Carbohydrate-modifying Sulfotransferases: Structure, Function, and Pathophysiology

3′-phosphoadenosine 5′-phosphosulfate HNK-1 sulfotransferase chondroitin GalNAc 4-O-sulfotransferase N-acetylgalactosamine 4-O-sulfotransferase high endothelial venules keratan sulfate Gal-6-O-sulfotransferase GlcNAc 6-O-sulfotransferase L-selectin ligand sulfotransferase sialic acid macular corneal dystrophy heparan sulfate GlcNSO36-O-sulfotransferase N-deacetylase/sulfotransferase Sulfated oligosaccharides play diverse roles in development, differentiation, and homeostasis. For example, heparan sulfate or heparan sulfate-like glycans were shown to play roles in binding growth factors to receptors (1Yayon A. Klagsbrun M. Esko J.D. Leder P. Ornitz D.M. Cell. 1991; 64: 841-848Abstract Full Text PDF PubMed Scopus (2070) Google Scholar, 2Rapraeger A.C. Krufka A. Olwin B.B. Science. 1991; 252: 1705-1708Crossref PubMed Scopus (1284) Google Scholar) and adhesion of herpes simplex virus 1 to the cell surface (3Shukla D. Liu J. Blaiklock P. Shworak N.W. Bai X. Esko J.D. Cohen G.H. Eisenberg R.J. Rosenberg R.D. Spear P.G. Cell. 1999; 99: 13-22Abstract Full Text Full Text PDF PubMed Scopus (847) Google Scholar). Abolition of sulfation in heparan sulfate synthesis results in neonatal death during mouse development (4Bullock S.L. Fletcher J.M. Beddington R.S. Wilson V.A. Genes Dev. 1998; 12: 1894-1906Crossref PubMed Scopus (394) Google Scholar) and abnormal development in Drosophila (5Lin X. Perrimon N. Nature. 1999; 400: 281-284Crossref PubMed Scopus (412) Google Scholar,6Tsuda M. Kamimura K. Nakato H. Archer M. Staatz W. Fox B. Humphrey M. Olson S. Futch T. Kaluza V. Siegfried E. Stam L. Selleck S.B. Nature. 1999; 400: 276-280Crossref PubMed Scopus (352) Google Scholar). These sulfate groups are formed by sulfotransferases. Sulfotransferases specifically transfer a sulfate group from the sulfate donor substrate, 3′-phosphoadenosine 5′-phosphosulfate (PAPS),1 to a specific position of a specific carbohydrate residue. Molecular cloning of these sulfotransferases was achieved initially by purifying a given enzyme and cDNA cloning based on the amino acid sequence of the purified enzyme. These pioneering clonings include heparan sulfateN-deacetylase/sulfotransferase (7Hashimoto Y. Orellana A. Gil G. Hirschberg C.B. J. Biol. Chem. 1992; 267: 15744-15750Abstract Full Text PDF PubMed Google Scholar, 8Eriksson I. Sandback D. Ek B. Lindahl U. Kjellen L. J. Biol. Chem. 1994; 269: 10438-10443Abstract Full Text PDF PubMed Google Scholar), chondroitin sulfate GalNAc 6-O-sulfotransferase (9Fukuta M. Uchimura K. Nakashima K. Kato M. Kimata K. Shinomura T. Habuchi O. J. Biol. Chem. 1995; 270: 18575-18580Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar), heparan sulfate GlcN 3-O-sulfotransferase (10Shworak N.W. Liu J. Fritze L.M. Schwartz J.J. Zhang L. Logeart D. Rosenberg R.D. J. Biol. Chem. 1997; 272: 28008-28019Abstract Full Text Full Text PDF PubMed Scopus (149) Google Scholar), and galactosylceramide 3-O-sulfotransferase (11Honke K. Tsuda M. Hirahara Y. Ishii A. Makita A. Wada Y. J. Biol. Chem. 1997; 272: 4864-4868Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar). These studies demonstrate that sulfotransferases also have the same type II membrane topology as other Golgi enzymes such as glycosyltransferases. The crystal structure of an estrogen sulfotransferase revealed the amino acid sequence motifs that correspond to the binding sites for 5′-phosphosulfate and 3′-phosphate groups of the donor substrate, PAPS (12Kakuta Y. Pedersen L.G. Carter C.W. Negishi M. Pedersen L.C. Nat. Struct. Biol. 1997; 4: 904-908Crossref PubMed Scopus (230) Google Scholar). Comparison of the amino acid sequences of these domains shows that they are conserved among the sulfotransferases cloned to date (13Kakuta Y. Pedersen L.G. Pedersen L.C. Negishi M. Trends Biochem. Sci. 1998; 23: 129-130Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar). Initial molecular cloning of a sulfotransferase was also achieved by expression cloning using antibodies specific to a given carbohydrate. These studies include cloning of HNK-1 sulfotransferase (HNK-1ST) (14Ong E. Yeh J.C. Ding Y. Hindsgaul