Glycosidase-catalyzed hydrolysis of 2-deoxyglucopyranosyl pyridinium salts: effect of the 2-OH group on binding and catalysis

Abstract

Three 2-deoxy-α-D-glucopyranosyl pyridinium tetrafluoroborates were tested for their binding affinity to a range of α-glucosidases and α-mannosidases. The α-isoquinolinium salt (11) binds approximately 275-fold more tightly to yeast α-glucosidase than does the isomeric quinolinium salt (12). In addition, compound 11 binds to the yeast enzyme approximately two-fold tighter than the corresponding glucopyranosyl isoquinolinium salt (9). The (kcat/khyd) values for the yeast α-glucosidase-catalyzed reactions of 11 and 9 are 1.6 × 105and 2.0 × 109, respectively, when compared to the spontaneous uncatalyzed reactions. Thus, the interaction of the 2-OH group in compound 9 with the yeast enzyme's active site generates a relative transition state stabilization of about 23.5 kJ mol-1. For both compounds 11 and 12, the observed rate accelerations for the yeast α-glucosidase-catalyzed hydrolysis, relative to the spontaneous reaction in solution, (kcat/khyd) are identical within experimental error.Key words: glycosidase, inhibitor, 2-deoxyglucose, pyridinium, catalysis.