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Hirano, K.; , . Roles of LacdiNAc Group on N- and O-glycans. Encyclopedia. Available online: https://encyclopedia.pub/entry/23218 (accessed on 11 July 2025).
Hirano K,  . Roles of LacdiNAc Group on N- and O-glycans. Encyclopedia. Available at: https://encyclopedia.pub/entry/23218. Accessed July 11, 2025.
Hirano, Kiyoko, . "Roles of LacdiNAc Group on N- and O-glycans" Encyclopedia, https://encyclopedia.pub/entry/23218 (accessed July 11, 2025).
Hirano, K., & , . (2022, May 23). Roles of LacdiNAc Group on N- and O-glycans. In Encyclopedia. https://encyclopedia.pub/entry/23218
Hirano, Kiyoko and . "Roles of LacdiNAc Group on N- and O-glycans." Encyclopedia. Web. 23 May, 2022.
Roles of LacdiNAc Group on N- and O-glycans
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This entry is adapted from the peer-reviewed paper 10.3390/biom12020195

The GalNAcβ1→4GlcNAc (LacdiNAc) group is widely expressed on N- and O-glycans in invertebrates, in particular, parasitic helminths. An increasing number of studies have shown that the disaccharide GalNAcβ1→4GlcNAc (LacdiNAc) group bound to N- and O-glycans in glycoproteins is expressed in a variety of mammalian cells. Biosynthesis of the LacdiNAc group was well studied, and two β4-N-acetylgalactosaminyltransferases, β4GalNAcT3 and β4GalNAcT4, have been shown to transfer N-acetylgalactosamine (GalNAc) to N-acetylglucosamine (GlcNAc) of N- and O-glycans in a β-1,4-linkage. The LacdiNAc group is often sialylated, sulfated, and/or fucosylated, and the LacdiNAc group, with or without these modifications, is recognized by receptors and lectins and is thus involved in the regulation of several biological phenomena, such as cell differentiation.

LacdiNAc β4-N-acetylgalactosaminyltransferase tumor malignancy epithelial-mesenchymal or mesenchymal-epithelial transition gene therapy

1. Introduction

Alterations of glycan structures of cell surface glycoproteins and glycolipids affect many biological phenomena, such as cell differentiation, immune response, cell adhesion, and the malignant transformation of cells [1]. The GalNAcβ1→4GlcNAc (LacdiNAc) group is widely expressed on N- and O-glycans in invertebrates, in particular, parasitic helminths [2], but was hardly detected in mammalian glycoproteins in early studies. However, advanced analytical methods for glycan structures have enabled us to show that the LacdiNAc group is also distributed in the glycoproteins of a variety of mammalian cells and tissues. It was also found that this disaccharide group is involved in several biological phenomena, such as the control of the half-life of glycohormones in circulation [3][4].

