Competitive inhibition of Trypanosoma brucei phosphoglucose isomerase by D-arabinose-5-phosphate derivatives.
We report four new strong high energy intermediate analog competitive inhibitors of fructose-6-phosphate isomerization catalyzed by purified Trypanosoma brucei phosphoglucose isomerase: D-arabinonhydroxamic acid-5-phosphate, D-arabinonate-5-phosphate, D-arabinonamide-5-phosphate and D-arabinonhydrazide-5-phosphate. For comparison, the inhibitory properties of the corresponding non-phosphorylated analogues D-arabinonhydroxamic acid, D-arabinonate, D-arabinonamide and D-arabinonhydrazide were also evaluated. D-Arabinonhydroxamic acid-5-phosphate appears as the most potent competitive inhibitor ever evaluated on a phosphoglucose isomerase with an inhibition constant value of 50 nM and a Michaelis constant over inhibition constant ratio of about 2000. Our results show that anionic high energy intermediate analogues, and more particularly D-arabinonhydroxamic acid-5-phosphate, display a weak but significant specificity for Trypanosoma brucei phosphoglucose isomerase versus yeast phosphoglucose isomerase, while neutral high energy intermediate analogues are not selective at all. This would indicate the presence of more positively charged residues in the active site for Trypanosoma brucei phosphoglucose isomerase as compared to that of yeast phosphoglucose isomerase.
Hardré
R
R
Laboratoire de Chimie Bioorganique et Bioinorganique, ERS 1824, Institute de Chimie Moléculaire d'Orsay, Université de Paris-Sud, France.
Salmon
L
L
Opperdoes
F R
FR
D000818:Animals; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D005956:Glucose-6-Phosphate Isomerase / Q000037:antagonists & inhibitors*; D007700:Kinetics; D010428:Pentosephosphates / Q000138:chemical synthesis / Q000494:pharmacology*; D015800:Protozoan Proteins / Q000737:chemistry / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000737:chemistry / Q000201:enzymology*
D004791:Enzyme Inhibitors; D010428:Pentosephosphates; D015800:Protozoan Proteins; C028055:arabinose 5-phosphate; D005956:Glucose-6-Phosphate Isomerase