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GLY FINAL 1207 PGD cleanxrefs2 O-Glycans O-Glycans O-Linked glycoproteins are usually large proteins with a molecular mass of >200 kDa. Glycosylation generally occurs in high-density clusters and may represent as much as 50‑80% of the overall mass. O-Linked glycans are most commonly attached to the peptide chain through serine (Ser) or threonine (Thr) residues. While O-linkage does link primarily to peptide residues through a hydroxyl group, there is no consensus sequence required. Tyrosine (Tyr), hydroxylysine (Hydroxy-Lys), or hydroxyproline (Hydroxy-Pro) may also be the peptide site of O-linked glycosylation. The most common O-linked glycans are the mucin-type glycans, which contain an initial GalNAc residue. There are eight mucin-type core structures (see Figure 6). Even with common mucin-type cores, O-linked glycans tend to be very heterogeneous, and there are other structures possible, in addition to several sialylated core structures. However, O-linked glycans are commonly linear or biantennary and have comparatively less branching than N-glycans. β1,3 Ser/ Thr Core 1 β1,6 β1,3 Ser/ Thr Core 2 β1,3 Ser/ Thr Core 3 β1,6 β1,3 Ser/ Thr Core 4 α1,3 Ser/ Thr Core 5 Glycan Component Classes Structures Mucins are glycoproteins that contain large numbers of high-density clusters of O-linked glycans. The mucin-type glycans of these proteins frequently form cross-linked connections in aqueous solutions, resulting in a high viscosity gel (mucus). Mucins can be secreted, but may also be membrane bound and form glycan-dense areas on the cell surface. In addition to mucin-type glycans, O-linked glycans may incorporate sugars other than GalNAc as the initial sugar bound to the serine/ threonine residues. Examples of alternative O-linked glycans are: • Nuclear and cytoplasmic glycoproteins that contain GlcNAc as the initiating sugar. • Fibrinolytic and coagulation factors that contain fucose as the initiating sugar. • Mannoproteins that are typical to yeasts and that incorporate mannose as the initiating sugar. O-Mannosyl glycans are also found in human α-dystroglycan and other nervous system glycoproteins. • Glycosaminoglycans (GAGs) that are components of proteoglycan structures and contain xylose bound exclusively to serine residues. • Plant cell wall extensins that contain both arabinose attached to hydroxyproline and galactose attached to serine. • Plant arabinogalactans that are attached to the hydroxyproline within the peptide backbone through O-linked galactose or glucose. • Galactose and αGlc(1→2)Gal residues that are bound to hydroxylysine within the triple helix structures of collagen. Complement factor C1q also contains αGlc(1→2)Gal-hydroxyproline sequences. • Glycogenin, a protein precursor required for glycogen synthesis, contains glucose O-linked to tyrosine; the initial glucose is subsequently elongated by glycogen synthase to generate glycogen. Key to Monosaccharide Symbols β1,6 Ser/ Thr Core 6 α1,6 β-D-Glucose (Glc) β-D-Xylose (Xyl) β-D-Mannose (Man) α-N-Acetylneuraminic acid; Sialic acid (NeuNAc) β-D-Galactose (Gal) β-D-Glucuronic acid (GlcA) β-D-N-Acetylglucosamine (GlcNAc) α-L-Iduronic acid (IdoA) β-D-N-Acetylgalactosamine (GalNAc) α-L-Fucose (Fuc) Ser/ Thr Core 7 α1,3 Core 8 Ser/ Thr Figure 6. Core structures of mucin-type O-glycans. Your Favorite Gene™, Your Comprehensive Gene Search Tool, visit sigma.com/yfg 13 GLY FINAL 1207 PGD cleanxrefs2 O-Glycans Glycan Component Classes Biosynthesis and Degradation O-linked glycosylation is a true post-translational event that occurs in the Golgi, and no oligosaccharide precursor is required for protein transfer. The serine/threonine residues are modified directly by covalent addition of N-acetylgalactosamine residues. Initiation of mucin-type O-glycosylation is dependent upon polypeptide N-acetylgalactosyl transferase (ppGalNAcT); at least twelve mammalian ppGalNAcT isozymes have been identified. The first step in the synthesis of mucin-type glycans requires catalysis by a ppGalNAcT in the presence of UDP-GalNAc as the carbohydrate donor. Subsequent elongation and termination of O-linked glycans is carried out by several glycosyltransferases. The