Selective irreversible inhibition of fructose 1,6-bisphosphate aldolase from Trypanosoma brucei

Journal of Medicinal Chemistry
Chantal DaxCasimir Blonski

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.

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Citations

Jun 29, 2011·Future Microbiology·Reto BrunMichael P Barrett
Apr 12, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jürgen BoschWim G J Hol
Sep 19, 2007·Current Opinion in Structural Biology·P GayathriM R N Murthy
Feb 15, 2020·Scientific Reports·Florencia FerraroGuzmán Álvarez
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Nov 13, 2018·Journal of Medicinal Chemistry·Paul W HeronJurgen Sygusch
Nov 10, 2011·ACS Medicinal Chemistry Letters·Charles-Gabin Mabiala-BassilouaMichel Thérisod
Feb 12, 2008·Bioorganic & Medicinal Chemistry Letters·Charles-Gabin Mabiala-BassilouaMichel Therisod
Aug 31, 2021·Frontiers in Molecular Biosciences·David B PirovichPatrick J Skelly

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