title: Sequencing, modeling, and selective inhibition of Trypanosoma brucei hexokinase.
abstract: For Trypanosoma brucei, a parasite responsible for African sleeping sickness, carbohydrate metabolism is the only source of ATP, and glycolytic enzymes are localized within membrane-bound organelles called glycosomes. Hexokinase, the first enzyme of the glycolytic pathway, was chosen as a target for selective drug design. We have cloned and sequenced the hexokinase gene of T. brucei. In parallel, we have synthesized several inhibitors. Kinetic analysis revealed differences in the binding mode of these compounds toward yeast and T. brucei hexokinases, while the m-bromophenyl glucosamide was found to be selective for T. brucei. The modeled structure of T. brucei hexokinase-inhibitor complex (using the crystal structure of the Schistosoma mansoni hexokinase as a template) allows us to propose a mode of action of this inhibitor for the trypanosome hexokinase and to account for the observed selectivity.
authors.affiliation: Groupe de Chimie Organique Biologique, Laboratoire Synthèse Physico-Chimie des Molécules d'Intérêt Biologique, UMR-CNRS-5068, Université Paul Sabatier, 31062 Cedex, Toulouse, France. willson@chimie.ups-tlse.fr
authors.forename: Michèle
authors.initials: M
authors.lastname: Willson
authors.forename: Yves Henri
authors.initials: YH
authors.lastname: Sanejouand
authors.forename: Jacques
authors.initials: J
authors.lastname: Perie
authors.forename: Véronique
authors.initials: V
authors.lastname: Hannaert
authors.forename: Fred
authors.initials: F
authors.lastname: Opperdoes
mesh_terms: D000244:Adenosine Diphosphate / Q000096:biosynthesis; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003001:Cloning, Molecular; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry; D005944:Glucosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D014347:Trypanosoma brucei gambiense / Q000201:enzymology* / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; D000244:Adenosine Diphosphate; D006593:Hexokinase; D005947:Glucose; D005944:Glucosamine