2. Biosynthesis of LacdiNAc Group and Its Modification in Mammalian Cells

The biosynthetic pathway of the LacdiNAc group is summarized in Figure 1. Two β4-N-acetylgalactosaminyltransferases (β4GalNAcTs), β4GalNAcT3 (gene ID: 283358) [5] and β4GalNAcT4 (gene ID: 338707) [6], which are involved in this biosynthesis, are type-II transmembrane proteins and have 43% sequence homology. These glycosyltransferases belong to the human β4-galactosyltansferase family and show high homology to chondroitin sulfate synthase 1 [5][6]. The enzymes transfer N-acetylgalactosamine (GalNAc) from UDP-GalNAc to non-reducing terminal N-acetylglucosamine (GlcNAc) of both N- and O-glycans in a β-1,4-linkage with a similar substrate specificity [7][8]. However, the tissue distribution of these is quite different [5][6]. Since β4GalNAcT3 and β4GalNAcT4 have been shown to localize in the trans-Golgi network [9][10] and share the same acceptors with β1,4-galactosyltrasferase I, which is abundantly expressed in most mammalian cells and forms the Galβ1→4GlcNAc (LacNAc) group, this might be the reason why the LacdiNAc group is a minor disaccharide compared to the LacNAc group on N-glycans in mammalian cells. It is also noted that some other glycosyltransferases are able to catalyze the formation of the LacdiNAc group. In fact, the overexpression of the Caenorhabditis elegance β4GalNAcT gene in Chinese hamster ovarian Lec8 cells resulted in the formation of the poly-LacdiNAc structure [11].
Figure 1. Biosynthetic pathway of N- (Asn-linked) and O- (Ser/Thr-linked) glycans with the LacdiNAc group in mammalian cells. The β4GalNAcT3 and β4GalNAcT4 can transfer GalNAc from UDP-GalNAc to the non-reducing terminal GlcNAc residue of both N- and O-glycans in a β-1,4-linkage to produce the LacdiNAc group. In some cases, this disaccharide receives sialylation, sulfation, and/or fucosylation.
The LacdiNAc group is often modified by sialylation, sulfation, and/or fucosylation. The LacdiNAc group, carrying α-2,6-linked sialic acid, is often detected in mammalian cells [10][12][13][14]. On the other hand, the sulfated form of the LacdiNAc group, which was first detected in the bovine pituitary hormone lutropin [15], is now found in several other human glycoproteins [16][17][18]. Two N-acetylgalactosamine-4-O-sulfotransferases (GalNAc4STs), GalNAc4ST-1 or CHST8 (gene ID: 64377) [19] and GalNAc4ST-2 or CHST9 (gene ID: 83539) [20], can transfer a sulfate group to the 4-position of the GalNAc residue, resulting in the formation of the sulfated LacdiNAc group [8]. Likewise, the fucosylated LacdiNAc group is detectable in mammalian glycoproteins [13][14][21], and the overexpression of α-1,3-fucosyltransferase in Chinese hamster ovarian Lec8 cells brought about the formation of the fucosylated LacdiNAc group [11]. The modification of the non-reducing terminal glycan groups of many glycoproteins affects their biological roles. For instance, the terminal sialic acid residues are recognized by siglecs, which are sialic acid-binding immunoglobulin-like receptors, and these bindings have been shown to regulate the binding/recognition of immunocytes to target cells [22]. It is not clear, however, whether the modification of the LacdiNAc group affects the function of its carrier proteins; several studies have shown that the modified LacdiNAc group is recognized by the respective receptors and lectins and thus participates in the activation or inhibition of their underlying signal pathways, as will be discussed below.

3. Biological Roles of LacdiNAc Group on N- and O-glycans

Some receptors and lectins recognize the LacdiNAc group on N- and O-glycans, and these bindings are involved in keeping homeostasis of mammals. The mannose/GalNAc-4-SO4 receptor on hepatic endothelial cells binds to the sulfated LacdiNAc group on N-glycans carried by a pituitary glycohormone, lutropin, thus resulting in the clearance of this hormone from the blood circulation [16][23]. Likewise, the sialylated LacdiNAc group on N-glycans is recognized by the asialoglycoprotein receptor in the liver, and this binding leads to the rapid clearance of the present glycoprotein [24]. It has been reported that a coagulation factor VII-albumin fusion protein, expressed in HEK293 cells, possesses the LacdiNAc group on its N-glycans [25]. However, when the β4GalNAcT3 and β4GalNAcT4 genes were knocked out in order to eliminate the GalNAc residue from the LacdiNAc group, the fusion protein failed to bind both to a mannose/GalNAc-4-SO4 receptor and an asialoglycoprotein receptor, causing its prolonged half-life in circulation [26]. Because remodeling of the glycan structures of biopharmaceutical molecules, such as immunoglobulins, can provide more effective molecules than the natural ones [27][28], it may be worth mimicking the LacdiNAc group on N-glycans of glycoproteins.
Since the LacdiNAc group, expressed abundantly on O-glycans of MUC5AC mucin in human gastric mucosa, has been shown to play an important role in the interaction with Helicobacter pylori [29][30], specific adhesion molecules to this disaccharide could be present on the bacterium and/or gastric epithelial cells, which has to be pursued in future.
A previous study has shown that galectin-3, which is a mammalian β-galactoside-binding lectin, can bind to the LacdiNAc group on N-glycan of macrophage and regulate the immune response [31]. Indeed, in vitro studies have demonstrated that galectin-3 possesses a high binding affinity to the LacdiNAc group through its carbohydrate-recognition domain [32][33]. Quite recently, Sedlář and co-workers have shown that the LacdiNAc disaccharide, added in cell culture medium, inhibits binding of galectin-3 to human adipose tissue-derived stem cells and human umbilical vascular endothelial cells in a concentration-dependent manner [34]. Since galectin-3 is involved in cell-to-substratum interaction [35][36], the glycomimetics of the LacdiNAc disaccharide are now under consideration as a possible therapeutic reagent for several diseases, including cancers [37].

References

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