Mucin-type O-glycosylation and its potential use in drug and vaccine development

• Published in: Biochimica et biophysica acta Vol. 1780; no. 3; pp. 546 - 563
• Main Authors: Tarp, Mads Agervig, Clausen, Henrik
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2008
• Subjects: Animals; Cancer vaccines; Cancer Vaccines - chemical synthesis; Cancer Vaccines - chemistry; Drug Design; GalNAc-transferases; Glycosylation; Glycosyltransferases; Humans; Mucin-type O-glycosylation; Mucins; Mucins - metabolism; N-Acetylgalactosaminyltransferases - metabolism; Polypeptide N-acetylgalactosaminyltransferase; Site-directed O-glycosylation; Cancer vaccines; GalNAc-transferases; Site-directed O-glycosylation; Mucin-type O-glycosylation; Glycosyltransferases; Mucins
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2007.09.010

Mucin-type O-glycans are found on mucins as well as many other glycoproteins. The initiation step in synthesis is catalyzed by a large family of polypeptide GalNAc-transferases attaching the first carbohydrate residue, GalNAc, to selected serine and threonine residues in proteins. During the last decade an increasing number of GalNAc-transferase isoforms have been cloned and their substrate-specificities partly characterized. These differences in substrate specificities have been exploited for in vitro site-directed O-glycosylation. In GlycoPEGylation™, polyehylene glycol (PEG) is transferred to recombinant therapeutics to specific acceptor sites directed by GalNAc-transferases. GalNAc-transferases have also been used to control density of glycosylation in the development of glycopeptide-based cancer vaccines. The membrane-associated mucin-1 (MUC1) has long been considered a target for immunotherapeutic and immunodiagnostic measures, since it is highly overexpressed and aberrantly O-glycosylated in most adenocarcinomas, including breast, ovarian, and pancreatic cancers. By using vaccines mimicking the glycosylation pattern of cancer-cells, it is possible to overcome tolerance in transgenic animals expressing the human MUC1 protein as a self-antigen providing important clues for an improved MUC1 vaccine design. The present review will highlight some of the potential applications of site-directed O-glycosylation.