Abstract

The majority of glycoside hydrolases is strongly inhibited by monosaccaride derivatives bearing a basic NH—group adjacent to C—i, i. e. by glycosylanines, 5—amino—5—deoxyhexopyranoses, and 1,5—iminoalditols. This inhibition with Kr—values up to 104—tines smaller than those of neutral analogs is explained by a catalytic site which features an acid and a carboxylated in iuxtaposition close to the anoneric carbon of the bound inhibitor or substrate. The inhibitor protonated by the acid forms an ion pair with the carboxylate. The stability of this ion pair and the lack of influence of added salt on the inhibition calls for an active site strongly shielded from the aqueous environment. The acid/carboxylate arrangement of functional groups is supported by inhibition studies with substrate related epoxides that are activated by proton transfer from the acid and form an ester with carboxylate. N—Alkylation of the basic inhibitors leads, in many cases, to an enhanced inhibition. Structural variation of the alkyl substituents permits a detailed characterisation of the aglycon site as exemplified by studies on lysosomal —glucosidase Inhibition by 1,5—dideoxy—i,5—imino—D—glucitol and —mannitol of D(—glucosi— dases and —mannosidases participating in the biosynthesis of carbohydrate chains linked to asparagine residues of glycoproteins results in altered glycan structures of newly synthesized proteins. The effects of these alteration on surrace expression and secretion of the proteins, on intracellular compartmentation and on the formation and infectivity of enveloped viruses is discussed.

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