Bakker, Mensonides, Teusink, van Hoek, Michels, Westerhoff, 2000

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Model Structure

Salivarian trypanosomes are extracellular parasites of the blood and tissue fluids of mammals. When it is within the bloodstream of its host Homo sapiens, Trypanosoma brucei, (the parasite that causes African sleeping disease in humans), displays very simple metabolism. In the bloodstream form (within its host) the parasite lacks a Krebs cycle and oxidative phosphorylation, and its metabolism is restricted to the glycolytic pathway alone. As in all trypansomes, most of the glycolytic enzymes of Trypanosoma brucei are contained within a specialised organelle called a glycosome (see the figure below). In addition to this structural difference between trypanosomes and other eukaryotic cells, trypanosomes also display differences at the biochemical level of their metabolism. Their glycolitic pathway is simpler, with few side chains and reduced allosteric enzymatic regulation. These differences between the host and parasite metabolism make the glycolytic pathway a potential target for drugs against African sleeping disease.

Most of the glycolytic enzymes of Trypanosoma brucei have been isolated and kinetically characterised. From this experimental data in 1997, Bakker et al developed a mathematical model of trypanosomal glycolysis (see Bakker et al, 1997 for more details). Model simulations predict how the steady-state glycolytic flux and metabolite concentrations depend on the substrate and product concentrations and the enzyme-kinetic parameters. The model explains certain aspects of cell physiology, but it does have its limitations.

Bloodstream-form trypanosomes contain 65-250 glycosomes, comprising 4 percent of the total cell volume. It is unclear why glycosomes are advantageous organelles for trypanosomes. At present, it is not possible to remove a glycosome without affecting the rest of the cell. In order to study the metabolic consequences of compartmentation, in 2000, Bakker et al., in a follow up study to their 1997 paper, developed a mathematical model which lacked a glycosomal membrane. This model has been described here in CellML and it can be downloaded in various formats as described in .

Although removal of the membrane did not affect steady-state flux (which argues against the idea that glycosomes increase flux by concentrating the pathway enzymes), it did cause the following:

  • The concentration of sugar phosphates rose to unphysiological levels, which was suggested to have pathological consequences; and

  • The cells failed to recover from glucose deprivation.

These results were explained by the biochemical organisation of the glycosome, and the authors concluded that the glycosome protects trypanosomes from the negative side effects of the turbo structure of glycolysis; that is, ATP is consumed before it is produced. The glycosome prevents a starving cell from consuming the ATP required to reinitiate glycolysis.

The complete original paper reference is cited below:

Compartmentation protects trypanosomes from the dangerous design of glycolysis, Barbara M. Bakker, Femke I.C. Mensonides, Bas Teusink, Pim van Hoek, Paul A. M. Michels, and Hans V. Westerhoff, 2000, Proceedings of the National Academy of Sciences , 97, 2087-2092. (Full text and PDF versions of the article are available to subscribers of the pnas website.) PubMed ID: 10681445

A scheme of glycolysis in the bloodstream form of the parasite Trypanosoma brucei. In the model described here, the glycosome is absent.