RECOGNITION OF SYNTHETIC O-METHYL, EPIMERIC, AND AMINO ANALOGS OF THEACCEPTOR ALPHA-L-FUCP-(1-]2)-BETA-D-GALP-OR BY THE BLOOD-GROUP-A AND BLOOD-GROUP-B GENE-SPECIFIED GLYCOSYLTRANSFERASES

The disaccharide alpha-L-Fucp-(1 --> 2)beta-D-Galp-O-(CH2)(7)CH3 (or f or 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 eigh t possible O-methyl, epimeric, and amino analogues of 6 having modific ations on the target Gal residue were chemically synthesized and kinet ically evaluated both as substrates and inhibitors for the A and B gly cosyltransferases. The results support earlier findings that both enzy mes will tolerate replacement of the hydroxyl groups at the 3 and 6 po sitions of the Gal residue. Substitution at or replacement of OH-4 of the Gal residue, however abolishes recognition. The 6-O-methyl and B-a mino compounds are substrates for both enzymes while the 3-epimeric (1 0) and 3-amino (12) compounds are inhibitors. For the B transferase, 1 0 is a competitive inhibitor with a K-i of 7.8 mu M. Attempts to deter mine a K-i for 12 with the B transferase were unsuccessful because of a complex mode of inhibition. Similarly, both 10 and 12 are potent inh ibitors of the A transferase, but the inhibition constants could not b e 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.