Characterization of inhibitory activities and binding mode of synthetic 6'-modified methyl N-acetyl-beta-lactosaminide toward rat liver CMP-D-Neu5Ac: D-galactoside-(2-->6)-alpha-D-sialyltransferase

Carbohydr Res. 1993 Sep 2:247:179-93. doi: 10.1016/0008-6215(93)84251-z.

Abstract

6'-Deoxy (12), 6'-thio (13), and 6'-O-tetrahydropyranosyl (14) analogues of methyl N-acetyl-beta-lactosaminide (3), were synthesized from lactose. NOE experiments proved that they adopt the same conformation as that of 3. Inhibition studies using these synthetic analogues, including the disulfide dimer 15, toward (2-->6)-alpha-sialytransferase (EC 2.4.99.1) revealed that the 6'-deoxy analogue 12 had remarkable inhibitory activity as the first acceptor-analogue inhibitor for this enzyme. It is noteworthy that the disulfide 15 also behaves as an inhibitor. The results indicated that chemical modification at the 6'-position of 3 did not cause much decrease in the binding affinity to the sialytransferase. Further, a novel possibility that the acceptor and the acceptor-analogue inhibitor can bind simultaneously to the sialytransferase was proposed based on the inhibition studies with 12 and CMP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Sugars / chemical synthesis*
  • Amino Sugars / pharmacology*
  • Animals
  • Binding Sites
  • Carbohydrate Conformation
  • Carbohydrate Sequence
  • Kinetics
  • Lactose / analogs & derivatives*
  • Lactose / chemical synthesis
  • Lactose / pharmacology*
  • Liver / enzymology*
  • Magnetic Resonance Spectroscopy
  • Mathematics
  • Models, Theoretical
  • Molecular Sequence Data
  • Optical Rotation
  • Rats
  • Sialyltransferases / antagonists & inhibitors*
  • Sialyltransferases / metabolism
  • beta-D-Galactoside alpha 2-6-Sialyltransferase

Substances

  • Amino Sugars
  • Sialyltransferases
  • Lactose
  • beta-D-Galactoside alpha 2-6-Sialyltransferase