Glycan engineering and production of 'humanized' glycoprotein in yeast cells.
Protein therapeutics, such as antibodies and cytokines, is the largest class of new drug candidates being developed by pharmaceutical companies. Although most of these glycoproteins are produced in mammalian cells, there is concern that their large-scale production could be affected by an inadequate supply of bovine serum. There is also the risk of viral infection spreading through the use of contaminated protein therapeutics. Consequently, protein expression systems in yeast have been established because protein manufacturing costs are cheaper than in mammalian cells, and yeast systems are virus-free. However, yeasts cannot generate human-type glycans, and thus cannot produce therapeutic glycoproteins for human use. There has therefore been considerable interest in glycan remodeling, from yeast-type to human-type. 'Humanized' glycoproteins can now be generated in yeast by disrupting yeast-specific glycosyltransferases and introducing genes responsible for sugar-nucleotide synthesis, its transported from the cytosol to Golgi lumen, as well as their transfer and hydrolysis. A compound that inhibits yeast O-mannosyltransferase suppresses yeast-specific O-mannosyl modification, and can produce mucin-type glycoproteins. These systems are just being developed to the stage where the production in glycoengineered yeast of biopharmaceutical glycoproteins such as cytokines, antibodies for therapeutics, and enzymes for replacement therapy for lysosomal diseases are being evaluated for clinical applications. Yeast glycoprotein expression systems are expected to become the dominant approach for the production of human glycoproteins in the near future.
Chiba
Yasunori
Y
Research Center for Medical Glycoscience, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki, Japan. y-chiba@aist.go.jp
Akeboshi
Hiromi
H
D000818:Animals; D006023:Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D006031:Glycosylation; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000188:drug therapy; D011134:Polysaccharides / Q000096:biosynthesis* / Q000235:genetics; D015202:Protein Engineering; D011994:Recombinant Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000627:therapeutic use; D012441:Saccharomyces cerevisiae / Q000235:genetics*
D006023:Glycoproteins; D011134:Polysaccharides; D011994:Recombinant Proteins