O. Fukuda M. J. Biol. Chem. 1998; 273: 5190-5195Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,15Bakker H. Friedmann I. Oka S. Kawasaki T. Nifant'ev N. Schachner M. Mantei N. J. Biol. Chem. 1997; 272: 29942-29946Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar). In one of these studies, it was revealed that there is a conserved amino acid sequence motif ZZ RDPXXZ among cloned sulfotransferases, where X and Z denote any amino acid and a hydrophobic amino acid, respectively (14Ong E. Yeh J.C. Ding Y. Hindsgaul O. Fukuda M. J. Biol. Chem. 1998; 273: 5190-5195Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). This motif turned out to correspond to a part of the binding site for the 3′-phosphate group of PAPS. Site-directed mutagenesis of these amino acids and crystal structure analysis, described above, showed that the arginine 189 and serine 197 in this region are involved in hydrogen bonding to the 3′-phosphate group, whereas the aspartic acid 190 and proline 191 residues reside in the core structure of the 3′-phosphate binding site forming a tight turn in the polypeptide (Fig.1). The lysine 128 residue in the 5′-phosphosulfate binding site may also be involved in binding to an acceptor in which sulfation takes place at the 3′-OH (Fig. 1), because the K128R mutant enzyme showed lower affinity to the acceptor compared with the wild-type enzyme (16Ong E. Yeh J.C. Ding Y. Hindsgaul O. Pedersen L.C. Negishi M. Fukuda M. J. Biol. Chem. 1999; 274: 25608-25612Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). The presence of the weak but discernible similarity among different sulfotransferases suggested the possibility that other sulfotransferases may be identified by their similarity to sulfotransferases already cloned. Indeed, following the cloning of HNK-1ST, two sulfotransferases were cloned based on their similarity to HNK-1ST. Studies on the substrate specificity of these sulfotransferases, however, unexpectedly revealed that these sulfotransferases encode for chondroitin GalNAc 4-O-sulfotransferases (Ch4STs) (17Yamauchi S. Mita S. Matsubara T. Fukuta M. Habuchi H. Kimata K. Habuchi O. J. Biol. Chem. 2000; 275: 8975-8981Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 18Hiraoka N. Nakagawa H. Ong E. Akama T.O. Fukuda M.N. Fukuda M. J. Biol. Chem. 2000; 275: 20188-20196Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar). This is rather striking, considering that HNK-1ST and Ch4ST catalyze very different reactions; HNK-1ST adds a sulfate to the 3-position of glucuronic acid, which is in turn attached to the 3-position of galactose inN-acetyllactosamine, whereas Ch4ST adds a sulfate to the 4-position of N-acetylgalactosamine, which is in turn attached to the 4-position of glucuronic acid. The hydroxyl groups in both C-3 of glucuronic acid and C-4 of N-acetylgalactosamine are projected above their respective pyranose rings. It is tempting to speculate that the active sites of HNK-1ST and Ch4ST may approach the acceptor from above the plane of the respective acceptor. These results suggest that seemingly unrelated sulfotransferases could be cloned by their similarity to the probed sulfotransferase (see also Fig.2). On the other hand, sulfotransferases sharing a similar reaction and acceptor are often related to each other. Following the cloning of Ch4ST, N-acetylgalactosamine 4-O-sulfotransferases (GalNAc4ST-1 and GalNAc4ST-2) that add a sulfate to the 4-position ofN-acetylgalactosamine in GalNAcβ1→4GlcNAc→R were thus molecularly cloned based on their similarity (19Xia G. Evers M.R. Kang H.G. Schachner M. Baenziger J.U. J. Biol. Chem. 2000; 275: 38402-38409Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar, 20Okuda T. Mita S. Yamauchi S. Fukuta M. Nakano H. Sawada T. Habuchi O. J. Biol. Chem. 2000; 275: 40605-40613Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 21Hiraoka N. Misra A. Belot F. Hindsgaul O. Fukuda M. Glycobiology. 