title: Recognition of synthetic O-methyl, epimeric, and amino analogues of the acceptor alpha-L-Fuc p-(1-->2)-beta-D-Gal p-OR by the blood-group A and B gene-specified glycosyltransferases.
abstract: The disaccharide alpha-L-Fuc p-(1-->2)-beta-D-Gal p-O-(CH2)7CH3 (6) is an acceptor for the glycosyltransferases responsible for the biosynthesis of the A and B blood-group antigens. These enzymes respectively transfer GalNAc and Gal in an alpha linkage to OH-3 of the Gal residue in 6. All eight possible O-methyl, epimeric, and amino analogues of 6 having modifications on the target Gal residue were chemically synthesized and kinetically evaluated both as substrates and inhibitors for the A and B glycosyltransferases. The results support earlier findings that both enzymes will tolerate replacement of the hydroxyl groups at the 3 and 6 positions of the Gal residue. Substitution at or replacement of OH-4 of the Gal residue, however abolishes recognition. The 6-O-methyl and 6-amino compounds are substrates for both enzymes while the 3-epimeric (10) and 3-amino (12) compounds are inhibitors. For the B transferase, 10 is a competitive inhibitor with a Ki of 7.8 microM. Attempts to determine a Ki for 12 with the B transferase were unsuccessful because of a complex mode of inhibition. Similarly, both 10 and 12 are potent inhibitors of the A transferase, but the inhibition constants could not be calculated because of a complex mode of inhibition, resembling that for the B transferase. With the A transferase, 12 had an estimated Ki in the 200 nM range.
authors.affiliation: Department of Chemistry, University of Alberta, Edmonton, Canada.
authors.forename: T L
authors.initials: TL
authors.lastname: Lowary
authors.forename: O
authors.initials: O
authors.lastname: Hindsgaul
mesh_terms: D000017:ABO Blood-Group System / Q000096:biosynthesis*; D000588:Amines / Q000378:metabolism; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000737:chemistry* / Q000378:metabolism*; D004798:Enzymes / Q000097:blood*; D005646:Fucosyl Galactose alpha-N-Acetylgalactosaminyltransferase / Q000378:metabolism; D005700:Galactosyltransferases / Q000378:metabolism; D016695:Glycosyltransferases / Q000378:metabolism*; D006801:Humans; D007536:Isomerism; D008956:Models, Chemical; D008969:Molecular Sequence Data; D017350:N-Acetylgalactosaminyltransferases / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D000017:ABO Blood-Group System; D000588:Amines; D004187:Disaccharides; D004798:Enzymes; C086568:n-octyl fucopyranosyl-1-2-galactopyranoside; D016695:Glycosyltransferases; D005700:Galactosyltransferases; D017350:N-Acetylgalactosaminyltransferases; C003742:UDPgalactosamine-galactose acetylgalactosaminyltransferase; C023155:blood-group-substance alpha-D-galactosyltransferase; D005646:Fucosyl Galactose alpha-N-Acetylgalactosaminyltransferase