Protein trafficking in kinetoplastid protozoa

Abstract

The kinetoplastid protozoa infect hosts ranging from invertebrates to plants and mammals, causing diseases of medical and economic importance. They are the earliest-branching organisms in eucaryotic evolution to have either mitochondria or peroxisome-like microbodies. Investigation of their protein trafficking enables us to identify characteristics that have been conserved throughout eucaryotic evolution and also reveals how far variations, or alternative mechanisms, are possible. Protein trafficking in kinetoplastids is in many respects similar to that in higher eucaryotes, including mammals and yeasts. Differences in signal sequence specificities exist, however, for all subcellular locations so far examined in detail--microbodies, mitochondria, and endoplasmic reticulum--with signals being more degenerate, or shorter, than those of their higher eucaryotic counterparts. Some components of the normal array of trafficking mechanisms may be missing in most (if not all) kinetoplastids: examples are clathrin-coated vesicles, recycling receptors, and mannose 6-phosphate-mediated lysosomal targeting. Other aspects and structures are unique to the kinetoplastids or are as yet unexplained. Some of these peculiarities may eventually prove to be weak points that can be used as targets for chemotherapy; others may turn out to be much more widespread than currently suspected.

Selective Tight Binding Inhibitors of Trypanosomal Glyceraldehyde-3-phosphate Dehydrogenase via Structure-Based Drug Design

“…Sleeping sickness, caused by the protozoon Trypanosoma brucei , is considered by the World Health Organization to be one of the main tropical parasitic diseases, in which parasites invade and then freely live in the bloodstream of the mammalian host. , The disease is fatal if left untreated. , Existing chemotherapy − has serious drawbacks, including severe side effects, low efficacy, increasing resistance, and no effect on the most virulent form of sleeping sickness caused by T. brucei rhodesiense . Other diseases caused by Trypanosomatidae include leishmaniasis ( Leishmania genus) and Chagas disease ( Trypanosoma cruzi ). , …”

“…The work presented here focuses on glycolysis in trypanosomes as a target for structure-based drug design. It has been shown that upon going from insect to bloodstream form the parasites become fully dependent on glycolysis for energy production. ,, Inhibiting glycolysis in parasites would be expected to slow their proliferation, as has been shown by Clarkson and Brohn for the combination of salicylhydroxamic acid and glycerol . Since the kinetic parameters for all of the enzymes in the glycolytic pathway in T. brucei are known, it has been possible to simulate parasite glycolytic flux in computro . , Based on the computational result that the presence of a competitive inhibitor of hexokinase at a concentration in the range of 0− K I ( K I is the dissociation equilibrium constant for the E·I complex) has little effect on glycolytic flux, it has been argued that competitive inhibitors of glycolytic enzymes will not be useful for blocking energy production …”

“…Other diseases caused by Trypanosomatidae include leishmaniasis (Leishmania genus) and Chagas disease (Trypanosoma cruzi). 2,4 The work presented here focuses on glycolysis in trypanosomes as a target for structure-based drug design. It has been shown that upon going from insect to bloodstream form the parasites become fully dependent on glycolysis for energy production.…”

Manipulating and elucidating mitochondrial gene expression with engineered proteins

“…To study the function of mtRNAs in kinetoplastids, synthetic PUF-PIN proteins were designed to target a specific GUUAUUGG sequence in the 3 0 -UTR of the edited transcript of the A6 subunit of the mitochondrial FoF1-ATPase [112]. These PUF-PIN proteins contained an N-terminal MTS from dihydroplipoyl dehydrogenase [118]. An A6-ASRE without a MTS (A6-ASRE (−) ) was used as a control.…”

Leishmanioses do continente americano

“…Na Leishmania, ele tem estrutura similar à observada em células de mamíferos, sendo encontrado entre o núcleo e cinetoplasto na região anterior do parasito (Figura 8). Estudos citoquímicos têm demonstrado a participação do complexo de Golgi no processo de glicosilação de glicoconjugados (Clayton, Häusler & Blattner, 1995).…”