygen and glucose. The opposite is true in the insect gut or hemolymph. This is reflected in the number of reactions of glycolysis and TCA cycle that can be carried out and in the elaboration of the kinetoplast/mitochondrion. Clearly, if an organism can dispense with the TCA cycle it can also dispense with its mitochondrion. The forms of T. brucei in the insect gut have a full complement of TCA and glycolysis enzymes. This is not surprising since nutrients are NOT abundant; in most organisms that use oxidative phosphorylation, ATP production is sensitive to cyanide because cytochromes a/a3 react with cyanide and can no longer transfer an electron to oxygen to form water; however, oxidative phosphorylation in the insect gut forms of Trypanosomes is only PARTIALLY CYANIDE SENSITIVE. Cytochrome a/a3 system is still CN--sensitive but in Trypanosomes there is an additional cytochrome O which is CN- - insensitive. Little is known about the cytochrome O system. In the insect, partial aerobic fermentation produces succinate, pyruvate, acetate as well as carbon dioxide. Proline is a major fuel source. The forms of T. brucei in the mammalian bloodstream use only inefficient glycolysis because there is so much nutrient available; since glycolysis produces much less ATP than the TCA cycle, respiration is 50 times that of normal mammalian cell and in the bloodstream, T. brucei uses 10 times the amount of fuel as in insect gut. Note from biochemistry lectures. If you use only glycolysis to make ATP as is done in anaerobic respiration in our muscles or in yeast, you cannot just excrete pyruvate, which is what the trypanosome does in fact do, since you will quickly reduce all of your NAD+ to NADH and the whole pathway will stop for lack of oxidized substrate. We convert pyruvate to lactate while yeast converts it to ethanol to oxidize our NADH back to NAD+ and keep glycolysis going. Trypanosomes excrete pyruvate and have another way of converting NADH back to NAD+. In trypanosomes, dihydroxyacetone phosphate metabolism is necessary for reoxidation of NADH. This is an aerobic system, however, requiring oxygen but oxygen consumption is CN- - insensitive so it does not use the usual cytochrome chain. An FAD-containing dehydrogenase linked to copper containing oxidase. This complex is the glycerophosphate oxidase system. Trypanosomes in the bloodstream depend on this mechanism of keeping NAD oxidized. This system is the target of two trypanocidal drugs: SURAMIN and SHAM (salicylhydroxamic acid) which is a chelating agent. Terminal oxidase contains copper. These drugs have their specificity because this is a metabolic pathway that mammals do not use. There is another oddity in the trypanosomes' metabolism of carbohydrates. Unlike mammalian cell, first nine reactions of glycolysis are organelle-associated (GLYCOSOME). Why trypanosomes need to compartmentalize glycolysis is not clear. A compartment does mean that all of the enzymes are concentrated in one place but diffusion does not seem to be limiting in cells that do not have glycosomes.