The L-enantiomers of D-sugar-mimicking iminosugars are noncompetitive inhibitors of D-glycohydrolase?

1,4-Dideoxy-1,4-imino-L-arabinitol (L-AB1) and 2,5-dideoxy-2,5-imino-L-mannitol (L-DMDP) are much more potent inhibitors of isomaltase than their D-enantiomers. D-Enantiomers inhibited isomaltase in a competitive manner. whereas L-enantiomers were noncompetitive inhibitors of the enzyme. Similarly D-isofagomine and L-isofagomine were competitive and noncompetitive inhibitors of human lysosomal beta-D-glucosidase (beta-glucocerebrosidase), with K-i values of 0.016 and 5.7 muM, respectively. The multiple inhibition analysis of beta-glucocerebrosidase by D-isofagomine and L-isofagomine indicated that the D-enantiomer best fits the catalysis site of beta-glucocerebrosidase. while the L-enantiomer has a favorable interaction with a regulatory site other than the active site. Our recent and present results suggest that D-iminosugars are competitive inhibitors Of D-glycohydrolases but their L-enantiomers are noncompetitive inhibitors. (C) 2004 Elsevier Ltd. All rights reserved.