Glycosyltransferases (GTs) catalyze the transfer of a sugar moiety from an activated donor sugar onto saccharide and nonsaccharide acceptors. A sequence-based classification spreads GTs in many families thus reflecting the variety of molecules that can be used as acceptors. In contrast, this enzyme family is characterized by a more conserved three-dimensional architecture. Until recently, only two different folds (GT-A and GT-B) have been identified for solved crystal structures. The recent report of a structure for a bacterial sialyltransferase allows the definition of a new fold family. Progress in the elucidation of the structures and mechanisms of GTs are discussed in this review. To accommodate the growing number of crystal structures, we created the 3D-Glycosyltransferase database to gather structural information concerning this class of enzymes.

Mutations in the gene encoding the glycosyltransferase polypeptide GalNAc-T3, which is involved in initiation of O-glycosylation, were recently identified as a cause of the rare autosomal recessive metabolic disorder familial tumoral calcinosis (OMIM 211900). Familial tumoral calcinosis is associated with hyperphosphatemia and massive ectopic calcifications. Here, we demonstrate that the secretion of the phosphaturic factor fibroblast growth factor 23 (FGF23) requires O-glycosylation, and that GalNAc-T3 selectively directs O-glycosylation in a subtilisin-like proprotein convertase recognition sequence motif, which blocks processing of FGF23. The study suggests a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation and protease processing to produce intact FGF23.The UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (GalNAc-transferase) 2 isoform GalNAc-T3 was recently implicated in familial tumoral calcinosis (FTC) (1, 2). GalNAc-T3 is a member of the large polypeptide GalNAc transferase gene family containing 20 genes of which 15 have been shown to encode functional enzymes. The GalNAc-transferase gene family is the largest mammalian family of glycosyltransferases, which are involved in catalysis of a single glycosidic linkage, GalNAc␣1-O-Ser/Thr, and collectively the GalNAc-transferase isoforms control the initiation of mucin-type O-glycosylation in the Golgi complex (3, 4). Mucin-type O-glycosylation is one of the most abundant forms of glycosylation of proteins, and is found on a large variety of cell membrane and secreted glycopeptides and glycoproteins. O-Glycosylation imparts unique physicochemical features to glycoproteins and O-glycans have been shown to play important functions in almost all known biological processes including intracellular sorting, cell-cell adhesion, and microbial adhesion events (5).Inactivating mutations in GALNT3 were originally discovered in FTC (1, 2, 6, 7), but more recently mutations in the gene encoding the phosphaturic factor FGF23 have also been identified in FTC (8 -10). Thus, FGF23 mutations affecting folding and secretion were identified in FTC patients without mutations in GalNAc-T3. Furthermore, ablation of FGF23 in mice leads to hyperphosphatemia resembling FTC (11). FTC patients with mutations in GalNAc-T3 or FGF23 exhibit hyperphosphatemia and have reduced serum intact FGF23 levels, which may suggest that GalNAc-T3 and FGF23 act in a common pathway. GalNAc-T3 and FGF23 were found to be co-expressed in a number of tissues (2).FGF23 is a key regulator of phosphate homeostasis (12, 13), and is an O-glycosylated glycoprotein of ϳ32 kDa (14). FGF23 is partially processed intracellularly by subtilisin-like proprotein convertases (SPC) at the consensus sequence RXXR2 (RHTR 179 ) between Arg 179 and Ser 180 (14 -16). This processing step appears to be essential in the regulation of phosphate homeostasis, because mutations in the SPC cleavage sequence prevent processing and result in autosomal dominant hypophosphatemic rickets (12). Ma...

Sialyltransferases (STs) represent an important group of enzymes that transfer N-acetylneuraminic acid (Neu5Ac) from cytidine monophosphate-Neu5Ac to various acceptor substrates. In higher animals, sialylated oligosaccharide structures play crucial roles in many biological processes but also in diseases, notably in microbial infection and cancer. Cell surface sialic acids have also been found in a few microorganisms, mainly pathogenic bacteria, and their presence is often associated with virulence. STs are distributed into five different families in the CAZy database (http://www.cazy.org/). On the basis of crystallographic data available for three ST families and fold recognition analysis for the two other families, STs can be grouped into two structural superfamilies that represent variations of the canonical glycosyltransferase (GT-A and GT-B) folds. These two superfamilies differ in the nature of their active site residues, notably the catalytic base (a histidine or an aspartate residue). The observed structural and functional differences strongly suggest that these two structural superfamilies have evolved independently.

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