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Advances in the production of human therapeutic proteins in yeasts and filamentous fungi

Nature Biotechnology volume 22, pages 1409–1414 (2004)Cite this article

A Corrigendum to this article was published on 01 December 2004

Abstract

Yeast and fungal protein expression systems are used for the production of many industrially relevant enzymes, and are widely used by the research community to produce proteins that cannot be actively expressed in Escherichia coli or require glycosylation for proper folding and biological activity. However, for the production of therapeutic glycoproteins intended for use in humans, yeasts have been less useful because of their inability to modify proteins with human glycosylation structures. Yeast glycosylation is of the high-mannose type, which confers a short in vivo half-life to the protein and may render it less efficacious or even immunogenic. Several ways of humanizing yeast-derived glycoproteins have been tried, including enzymatically modifying proteins in vitro and modulating host glycosylation pathways in vivo. Recent advances in the glycoengineering of yeasts and the expression of therapeutic glycoproteins in humanized yeasts have shown significant promise, and are challenging the current dominance of therapeutic protein production based on mammalian cell culture.

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Figure 1: Protein structure of interferon-β illustrates the impact of glycosylation on hydrodynamic volume; glycosylated interferon-β (top) and glycosylated interferon-β with glycosylation highlighted in blue (bottom).
Figure 2: Glycosylation pathways in humans and yeast.
Figure 3: MALDI-TOF mass spectrometry of oligosaccharides released from purified kringle 3 protein produced in wild-type P. pastoris and glycoengineered strains of P. pastoris.

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Authors and Affiliations

  1. the Department of Biological Sciences and the Department of Chemistry, Thayer School of Engineering, Dartmouth College, Hanover, 03755, New Hampshire, USA

    Tillman U Gerngross

  2. GlycoFi Inc., 21 Lafayette Street, Lebanon, 03766, New Hampshire, USA

    Tillman U Gerngross

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Correspondence to Tillman U Gerngross.

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T.U.G. has equity exceeding 5% in a company (GlycoFi) that develops yeast-based protein expression systems.

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Gerngross, T. Advances in the production of human therapeutic proteins in yeasts and filamentous fungi. Nat Biotechnol 22, 1409–1414 (2004). https://doi.org/10.1038/nbt1028

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