title: Selective irreversible inhibition of fructose 1,6-bisphosphate aldolase from Trypanosoma brucei.
abstract: An irreversible competitive inhibitor hydroxynaphthaldehyde phosphate was synthesized that is highly selective against the glycolytic enzyme fructose 1,6-bisphosphate aldolase from Trypanosoma brucei (causative agent of sleeping sickness). Inhibition involves Schiff base formation by the inhibitor aldehyde with Lys116 followed by reaction of the resultant Schiff base with a second residue. Molecular simulations indicate significantly greater molecular geometries conducive for nucleophilic attack in T. brucei aldolase than the mammalian isozyme and suggest Ser48 as the Schiff base modifying residue.
authors.affiliation: LSPCMIB, UMR-CNRS 5068, Groupe de Chimie Organique Biologique, Université Paul Sabatier, Bat. IIR1, 118 Route de Narbonne 31062, Toulouse Cedex 9, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Dax
authors.forename: Francis
authors.initials: F
authors.lastname: Duffieux
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chabot
authors.forename: Mathieu
authors.initials: M
authors.lastname: Coincon
authors.forename: Jurgen
authors.initials: J
authors.lastname: Sygusch
authors.forename: Paul A M
authors.initials: PA
authors.lastname: Michels
authors.forename: Casimir
authors.initials: C
authors.lastname: Blonski
mesh_terms: D000447:Aldehydes / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D005634:Fructose-Bisphosphate Aldolase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry; D010755:Organophosphates / Q000138:chemical synthesis* / Q000737:chemistry; D012545:Schiff Bases / Q000737:chemistry; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
chemical_list: C509699:2,6-dihydroxynaphthalene-1-carboxaldehyde 6-phosphate; D000447:Aldehydes; D009284:Naphthols; D010755:Organophosphates; D012545:Schiff Bases; D014344:Trypanocidal Agents; D005634:Fructose-Bisphosphate Aldolase