Synthesis of LacdiNAc-terminated glycoconjugates by mutant galactosyltransferase - A way to new glycodrugs and materials

Abstract

Human placental β1,4-galactosyltransferase-I (EC 2.4.1.38) transfers the galactosyl moiety from UDP-Gal to various GlcNAc or Glc acceptors in vivo. Here, we describe the construction of its Y284L mutant as a His 6 propeptidecatβ4GalT1 construct, in which the Gal-transferase activity was totally abolished in favor of its GalNAc-transferase activity. We used this mutant in the synthesis of three monoand bivalent LacdiNAc glycomimetics with good yields. These compounds proved to be powerful ligands of two activation receptors of natural killer cells, NKR-P1 and CD69. A synthetic bivalent tethered di-LacdiNAc is the best currently known precipitation agent for both of these receptors and has promising potential for the development of immunoactive glycodrugs.

Dimerization of an Immunoactivating Peptide Derived from Mycobacterial hsp65 Using N-Hydroxysuccinimide Based Bifunctional Reagents Is Critical for Its Antitumor Properties

“…10 Introduction of charged groups into Nacetylhexosamine sequences increases significantly the affinity for CD69. 11 Sialylated oligosaccharides bearing negatively charged groups in Siaα2→6Gal or Siaα2→6GalNAc (SiaTn) sequences are among such high-affinity ligands for the CD69 receptor. Since these sequences form an integral part of tumor surface sialomucins, 12 they may be among the ligands initiating activation-induced apoptosis in killer lymphocytes.…”

Loss-of-Function Mutation in Bi-Functional Marine Bacterial Sialyltransferase

“…39) For example, human 1,4-galactosyltransferase was converted to 1,4-N-acetyl-galactosaminyltransferase by a single point mutation. 40) In addition, data have been obtained regarding the structure-activity relationships of sialyltransferases 41) but the roles of the amino acid residues surrounding the catalytic site have not been fully explored. In this study, we obtained information with regard to the roles of the amino acid residues located in the donor substrate-binding site of ÁNpp23ST.…”

Charged Hexosaminides as New Substrates for β‐N‐Acetylhexosaminidase‐Catalyzed Synthesis of Immunomodulatory Disaccharides

“…[21] In both cases, the dicarboxylated disaccharide 9 and both sulfated disaccharides 12 and 13 displayed the highest effect. This correlated well with the competitive studies shown in Table 2.…”

“…[21] d-Mannose was used as the negative control, no inhibitory effects could be observed up to 10 mM concentrations (not shown). The results are summarized in Table 2 as Àlog IC 50 .…”