Glycoconjugate Journal

, Volume 23, Issue 7–8, pp 525–541 | Cite as

UDP-Gal: GlcNAc-R β1,4-galactosyltransferase—a target enzyme for drug design. Acceptor specificity and inhibition of the enzyme

  • Inka BrockhausenEmail author
  • Melinda Benn
  • Shridhar Bhat
  • Sandra Marone
  • John G. Riley
  • Pedro Montoya-Peleaz
  • Jason Z. Vlahakis
  • Hans Paulsen
  • John S. Schutzbach
  • Walter A. Szarek


Galactosyltransferases are important enzymes for the extension of the glycan chains of glycoproteins and glycolipids, and play critical roles in cell surface functions and in the immune system. In this work, the acceptor specificity and several inhibitors of bovine β1,4-Gal-transferase T1 (β4GalT, EC were studied. Series of analogs of N-acetylglucosamine (GlcNAc) and GlcNAc-carrying glycopeptides were synthesized as acceptor substrates. Modifications were made at the 3-, 4- and 6-positions of the sugar ring of the acceptor, in the nature of the glycosidic linkage, in the aglycone moiety and in the 2-acetamido group. The acceptor specificity studies showed that the 4-hydroxyl group of the sugar ring was essential for β4GalT activity, but that the 3-hydroxyl could be replaced by an electronegative group. Compounds having the anomeric β-configuration were more active than those having the α-configuration, and O-, S- and C-glycosyl compounds were all active as substrates. The aglycone was a major determinant for the rate of Gal-transfer. Derivatives containing a 2-naphthyl aglycone were inactive as substrates although quinolinyl groups supported activity. Several compounds having a bicyclic structure as the aglycone were found to bind to the enzyme and inhibited the transfer of Gal to control substrates. The best small hydrophobic GlcNAc-analog inhibitor was found to be 1-thio-N-butyrylGlcNβ-(2-naphthyl) with a Ki of 0.01 mM. These studies help to delineate β4GalT–substrate interactions and will aid in the development of biologically applicable inhibitors of the enzyme.


Galactosyltransferase Substrate specificity Substrate analogs Enzyme kinetics Inhibitors 











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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Inka Brockhausen
    • 1
    Email author
  • Melinda Benn
    • 1
  • Shridhar Bhat
    • 2
  • Sandra Marone
    • 2
  • John G. Riley
    • 2
  • Pedro Montoya-Peleaz
    • 2
  • Jason Z. Vlahakis
    • 2
  • Hans Paulsen
    • 3
  • John S. Schutzbach
    • 1
  • Walter A. Szarek
    • 2
  1. 1.Departments of Medicine and Biochemistry, Human Mobility Research CentreQueen’s University, KingstonOntarioCanada
  2. 2.Department of ChemistryQueen’s University, KingstonOntarioCanada
  3. 3.Institute of Organic ChemistryUniversity of HamburgHamburgGermany

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