Compartmentation of glycolysis in trypanosomes: a potential target for new trypanocidal drugs.

In African trypanosomes most enzymes of the glycolytic pathway are found in a microbody-like organelle, called the glycosome. The analysis of their structural and functional properties has shown that these glycosomal enzymes possess some specific features which are absent from the cytosolic proteins of trypanosomes and from the glycolytic enzymes of other organisms, where glycolysis is not compartmentalized within an organelle. The specific properties of the glycosomal enzymes may be responsible for the routing of the proteins from their site of synthesis, the cytosol, into the glycosome, or they may be involved in the proper functioning of the enzymes within the organelle. Whatever the role of the unique features, they are potential targets for compounds that could specifically interfere with glycolysis in trypanosomes. Therefore, a detailed study of the glycolytic enzymes of trypanosomes may lead to the development of therapeutically useful drugs against these harmful parasites

The evolutionary origin of glycosomes.

The glycolytic pathway of the Kinetoplastida is organized in a unique manner: the majority of its enzymes are contained in organelles called glycosomes. In this article Paul Michels and Fred Opperdoes argue that the glycosomes are equivalent to the microbodies and peroxisomes identified in other eukaryotic cells. They explore the possible evolutionary origin of the glycosome by comparing many of its structural and functional properties with those of other members of the microbody family and with some features of other organelles, the mitochondria and chloroplasts, which have been studied in much more detail

Enzymes of carbohydrate metabolism as potential drug targets.

The potential for chemotherapeutic exploitation of carbohydrate metabolism in the Trypanosomatidae is reviewed. This review is based largely on discussions held at a meeting of the COST B9 Action, entitled 'Bioenergetics of Protozoan Parasites'. The major questions posed were: which enzymes are the best to target; what further information is required to allow their use for rational drug development; what compounds would constitute the best inhibitors and which of the enzymes of the pentose-phosphate pathway are present inside the glycosomes, as well? Only partial answers could be obtained in many cases, but the interactive discussion between the multidisciplinary group of participants, comprising chemists, biochemists and molecular biologists, provided thought-provoking ideas and will help direct future research

The evolution of kinetoplastid glycosomes

The available data on carbohydrate metabolism in Kinetoplastida have been reviewed. Based on the metabolic pattern of different kinetoplastid organisms, on the subcellular distribution of their glycolytic enzymes, and on the structural and regulatory properties of these proteins, we propose that the glycosome developed from an endosymbiont, as a specific manner to control carbohydrate and energy metabolism. It is discussed how the enzymes were subcellularly recompartmentalized during evolution as adaptation to the environment encountered by the organisms

Horizontal gene transfer in trypanosomatids.

Trypanosomes harbour a large number of structural and biochemical peculiarities. Kinetoplast DNA, mitochondrial RNA editing, the sequestration of glycolysis inside glycosomes and unique oxidative-stress protection mechanisms (to name but a few) are found only in the members of the order Kinetoplastida. Thus, it is not surprising that they have provoked much speculation about why and how such oddities have evolved in trypanosomes. However, the true reasons for their existence within the eukaryotic world are still far from clear. Here, Fred Opperdoes and Paul Michels argue that the trypanosome-specific evolution of novel processes and organization could only have been made possible by the acquisition of a large number of foreign genes, which entered a trypanosomatid ancestor through lateral gene transfer. Many different organisms must have served as donors. Some of them were viruses, and others were bacteria, such as cyanobacterial endosymbionts and non-phototrophic bacteria

Comparison of the peroxisomal matrix protein import system of different organisms. Exploration of possibilities for developing inhibitors of the import system of trypanosomatids for anti-parasite chemotherapy.

In recent decades, research on peroxisome biogenesis has been particularly boosted since the role of these organelles in metabolism became unraveled. Indeed in plants, yeasts and fungi, peroxisomes play an important role in the adaptation of metabolism during developmental processes and/or altered environmental conditions. In mammals their importance is illustrated by the fact that several severe human inherited diseases have been identified as peroxisome biogenesis disorders (PBD). Particularly interesting are the glycosomes - peroxisome-like organelles in trypanosomatids where the major part of the glycolytic pathway is sequestered - because it was demonstrated that proper compartmentalization of matrix proteins inside glycosomes is essential for the parasite. Although the overall process of peroxisome biogenesis seems well conserved between species, careful study of the literature reveals nonetheless many differences at various steps. In this review, we present a comparison of the first two steps of peroxisome biogenesis - receptor loading and docking at the peroxisomal membrane - in yeasts, mammals, plants and trypanosomatids and highlight major differences in the import process between species despite the conservation of (some of) the proteins involved. Some of the unique features of the process as it occurs in trypanosomatids will be discussed with regard to the possibilities for exploiting them for the development of compounds that could specifically disturb interactions between trypanosomatid peroxins. This strategy could eventually lead to the discovery of drugs against the diseases caused by these parasites