RESEARCH-UNIT FOR TROPICAL DISEASES (TROP)

Leader: Fred R. OPPERDOES
Email: opperdoesbchm.ucl.ac.be
website: www.icp.ucl.ac.be/trop/
contact: BCHM-TROP
               Avenue Hippocrate 74 UCL 74.39
               1200 BRUXELLES
               Tel: +32 2/764.74.39
               Fax: +32 2/762.68.53
TROP Unit Directory (People)
Research interest
    Metabolic Compartmentation in Trypanosomes: Trypanosomes are responsible for human sleeping sickness in tropical Africa and for a similar disease called ‘nagana' in cattle. These are very serious diseases, with fatal outcome if left untreated. The presently available drugs are not very efficient and cause serious side effects. Moreover, development of drug resistant parasites is becoming a major problem. Therefore new drugs are badly needed.
    Trypanosoma brucei, when it resides in the mammalian bloodstream, relies entirely on glycolysis for its ATP supply. Moreover, the parasite is characterized by a unique form of metabolic compartmentation; the majority of the enzymes of the glycolytic pathway is sequestered in peroxisomelike organelles called glycosomes. For the above reasons the glycolytic pathway is considered a validated and promising target for new drugs to be designed. Since many years we study the kinetic and structural properties of the glycolytic enzymes of T. brucei and closely related parasites such as Trypanosoma cruzi and Leishmania mexicana, and use the collected information for the design of effective and selective inhibitors by structure-based and catalytic mechanism-based approaches. In addition our research aims at understanding what controls the glycolytic flux in vivo. The flux control is being studied in a quantitative manner by using a mathematical model prepared on the basis of the experimentally determined kinetic properties of all enzymes constituting the pathway, and by in vivo experiments in which the activity of different enzymes of the pathway is varied by either biochemical or genetic means. Such experiments could provide both insight into the consequences of
the compartmentation of the pathway and information as to which enzymes of the pathway are the best targets for drugs.
    Several enzymes of another pathway of carbohydrate metabolism: the hexose monophosphate pathway, involved in the generation of intermediates essential for cell growth, cell division and protection against oxidative stress, are associated with the glycosomes as well. This triggered the interest in their function as glycosomal proteins. Not only the role of the glycosome in trypanosomatid metabolism is the topic of the research, but also the assembly of the organelle. This group is studying the proteins, called peroxins, involved in glycosome biogenesis and particularly the mechanism by which they accomplish the import of matrix proteins.
Leader: Fred R. OPPERDOES(opperdoesbchm.ucl.ac.be)
               Paul A.M. MICHELS(michelsbchm.ucl.ac.be)