2001; 11: 495-504Crossref PubMed Scopus (38) Google Scholar). It has been demonstrated thatN-acetylgalactosamine 4-O-sulfation in hormonal glycoproteins such as lutropin is essential for maintaining an effective half-life for the hormonal glycoproteins once they are released into the bloodstream. Unsulfated forms are quickly taken up by galactose-binding lectin in the liver, whereas sialylated forms survive too long in the bloodstream, potentially causing an over-response in target tissues (22Fiete D. Srivastava V. Hindsgaul O. Baenziger J.U. Cell. 1991; 67: 1103-1110Abstract Full Text PDF PubMed Scopus (262) Google Scholar). This hypothesis can be tested now by generating mutant mice with defective GalNAc4ST-1 and/or GalNAc4ST-2 by gene targeting. Lymphocyte homing and recirculation are important processes for detection of foreign antigens by the immune system. Counter-receptors expressed on high endothelial venules (HEV) capture circulating lymphocytes through L-selectin-dependent adhesion that requires sulfation in O- linked oligosaccharides attached to the counter-receptors. Previous studies showed that these sulfated oligosaccharides are either 6-sulfosialyl Lewis x (Siaα2→3Galβ1→4(Fucα1→3(sulfo→6))GlcNAcβ1→R) or 6′-sulfo-sialyl Lewis x (Siaα2→3(sulfo→6)Galβ1→4(Fucα1→3)GlcNAcβ1→R) (23Hemmerich S. Leffler H. Rosen S.D. J. Biol. Chem. 1995; 270: 12035-12047Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). To determine the roles of sulfation in L-selectin ligands, a sulfotransferase was molecularly cloned by screening the expressed sequence tag data base using cDNAs encoding Ch6ST (9Fukuta M. Uchimura K. Nakashima K. Kato M. Kimata K. Shinomura T. Habuchi O. J. Biol. Chem. 1995; 270: 18575-18580Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) and keratan sulfate Gal 6-O-sulfotransferase (KS6ST) (24Fukuta M. Inazawa J. Torii T. Tsuzuki K. Shimada E. Habuchi O. J. Biol. Chem. 1997; 272: 32321-32328Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar) as probes. This strategy was chosen because Gal- and GalNAc-6-O-sulfotransferases were assumed to be homologous to other 6-O-sulfotransferases. Two independent studies cloned this GlcNAc 6-O-sulfotransferase (GlcNAc6ST-2) from mouse and human, and they were called L-selectin ligand sulfotransferase (LSST) and HEC-GlcNAc6ST, respectively (25Hiraoka N. Petryniak B. Nakayama J. Tsuboi S. Suzuki M. Yeh J.C. Izawa D. Tanaka T. Miyasaka M. Lowe J.B. Fukuda M. Immunity. 1999; 11: 79-89Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 26Bistrup A. Bhakta S. Lee J.K. Belov Y.Y. Gunn M.D. Zuo F.R. Huang C.C. Kannagi R. Rosen S.D. Hemmerich S. J. Cell Biol. 1999; 145: 899-910Crossref PubMed Scopus (246) Google Scholar). The mouse and human sequences share 73% identical amino acid residues and thus are regarded as orthologs to each other. In parallel, Uchimuraet al. (27Uchimura K. Muramatsu H. Kadomatsu K. Fan Q.W. Kurosawa N. Mitsuoka C. Kannagi R. Habuchi O. Muramatsu T. J. Biol. Chem. 1998; 273: 22577-22583Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar) earlier cloned a cDNA encoding another GlcNAc 6-O-sulfotransferase, GlcNAc6ST-1, by its similarity with mouse Ch6ST. The amino acid sequence of LSST shares 35.6, 35.4, and 32.3% identity with those of mouse GlcNAc6ST-I, human KS6ST, and chicken Ch6ST, respectively. Transfection studies using cDNAs encoding GlcNAc6ST-2, core2GlcNAcT-1, α1,3-fucosyltransferase VII, and CD34 showed that both mouse and human LSST form 6-sulfosialyl Lewis x predominantly in core2 branched O- glycans (25Hiraoka N. Petryniak B. Nakayama J. Tsuboi S. Suzuki M. Yeh J.C. Izawa D. Tanaka T. Miyasaka M. Lowe J.B. Fukuda M. Immunity. 1999; 11: 79-89Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar, 26Bistrup A. Bhakta S. Lee J.K. Belov Y.Y. Gunn M.D. Zuo F.R. Huang C.C. Kannagi R. Rosen S.D. Hemmerich S. J. Cell Biol. 1999; 145: 899-910Crossref PubMed Scopus (246) Google Scholar). Chinese hamster ovary cells expressing these O- glycans enhance L-selectin-mediated adhesion compared with Chinese hamster ovary cells expressing non-sulfated sialyl Lewis x. By contrast, GlcNAc6ST-1 preferentially adds a sulfate to N-glycans, showing no enhanced L-selectin-mediated adhesion (25Hiraoka N. Petryniak B. Nakayama J. Tsuboi S. Suzuki M. Yeh J.C. Izawa D. Tanaka T. Miyasaka M. Lowe J.B. Fukuda M. Immunity. 