ST6 Beta-Galactoside Alpha-2,6-Sialyltranferase 2 (ST6GAL2)

Abstract

Sialic acids are derivatives of the negatively charged acidic sugar neuraminic acid. Over 50 naturally occurring members of the sialic acid family have been discovered to date (Angata and Varki 2002); N-acetylneuraminic acid (NeuAc), N-glycolylneuraminic acid (NeuGc), and deaminoneuraminic acid (KDN) are representative members of this family. The importance of these molecules is demonstrated by the fact that impairment of their biosynthesis is lethal to mice embryos (Schwarzkopf et al. 2002). Sialic acids usually form the terminal ends of the carbohydrate groups of glycoconjugates. Because of their negative charge and their exposed positions on cell-surface molecules, they often function as key determinants of oligosaccharide structures that mediate a variety of biological processes including cell–cell interaction, cell migration, adhesion, metastasis, and pathogen infection. In fact, there are numerous sialic acid recognition molecules such as the sialic acid-binding immunoglobulin-like lectins (siglecs) (Crocker et al. 2007). A superfamily of glycosyltransferases called sialyltransferases catalyzes the synthesis of sialylglycoconjugates by transferring a sialic acid molecule from the donor substrate CMP-Sia to an acceptor carbohydrate. To date, cDNA cloning of 20 mammalian sialyltransferases has been completed, and their enzymatic properties have been analyzed. These enzymes are grouped into four families according to the type of carbohydrate linkage they synthesize: β-galactoside α2,3-sialyltransferases (ST3Gal family), β-galactoside α2,6-sialyltransferases (ST6Gal family), N-acetylgalactosamine (GalNAc) α2,6-sialyltransferases (ST6GalNAc family), and α2,8-sialyltransferases (ST8Sia family). All animal sialyltransferases characterized to date have type II transmembrane topology and are thought to localize to the Golgi body. These sialyltransferases are classified into CAZy (carbohydrate-active enzymes) glycosyltransferase family 29 (Coutinho et al. 2003). All animal sialyltransferases have common structural features composed of a short N-terminal cytoplasmic tail, a transmembrane domain, a stem region, and a catalytic domain, which contains highly conserved motifs called sialylmotifs L (long), S (short), III (third position in the sequence), and VS (very short). The members of the ST6Gal family transfer sialic acid from CMP-sialic acid (CMP-Sia) to the galactose residues at the nonreducing ends of glycoconjugates through an α2,6-linkage. Two members of the ST6Gal family, ST6Gal-I and ST6Gal-II, have been identified in mammals to date. These enzymes commonly utilize the Galβ1–4GlcNAc structure on glycoproteins and oligosaccharides as acceptor substrates (Takashima et al. 2002, 2003; Krzewinski-Recchi et al. 2003); however, ST6Gal-II utilizes the LacdiNAc structure (GalNAcβ1–4GlcNAc) as a preferred acceptor substrate over the Galβ1–4GlcNAc structure (Rohfritsch et al. 2006; Laporte et al. 2009). The ST6Gal-I gene is ubiquitously expressed, whereas the ST6Gal-II gene is expressed in tissue- and stage-specific manner. The overall amino acid sequence identity of human ST6Gal-II is 48.9 % to human ST6Gal-I, 77.1 % to mouse ST6Gal-II, and 73.2 % to bovine ST6Gal-II, respectively. Analysis of the genomic structures of the ST6Gal-I and ST6Gal-II genes suggested that these genes arose from a common ancestral gene (Harduin-Lepers et al. 2005; Takashima 2008; Harduin-Lepers 2010).