Competitive inhibition of Trypanosoma brucei phosphoglucose isomerase by D-arabinose-5-phosphate derivatives

We report four new strong high energy intermediate analog competitive inhib itors of fructose-6-phosphate isomerization catalyzed by purified Trypanoso ma brucei phosphoglucose isomerase: D-arabinonhydroxamic acid-5-phosphate, D-arabinonate-5-phosphate, D-arabinonamide-5-phosphate and D-arabinonhydraz ide-5-phosphate. For comparison, the inhibitory properties of the correspon ding non-phosphorylated analogues D-arabinonhydroxamic acid, D-arabinonate, D-arabinonamide and D-arabinonhydrazide were aslo evaluated. D-Arabinonhyd roxamic acid-5-phosphate appears as the most potent competitive inhibitor e ver evaluated on a phosphoglucose isomerase with an inhibition constant val ue of 50 nM and a Michaelis constant over inhibition constant ratio of abou t 2000. Our results show that anionic high energy intermediate analogues, a nd 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 intermedi ate 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 isome rase.