Synthesis of 5-amino-5-deoxy-D-mannopyranose and 1,5-dideoxy-1,5-imino-D-mannitol, and inhibition of alpha- and beta-D-mannosidases.
The title compounds and the corresponding L-gulo derivatives were synthesised in 6 steps from benzyl 2,3:5,6-di-O-isopropylidene-alpha-D-mannofuranoside. The Ki values, determined from inhibition studies with alpha-D-mannosidases from jack beans, almonds, and calf liver, and beta-D-mannosidase from Aspergillus wentii, ranged from 70 to 400 microM for the mannitol derivative and from 1.2 to 20 microM for 5-amino-5-deoxy-D-mannopyranose, i.e., inhibition is 10(2)-10(4)-fold stronger than with D-mannose. Marked enhancement of inhibition with increasing pH is ascribed to the ionisation of a carboxyl group at the active site, forming an ion pair with the protonated inhibitor. The inhibition equilibrium between the jack-bean enzyme and the mannose derivative was approached slowly with kapp 2.0 X 10(5) M-1 X min-1. The mannose-derived inhibitor was also inhibitory against beta-D-glucosidases from almonds and Asp. wentii, with Ki values only 20-150-times larger than those for the inhibition of these enzymes by 5-amino-5-deoxy-D-glucopyranose. This moderate discrimination in binding of D-gluco and D-manno derivatives is in marked contrast to the high specificity shown by the glucosidase in catalysing the hydrolysis of mannosidases. A similar low specificity with respect to binding, combined with highly specific catalysis, was also seen with the mannosidases acting on inhibitors and substrates with the D-gluco configuration.
D017485:1-Deoxynojirimycin; D000818:Animals; D001230:Aspergillus / Q000201:enzymology; D001665:Binding Sites; D002417:Cattle; D006595:Hexosamines / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008353:Mannitol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008358:Mannose / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008361:Mannosidases / Q000037:antagonists & inhibitors*; D009904:Optical Rotation; D010944:Plants / Q000201:enzymology; D043323:alpha-Mannosidase; D044902:beta-Mannosidase
D006595:Hexosamines; D007202:Indicators and Reagents; D017485:1-Deoxynojirimycin; C008322:mannosamine; D008353:Mannitol; C042210:5-amino-5-deoxymannopyranoside; D008361:Mannosidases; D043323:alpha-Mannosidase; D044902:beta-Mannosidase; D008358:Mannose