Chemical and chemoenzymatic synthesis of glycosyl-amino acids and glycopeptides related to Trypanosoma cruzi mucins

Org Biomol Chem. 2007 Aug 21;5(16):2645-57. doi: 10.1039/b707772f.

Abstract

This study describes the synthesis of the alpha- and beta-linked N-acetyllactosamine (Galp-beta-1,4-GlcNAc; LacNAc) glycosides of threonine (LacNAc-Thr). LacNAc-a-Thr was prepared by direct chemical coupling of a 2-azido-2-deoxy-lactose disaccharide donor to a suitable partially protected threonine unit. In contrast, stepwise chemical generation of beta-linked N-acetylglucosamine followed by enzymatic galactosylation to give LacNAc-beta-Thr proved effective, whereas use of a 2-azido-2-deoxy-lactose donor in acetonitrile failed to give the desired beta-linked disaccharyl glycoside. This study illustrates that it is possible to overcome the inherent stereoselection for 1,2-trans chemical glycosylation with a GlcNAc donor, and that the well-established preference of bovine beta-1,4-galactosyltransferase for beta-linked acceptor substrates can also be overcome. Using this knowledge, short glycopeptide fragments based on T. cruzi mucin sequences, Thr-Thr-[LacNAcThr]-Thr-Thr-Gly, were synthesised. All LacNAc-based compounds outlined were shown to serve as acceptor substrates for sialylation by T. cruzi trans-sialidase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Animals
  • Enzyme Activation
  • Escherichia coli / chemistry
  • Escherichia coli / genetics
  • Glycopeptides / chemical synthesis*
  • Glycopeptides / chemistry
  • Glycoproteins / chemistry*
  • Glycoproteins / genetics
  • Glycoproteins / isolation & purification
  • Glycosides / chemical synthesis*
  • Glycosides / chemistry
  • Molecular Conformation
  • Mucins / chemistry*
  • Neuraminidase / chemistry*
  • Neuraminidase / genetics
  • Neuraminidase / isolation & purification
  • Stereoisomerism
  • Trypanosoma cruzi / chemistry*
  • Trypanosoma cruzi / enzymology
  • Trypanosoma cruzi / genetics

Substances

  • Amino Acids
  • Glycopeptides
  • Glycoproteins
  • Glycosides
  • Mucins
  • trans-sialidase
  • Neuraminidase