1999; 11: 79-89Abstract Full Text Full Text PDF PubMed Scopus (211) Google Scholar). Human and mouse LSST were also shown to add a sulfate to extended core1 O- glycans, forming Galβ1→4(sulfo→6)GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr (28Yeh J. Hiraoka N. Petryniak B. Nakayama J. Ellies L.G. Rabuka D. Hindsgaul O. Marth J.D. Lowe J.B. Fukuda M. Cell. 2001; 105: 957-969Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar). This structure is the minimum epitope for MECA-79 antibody, which decorates the lumenal surface of HEV and inhibits lymphocyte attachment to HEV (29Streeter P.R. Rouse B.T. Butcher E.C. J. Cell Biol. 1988; 107: 1853-1862Crossref PubMed Scopus (526) Google Scholar). Moreover, biantennary O- glycans containing both core2 branch and extended core1 structures can have twin 6-sulfosialyl Lewis x. Siaα2→3Galβ1→4(Fucα1→3(sulfo→6))GlcNAcβ1↘6Siaα2→3Galβ1→4(Fucα1→3(sulfo→6))GlcNAcβ1→3GalNAcα1→Ser/ThrEq. 1 STRUCTURE1 Such O- glycans apparently have superior L-selectin ligand activity compared with those containing a core2 branch or extended core1 alone (28Yeh J. Hiraoka N. Petryniak B. Nakayama J. Ellies L.G. Rabuka D. Hindsgaul O. Marth J.D. Lowe J.B. Fukuda M. Cell. 2001; 105: 957-969Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar). For L-selectin ligands, it has been reported that 6′-sulfo-sialyl Lewis x may also be present (23Hemmerich S. Leffler H. Rosen S.D. J. Biol. Chem. 1995; 270: 12035-12047Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). α1,3-Fucosyltransferase VII, however, cannot add a fucose once sialyl N-acetyllactosamine contains 6′-sulfogalactose, whereas KS6ST cannot add a sulfate to 6′-galactose in sialyl Lewis x (30Maly P. Thall A. Petryniak B. Rogers C.E. Smith P.L. Marks R.M. Kelly R.J. Gersten K.M. Cheng G. Saunders T.L. Camper S.A. Camphausen R.T. Sullivan F.X. Isogai Y. Hindsgaul O. von Andrian U.H. Lowe J.B. Cell. 1996; 86: 643-653Abstract Full Text Full Text PDF PubMed Scopus (663) Google Scholar, 31Torii T. Fukuta M. Habuchi O. Glycobiology. 2000; 10: 203-211Crossref PubMed Scopus (49) Google Scholar). If 6′-sulfo-sialyl Lewis x is actually present in L-selectin ligand oligosaccharides, a novel sulfotransferase or a novel α1,3-fucosyltransferase must be present. Before attempting to clone such an enzyme, it is critical to determine whether 6′-sulfo-sialyl Lewis x actually exists in HEV and other organs. The GlcNAc6ST gene family includes a GlcNAc 6-O-sulfotransferase that forms keratan sulfate together with KS6ST. Molecular cloning of this GlcNAc6ST in humans was achieved by an entirely different approach. It has been reported that impaired GlcNAc 6-O-sulfation in corneal keratan sulfate causes macular corneal dystrophy (MCD) in patients, with a symptom of opaque cornea (32Nakazawa K. Hassell J.R. Hascall V.C. Lohmander L.S. Newsome D.A. Krachmer J. J. Biol. Chem. 1984; 259: Full Text PDF PubMed Google Scholar, R. R. Hassell J.R. PubMed Scopus Google Scholar). By analysis, the critical region for has been to a region by and J.M. F. F. J. J. J. 1996; Google Scholar). two cell one cDNA encoding this GlcNAc6ST or was to reside this Moreover, of revealed that are in either its region or its region T.O. K. Nakayama J. H. K. T. A. Kawasaki S. Y. N. S. T. Y. S. A. Fukuda M.N. Nat. 2000; PubMed Scopus Google Scholar). 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Glycobiology. 2000; Scholar), that both mouse and human may be involved in ligand It is tempting to speculate that into and in the human may of sulfotransferases in the human, two different enzymes with and of the sulfotransferases and is that there to be one enzyme that has identical or similar in such an In to have an by acceptor specificity in can be sulfated at the 3-position of galactose by molecular cloning of (11Honke K. Tsuda M. Hirahara Y. Ishii A. Makita A. Wada Y. J. Biol. Chem. 1997; 272: 4864-4868Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar), sulfotransferases that add a sulfate to the 3-position of galactose were cloned K. Tsuda M. S. Wada Y. N. I. Nakayama J. N. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. Hiraoka N. Suzuki M. K. Misra J. Hindsgaul O. Fukuda M. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar, A. S. K. J. Biol. 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