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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aldehydes / chemical synthesis*
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Aldehydes / chemistry
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Animals
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Fructose-Bisphosphate Aldolase / antagonists & inhibitors*
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Fructose-Bisphosphate Aldolase / chemistry*
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Kinetics
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Models, Molecular
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Naphthols / chemical synthesis*
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Naphthols / chemistry
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Organophosphates / chemical synthesis*
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Organophosphates / chemistry
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Schiff Bases / chemistry
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Trypanocidal Agents / chemical synthesis*
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Trypanocidal Agents / chemistry
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Trypanosoma brucei brucei / enzymology*
Substances
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2,6-dihydroxynaphthalene-1-carboxaldehyde 6-phosphate
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Aldehydes
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Naphthols
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Organophosphates
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Schiff Bases
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Trypanocidal Agents
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Fructose-Bisphosphate Aldolase