Selective irreversible inhibition of fructose 1,6-bisphosphate aldolase from Trypanosoma brucei.
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.
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LSPCMIB, UMR-CNRS 5068, Groupe de Chimie Organique Biologique, Université Paul Sabatier, Bat. IIR1, 118 Route de Narbonne 31062, Toulouse Cedex 9, France.
Duffieux
Francis
F
Chabot
Nicolas
N
Coincon
Mathieu
M
Sygusch
Jurgen
J
Michels
Paul A M
PA
Blonski
Casimir
C
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*
C509699:2,6-dihydroxynaphthalene-1-carboxaldehyde 6-phosphate; D000447:Aldehydes; D009284:Naphthols; D010755:Organophosphates; D012545:Schiff Bases; D014344:Trypanocidal Agents; D005634:Fructose-Bisphosphate Aldolase