relative expression and subcellular distribution of the various glycosyltransferases determine the outcome of O-glycan biosynthesis. For additional discussion of Glycosyltransferases, see page 87. Termination of O-linked glycans usually includes Gal, GlcNAc, GalNAc, Fuc, or sialic acid. By far the most common modification of the core Gal-β(1→3)GalNAc is mono-, di-, or trisialylation (Core 1 and 2) (see Figure 7). A less common, but widely distributed O-linked hexasaccharide structure contains β(1→4)-linked Gal and β(1→6)-linked GlcNAc, as well as sialic acid. α2,3 More complex O-glycans serve other functions. ZP glycoproteins are O-linked glycans present in high concentrations in the zona pellucida surrounding mammalian eggs. Human ZP matrix contains four ZP glycoproteins, while the mouse ZP matrix has only three.3 The roles of ZP glycoproteins have not been fully determined but are thought to be associated with sperm reception. O-Linked glycans are also involved in hematopoiesis and inflammation response mechanisms. The P-selectin glycoprotein ligand 1 (PSGL-1) contains, among other glycans, a Core 2 O-glycan capped with sialyl Lewis X (C2‑O-sLeX, see Figure 8). PSGL-1 is the primary adhesion target for P-selectin and a target for E-selectin, which are involved in leukocyte rolling and recruitment into sites of inflammation.4 β1,4 α2,3 β1,3 β1,4 β1,3 β1,4 α1,3 β1,6 β1,3 β1,3 Ser/ Thr α2,6 α2,3 Proteins that are O-linked with GlcNAc may alternatively be phosphorylated at the same peptide site, and similarly to phosphorylation, O-GlcNAc processing has been associated with cellular signaling events, including insulin signaling and RNA transcription regulation.1,2 β1,3 Ser/ Thr Figure 8. Structure of the O-linked Core 2 glycan with attached sialyl Lewis X (sLex) moiety. Ser/ Thr α2,6 The human ABO blood antigens are small O-linked glycans that may be attached to membrane glycoproteins or to cell surface glycolipids. The antigens may also be secreted by tissues as free oligosaccharides or as components of soluble glycoproteins and glycosphingolipids. The blood group O(H) determinant does not generate an immune response, but when modified by addition of either α(1→3)GalNAc (blood group A antigen) or α(1→3)Gal (blood group B antigen), the resultant trisaccharide initiates an immune response (see Figure 9). α2,8 α1,2 Figure 7. Disialylated (top) and trisialylated (bottom) O-linked Core 1 glycans O-glycan degradation requires α-N-acetylgalactosaminidase in addition to the same exoglycosidases needed for N-glycan degradation. β1,0 R A Functions Secreted mucins at the apical membrane of epithelial cells can link through disulfide bonds and capture water molecules, forming a mucus membrane. The membrane physically protects the cell from hostile environmental factors such as stomach acids and circulating proteases. Mucin secretion by salivary glands provides lubrication for swallowing. Mucins also block infection by pathogens by presenting a wall of O-linked glycans to attract and bind bacterial carbohydrate binding receptors. Many bacterial pathogens express adhesins, carbohydraterecognition proteins specific for cell surface O-glycan structures that function as receptors for binding and infecting host cells. The adhesins bind to the mucin surface glycans, preventing further progress by the pathogen; the bound pathogen can then be eliminated. α1,2 α1,3 β1,0 R B α1,2 α1,3 β1,0 R C Glycosylation by a single GlcNAc moiety is a unique form of O-glycosylation, in that it has been shown to be dynamic, rather than static like other types of O-linked glycosylation. This modification is reversible and catalyzed by the enzymes uridine diphospho-N-acetylglucosmine:polypeptide β-N-acetylglucosaminyltransferase (O-GlcNAc transferase) and neutral β-N-acetylglucosaminidase (O-GlcNAcase). 