N-glycan modification in Aspergillus species

Appl Environ Microbiol. 2008 Feb;74(4):1076-86. doi: 10.1128/AEM.01058-07. Epub 2007 Dec 14.

Abstract

The production by filamentous fungi of therapeutic glycoproteins intended for use in mammals is held back by the inherent difference in protein N-glycosylation and by the inability of the fungal cell to modify proteins with mammalian glycosylation structures. Here, we report protein N-glycan engineering in two Aspergillus species. We functionally expressed in the fungal hosts heterologous chimeric fusion proteins containing different localization peptides and catalytic domains. This strategy allowed the isolation of a strain with a functional alpha-1,2-mannosidase producing increased amounts of N-glycans of the Man5GlcNAc2 type. This strain was further engineered by the introduction of a functional GlcNAc transferase I construct yielding GlcNAcMan5GlcNac2 N-glycans. Additionally, we deleted algC genes coding for an enzyme involved in an early step of the fungal glycosylation pathway yielding Man3GlcNAc2 N-glycans. This modification of fungal glycosylation is a step toward the ability to produce humanized complex N-glycans on therapeutic proteins in filamentous fungi.

Publication types

  • Comparative Study

MeSH terms

  • Aspergillus / metabolism*
  • Base Sequence
  • Cloning, Molecular
  • DNA Primers / genetics
  • Gene Transfer Techniques
  • Mannosyltransferases / genetics
  • Molecular Sequence Data
  • Polysaccharides / biosynthesis*
  • Polysaccharides / genetics
  • Protein Engineering / methods*
  • Recombinant Fusion Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
  • Transformation, Bacterial / genetics*
  • alpha-Mannosidase / metabolism

Substances

  • DNA Primers
  • Polysaccharides
  • Recombinant Fusion Proteins
  • Mannosyltransferases
  • alpha-Mannosidase

Associated data

  • GENBANK/DQ841152
  • GENBANK/DQ841153