Probing the Conformational Changes in the Enzymatic Hydrolysis of 2-Acetamido-2-deoxy-β-D-glucopyranosides

• Published in: Helvetica chimica acta Vol. 87; no. 10; pp. 2566 - 2573
• Main Authors: Böhm, Matthias, Vasella, Andrea
• Format: Journal Article
• Language: English
• Published: Zürich WILEY-VCH Verlag 01.10.2004; WILEY‐VCH Verlag
• ISSN: 0018-019X; 1522-2675
• DOI: 10.1002/hlca.200490229

The isoquinuclidines 7 and 8 were synthesised and tested as inhibitors of hexosaminidases from jack beans and from bovine kidney. These isoquinuclidines mimick the 1,4B‐conformer of a N‐acetyl‐glucosamine‐derived β‐d‐glucopyranoside; they are competitive inhibitors with Ki values from 0.014 to 0.30 μM. The strong inhibition of these enzymes agrees with the hypothesis that the enzymatic hydrolysis of 2‐acetamido‐2‐deoxy‐β‐d‐glucopyranosides proceeds via a boat‐like conformer with a pseudo‐axial scissile glycosidic bond and a pseudo‐axial acetamido substituent optimally oriented to effect an intramolecular substitution of the aglycon.