N-ACETYLGLUCOSAMINONO-1,5-LACTONE OXIME AND THE CORRESPONDING (PHENYLCARBAMOYL)OXIME - NOVEL AND POTENT INHIBITORS OF BETA-N-ACETYLGLUCOSAMINIDASE

Using N-acetylglucosaminono-1,5-lactone (1) as the reference, the inhibitory activity of its (formal) derivatives N-acetylglucosaminono-1,5-lactone oxime (2) and N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)-oxime (3) was tested against beta-N-acetylglucosaminidase of different origins (animal, plant, fungus). Displaying inhibition constants of 0.45-mu-M and 0.62-mu-M, for the animal and plant enzyme, respectively, the simple oxime 2 was about equally potent as the parent lactone 1, and 50-400 times more efficient than two recently described new beta-N-acetylglucosaminidase inhibitors. The (phenylcarbamoyl)oxime 3 performed even better, particularly with the fungal enzyme (K(i) = 40 nM), i.e. was about 350 times more potent than the lactone. In all cases competitive inhibition was observed with 4-nitrophenyl-beta-N-acetylglucosaminide as the substrate. With K(i)/K(m) ratios up to 3300 for 2 and 13 600 for 3, the mode of action of these novel inhibitors is probably that of transition state mimicry. Suggestions are made for their use as a tool in biological research.