A new strategy for the synthesis of dinucleotides loaded with glycosylated amino acids--investigations on in vitro non-natural amino acid mutagenesis for glycoprotein synthesis

Chembiochem. 2005 Oct;6(10):1805-16. doi: 10.1002/cbic.200500079.

Abstract

The in vitro non-natural amino acid mutagenesis method provides the opportunity to introduce non-natural amino acids site-specifically into proteins. To this end, a chemically synthesised aminoacylated dinucleotide is enzymatically ligated to a truncated suppressor transfer RNA. The loaded suppressor tRNA is then used in translation reactions to read an internal stop codon. Here we report an advanced and general strategy for the synthesis of the aminoacyl dinucleotide. The protecting group pattern developed for the dinucleotide facilitates highly efficient aminoacylation, followed by one-step global deprotection. The strategy was applied to the synthesis of dinucleotides loaded with 2-acetamido-2-deoxy-glycosylated amino acids, including N- and O-beta-glycosides and O- and C-alpha-glycosides of amino acids, thus enabling the extension of in vitro non-natural amino acid mutagenesis towards the synthesis of natural glycoproteins of high biological interest. We demonstrate the incorporation of the glycosylamino acids--although with low suppression efficiency--into the human interleukin granulocyte-colony stimulating factor (hG-CSF), as verified by the ELISA technique.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry*
  • Amino Acids / genetics
  • Cloning, Molecular
  • Glycoproteins / biosynthesis
  • Glycoproteins / chemical synthesis*
  • Glycoproteins / genetics
  • Glycosylation
  • Granulocyte Colony-Stimulating Factor / chemistry
  • Granulocyte Colony-Stimulating Factor / genetics
  • Humans
  • Magnetic Resonance Spectroscopy
  • Mutagenesis, Site-Directed
  • Nucleotides / chemical synthesis*
  • RNA, Transfer / chemistry*
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization

Substances

  • Amino Acids
  • Glycoproteins
  • Nucleotides
  • Granulocyte Colony-Stimulating Factor
  • RNA, Transfer