Proteoglycan
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Glycosaminoglycan Sulfotransferase

(First version published:May15, 2001)
Sulfated glycosaminoglycans are classified into chondroitin sulfate (CS), dermatan sulfate (DS), keratan sulfate (KS), heparan sulfate (HS) and heparin on the basis of their disaccharide structure. Backbone structure of these glycosaminoglycans are modified by C-5 epimerases and sulfotransferases to yield divergent structures (Fig. 1). These divergent structures are related with various physiological functions. Sulfotransferases transfer sulfate from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to strictly defined position of each sugar residue of the repeating disaccharide units, and play pivotal roles to generate characteristic disaccharide structures of glycosaminoglycans. To date, isolation and subsequent cloning of glycosaminoglycan sulfotransferases have been nearly completed.
Fig.1
Figure
Substrate specificity of sulfotransferases
Sulfotransferases involved in biosynthesis of glycosaminoglycans and their substrate specificities are listed in Table 1. In Table 1, human orthologs of every sulfotransferases are shown. Prototypes of each gene family (see below about 7 gene families), which were purified to the homogeneity or cloned first in each family, are also indicated. Sulfotransferases recognize not only the sugar residues to which sulfate is transferred, but also the sequences around the targeting sugar residues. GalNAc4S-6ST transfers sulfate to position 6 of GalNAc(4S) residue contained in the nonreducing terminal sequence, GalNAc(4S)-GlcA(2S)-GalNAc(6S); the activity of GalNAc4S-6ST is markedly stimulated by the presence of GlcA(2S) in this sequence 22. When desulfated DS, which contains small amount of GlcA residues in addition to major IdoA residues, is used as an acceptor for C4ST-1, sulfate is transferred exclusively to position 4 of the GalNAc residue located to the reducing side of GlcA 5. UA2OST is able to sulfate both CS and DS; when CS is used as the acceptor, sulfate is transferred to position 2 of the GlcA residue in the sequence, GalNAc(4S)-GlcA-GalNAc(6S) 37. HS2ST transfers sulfate to position 2 of IdoA residue adjacent to GlcNS but not GlcNS(6S) 34. Three isoforms of HS6ST show different substrate specificities regarding recognition of the structures around the targeting GlcNS residues; HS6ST-1 and HS6ST-2 prefer IdoA and GlcA, respectively, and HS6ST-3 shows intermediate property 40. GlcNAc6ST-1 and C-GlcNAc6ST transfer sulfate to position 6 of GlcNAc residue located to the nonreducing terminal of KS 8. These observations suggest that expression pattern of sulfotransferases in the individual tissue may contributes formation of characteristic sequence of glycosaminoglycans synthesized in the tissue.

Sulfotransferase genes
Glycosaminoglycan sulfotransferases are classified into 7 gene families on the basis of the amino acid sequences; C6ST/KSGal6ST/GlcNAc6ST family, C4ST/D4ST family, GalNAc4S-6ST family, HS2ST/UA2OST family, NDST family, HS6ST family and HS3ST family (Fig. 2). Weak homology is observed among NDSTs, HS3STs and GalNAc4S-6ST. Some members of C6ST family (C6ST-2, KSGal6ST and GlcNAc6ST-1) and C4ST family (GalNAc4ST-1, -2 and HNK-1ST) show sulfotransferase activity toward sugar chain of glycoproteins, suggesting that sulfotransferases involved in biosynthesis of proteoglycans and glycoproteins may be evolved from the common ancestral genes. No isoforms of HS2ST, UA2OST and GalNAc4S-6ST are known. 2-O-sulfation of uronate in heparan sulfate is assumed to be catalyzed by a single HS2ST, since 2-O-sulfated uronates in heparan sulfate were not detected in HS2ST-deficient mice 75.

FIg.2 Phylogenic tree of GAG sulfotransferases
Function of sugar chains attached to sulfotransferases
Most of the purified glycosaminoglycan sulfotransferases were shown to be glycoproteins containing N-linked oligosaccharides because N-Glycanase digestion lowered molecular mass of these proteins. The oligosaccharide contents of C6ST-1, C4ST-1 and GalNAc4S-6ST amount to 40% of the purified proteins. Of four potential N-glycosylation sites in C4ST-1, N-glycan attached to the fourth N-glycosylation sites from the N-terminus (N-4 glycan) was essential for the enzyme activity. The recombinant C4ST-1 containing N-4 glycan alone was much more unstable at 37 than the control recombinant protein, suggest that N-glycans other than N-4 glycan contribute to the stability of C4ST-1. 76. There are 6 potential N-glycosylation sites in C6ST-1. N-4 and N-6 glycan of C6ST-1 were required for the enzyme activity. N-4 glycan of C6ST-1 was essential for the proper Golgi localization. N-5 glycan of C6ST-1 was not required for sulfation of GalNAc residue of chondroitin but required for sulfation of Gal residue of keratan sulfate 77.

Biological functions of sulfotransferases
Production and analysis of mice deficient in various sulfotransferases and gene knockdown experiments in various animals as well as studies on human hereditary diseases have been revealed divergent physiological roles of sulfotransferases. In Table 2, various functions of sulfotransferases currently reported are indicated. C-GlcNAc6ST and C6ST-1 were reported to be genes responsible for macular corneal dystrophy 10 and Spondyloepiphyseal dysplasia (SED Omani type) 65, respectively. Deficient in C4ST-1 51, HS2ST 60 and NDST-1 53-55 in mice resulted in neonatal death, and deficient in HS6ST-1 in mice caused late embryonic lethality, indicating that these sulfotransferases play essential roles in maintaining normal life through biosynthesis of glycosaminoglycans with characteristic structures. To study the role of NDST-1 in inflammation and liver function, endothelial cell-specific 56 and hepatocyte-specific 57 Ndst-1 knockout mice were generated. Analysis of these mice clearly showed that endothelial HS and hepatic HS play crucial roles in the neutrophil infiltration and the clearance of lipoprotein particles, respectively. HS3ST-3B 47 and C4ST-178 were found to be genes required for infection of herpes simplex virus type 1 (HSV-1) to wild type CHO cells and sog9 cells isolated from HS-deficient gro2C cells that are partially resistant to HSV-1 infection, respectively. Cell surface HS containing -IdoA(2S)-GlcN(3S)- unit which is a product of HS3ST-3B and cell surface CS-E containing –GlcA-GalNAc(4S, 6S)- unit which is synthesized by the successive reaction of C4ST-1 and GalNAc4S-6ST are thought to provide sites for the binding of viral glycoproteins gD and gC, respectively.
Osami Habuchi (Aichi University of Education)
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Kimata K, Habuchi O, Habuchi H, Watanabe H, Kockout Mice and Proteoglycans, Complehensive Glycoscience Vol. 4, Capter 3.11, Elsevier, 2007
Sep. 15, 2007
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