Human Blood Group A and B Glycosyltransferases

Human blood group A and B glycosyltransferases (GTA and GTB: EC 2.4.1.40 and 2.4.1.37) are responsible for the biosynthesis of A and B blood group antigens, which are important in cell development, cell differentiation and oncogenesis [80,81]. Both GTA and GTB are retaining enzymes. GTA catalyzes the transfer of GalNAc from UDP-GalNAc to the (O)H antigen (Fuca1 ^ 2Gal/8-OR) to give the A antigen GalNAca1 ^ 3[Fuca1 ^ 2]Gal^-OR. GTB uses the same acceptor but catalyzes the transfer of Gal from UDP-Gal to form the B antigen, Gala1 ^ 3[Fuca1 ^ 2]Gal|8-OR (Fig. 6).

Chemical mapping studies reveal that OH-4 of the Gal residue is a key polar group for both GTA and GTB, whereas OH-3 of the Gal unit to which the glycosyl residue transfers is not essential for recognition by either enzyme [82,83]. As shown in Figure 7, both enzymes tolerate deoxygenation, substitution, and derivatization of the 6-OH group of the Gal unit [82]. Deoxygenation of any of the hydroxyl groups on the Fuc residue is tolerated by GTA. Methylation of O3' and O4' is tolerated by both GTA and GTB. The arabino derivative, where the CH3 group of the Fuc residue

Figure 6 Reactions catalyzed by blood group A and B glycosyltransferases.
Figure 7 Unnatural acceptors for GTA (left) and GTB (right).

is replaced by H, was found to be an acceptor for GTA [84]. Both GTA and GTB, like a1,3-GalT and human milk a1,3/4-FucT, can also act on highly hindered tertiary alcohol acceptors and will even accommodate a large propyl group at the glycosyl-ation site [76]. While crossovers in donor specificity have been reported (i.e., GTA can utilize UDP-Gal and vice versa) [85,86], UDP-Glc is a donor only for GTB and UDP-GlcNAc only for GTA [87]. Donor monosaccharide mapping of GTB shows that modifications to Gal are tolerated at all positions. The rates of transfer relative to UDP-Gal are 2-deoxy-Gal (175%), 3-deoxy-Gal (0.1%), 4-deoxy-Gal (0.2%), 6-deoxy-Gal (18%), and arabinose (0.1%) [72].

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