The design and synthesis of a selective inhibitor of fucosyltransferase VI.
Inversion of configuration of the C-2[prime or minute] hydroxyl of methyl N-acetyllactosamine was accomplished by a two-step procedure involving oxidation to a ketone followed by reduction with NaBH(4). After deprotection, the resulting derivative was examined as a substrate for [small alpha]-(2,6)- and [small alpha]-(2,3)-sialyltransferase and fucosyltransferase III, IV, V and VI. It was found that none of these enzymes could glycosylate. However, it showed exquisite selectivity for inhibition of fucosyltransferase VI. The kinetic data support an unusual mechanism in which the inhibitor can bind to the GDP-fucose complex as well as another enzyme form.
Galan
M Carmen
MC
Complex Carbohydrate Research Center, University of Georgia, Athens 30602, USA.
Venot
Andre P
AP
Phillips
Robert S
RS
Boons
Geert-Jan
GJ
D000606:Amino Sugars / Q000737:chemistry* / Q000494:pharmacology; D002236:Carbohydrate Conformation; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005647:Fucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D016256:Lewis X Antigen
D000606:Amino Sugars; D004791:Enzyme Inhibitors; D016256:Lewis X Antigen; C000458:N-acetyllactosamine; C066693:FUT4 protein, human; D005647:Fucosyltransferases