Biosynthesis of the O ‐Glycan Chains of Mucins and Mucin Type Glycoproteins

Abstract

Mucins and mucin-like glycoproteins are rich in GalNAca-Ser/Thr-linked oligosaccharides (0-glycans). and are found on cell surfaces and in cellular secretions with diverse biological functions. 0-glycan structures are cell type specific and often change during growth and differentiation as well as in many disease states. The complex 0-glycans are assembled by a series of specific reactions involving glycosyltransferases and sulfotransferases that exist as families of related enzymes. The control of the expression of these enzymes as well as their distinct properties are still poorly understood. With the gene cloning and characterization of transferases, and studies of the inter-relationship of enzymes in models of disease, we are beginning to unravel the regulation of biosynthetic pathways, and ultimately the functions of complex mucin-type glycans. TntroductionGalNAc-Ser or -Thr 0-linked oligosaccharides (0-glycans) occur on soluble, secreted and membrane bound glycoproteins. Mucins, comprising the main class of these glycoproteins, have heavily 0-glycosylated Ser/Thr/Pro-rich tandem repeat regions and, with the exception of the membrane-bound MUC1, are secreted glycoproteins. Eight different human mucin genes (MUC1,2,3,4,5A,5B,6,7) have been sequenced and another type, MUC8, has been identified [1-3]. The expression of these glycoprotein genes is often cell-specific, and may change in disease. Mucinlike glycoproteins also have domains that are rich in 0-glycans but lack the typical mucin tandem repeat sequences and are less heavily 0-glycosylated. Examples of cell surface-bound mucin-like glycoproteins are leukosialin and PSGL-1 , found on leukocytes, and cell adhesion molecules MadCAM-1 and GlyCAM-1, found on endothelial cells [4]. Carbohydrates in Chemistry and Biology

Fluorinated per-acetylated GalNAc metabolically alters glycan structures on leukocyte PSGL-1 and reduces cell binding to selectins

“…First, the attachment of 4F-GalNAc may reduce the extent of Core 2 glycan formation. In support of this, Brockhausen et al 48,49 have shown that Core-2 forming enzyme ␤1,6GlcNAcT recognizes many of the ϪOH groups in the glycan core 1 (Gal␤1,3GalNAc) structure. Hydroxyl groups at the C-4 and C-6 positions of both Gal and GalNAc along with the C-2 N-acetyl group are shown to be essential for full activity of this enzyme.…”

Initiation of Protein O Glycosylation by the Polypeptide GalNAcT-1 in Vascular Biology and Humoral Immunity

“…This initial enzymatic step by a polypeptide GalNAc transferase (ppGalNAcT) is followed in the Golgi apparatus by the regulated attachment of other saccharide linkages to this GalNAc residue by other glycosyltransferases, contributing to the changing O-glycan repertoire of a given cell (8,45). Full disclosure of ppGalNAcT structure and expression was made possible by biochemical purification of the enzymatic activity, followed by acquisition of the amino acid sequence (17,24).…”