14 sigma.com/glycobiology Figure 9. Structures of (A) blood group H(O), (B) blood group A, and (C) blood group B antigens. R represents the hydroxyl-containing amino acid or lipid binding site for the antigen. To place an order, call your local office or visit sigma.com/order GLY FINAL 1207 PGD cleanxrefs2 O-Glycans Lacto-N-difucohexaose I α-L-Fuc-(1→2)-β-D-Gal-(1→3)[α-L-Fuc-(1→4)]-β-D-GlcNAc-(1→3)-β-D-Gal(1→4)-D-Glc; Leb-lactose; Lewis-b hexasaccharide; LNDFH I C38H65NO29 FW 999.91 [16789‑38‑1] from human milk, ≥95% (HPAE/PAD) Blood group Leb active hexasaccharide. store at: 2-8°C Schindler's Disease has been identified as a congenital disorder of glycosylation that affects O-linked glycans and is due to an α-Nacetylgalactosaminidase deficiency. References: 1. Slawson, C., et al., O-GlcNAc cycling: how a single sugar post-translational modification is changing the way we think about signaling networks. J. Cell. Biochem., 97, 71‑83 (2006). 2. Wells, L., and Hart, G.W., O-GlcNAc turns twenty: functional implications for posttranslational modification of nuclear and cytosolic proteins with a sugar. FEBS Lett., 546, 154‑8 (2003). 3. Gupta, S.K., et al., Structural and functional attributes of zona pellucida glycoproteins. Soc. Reprod. Fertil. Suppl., 63, 203‑16 (2007). 4. Sperandio, M., Selectins and glycosyltransferases in leukocyte rolling in vivo. FEBS J., 273, 4377‑4389 (2006). α1 2 β1 3 α1 4 β1 3 L7033-1MG β1 4 Glycan Component Classes T antigen and Tn antigen are O-glycans that have incomplete glycosylation. T antigen (tumor-associated or TF (Thomsen-Fridenreich) antigen) is the Core 1 disaccharide (Gal-β(1→3)GalNAc) that results after desialylation by viral or bacterial neuraminidase. T antigen may also result due to changes in the glycosyltransferases available. Tn antigen is an O-linked GalNAc that is not extended by a glycosyltransferase into a complete core structure. These antigens are not expressed on the surface of normal cells, but are commonly present in cancerous cells and may serve as tumor markers. 1 mg Lacto-N-difucohexaose II β-D-Gal-(1→3)-[α-L-Fuc-(1→4)]-β-D-GlcNAc-(1→3)-β-D-Gal-(1→4)-[α-L-Fuc(1→3)]-D-Glc; LNH C38H65NO29 FW 999.91 [62258‑12‑2] from human milk, ~95% Lewis-a trisaccharide linked to 3‑fucosyllactose O-Linked Neutral Glycans store at: 2-8°C N-Acetyl-D-lactosamine 2‑Acetamido-2‑deoxy-4‑O-β-D-galactopyranosyl-D-glucopyranose; N-Acetyl4‑O-(β-D-galactopyranosyl)-D-glucosamine; β-D-Gal-(1→4)-D-GlcNAc; LN C14H25NO11 FW 383.35 [32181‑59‑2] ≥98% Useful in studies of galactosidase, fucosyltransferase, sialyltransferase, and lectin inhibition. Synthetic β1 3 α1 4 L6645-.5MG β1 3 α1 3 β1 4 0.5 mg store at: −20°C β1 4 A7791-5MG 5 mg A7791-10MG 10 mg A7791-25MG 25 mg A7791-100MG 100 mg 2′-Fucosyl-D-lactose Key to Monosaccharide Symbols α-L-Fuc-(1→2)-β-D-Gal-(1→4)-D-Glc C18H32O15 FW 488.44 [41263‑94‑9] from human milk, ~98% (HPAE/PAD) β-D-Glucose (Glc) β-D-Xylose (Xyl) β-D-Mannose (Man) α-N-Acetylneuraminic acid; Sialic acid (NeuNAc) β-D-Galactose (Gal) β-D-Glucuronic acid (GlcA) β-D-N-Acetylglucosamine (GlcNAc) α-L-Iduronic acid (IdoA) β-D-N-Acetylgalactosamine (GalNAc) α-L-Fucose (Fuc) store at: 2-8°C 2 β 4 F0393-1MG 1 mg F0393-5MG 5 mg Antibody Explorer — all your antibody needs in one place, visit sigma.com/antibody 15 GLY FINAL 1207 PGD cleanxrefs2 O-Glycans O-Linked Sialylated Glycans Glycan Component Classes Lacto-N-fucopentaose I α-L-Fuc (1→2)-β-D-Gal-(1→3)-β-D-GlcNAc-(1→3)-β-D-Gal-(1→4)-D-Glc; LNFP I C32H55NO25 FW 853.77 [7578‑25‑8] 3′-N-Acetylneuraminyl-N-acetyllactosamine sodium salt α-NeuNAc-(2→3)-β-D-Gal-(1→4)-D-GlcNAc; 3′-Sialyl-N-acetyllactosamine; 3′SLN C25H42N2O19 FW 674.60 [81693‑22‑3] from human milk, ≥90% (HPAE/PAD) Blood group H-active pentasaccharide. store at: −20°C store at: 2-8°C α2 α1 2 β1 3 β1 3 β1 4 3 β1 4 A6936-.5MG 0.5 mg A6936-2MG 2 mg 3'-Sialyllactose L5908-5MG 5 mg 3′-N-Acetylneuraminyl-D-lactose sodium salt; NANA-Lactose; α-NeuNAc(2→3)-β-D-Gal-(1→4)-D-Glc; 3'-Sialyl-D-lactose; 3'-SL C23H39NO19 FW 633.55 [35890‑38‑1] Lacto-N-fucopentaose III β-D-Gal-(1→4)-[α-L-Fuc-(1→3)]-β-D-GlcNAc-(1→3)-β-D-Gal-(1→4)-D-Glc; Lexlactose; Lewis-X pentasaccharide; LNFP III C32H55NO25 FW 853.77 [25541‑09‑7] from human milk, ≥95% (HPAE) α2,3 β1,4 from human milk, ≥98% (HPAE/PAD) store at: 2-8°C store at: −20°C A9079-1MG α1,3 β1 4 1 mg from bovine colostrum, ~98% (HPAE/PAD) β1 3 store at: −20°C β1 4 A8681-1MG L7777-1MG 1 mg 6′-Sialyllactose sodium salt 1 mg 6′-N-Acetylneuraminyl-lactose sodium salt; α-NeuNAc-(2→6)-β-D-Gal-(1→4)D-Glc; 6'-SL C23H38NO19Na FW 655.53 [74609‑39‑5] Lacto-N-tetraose β-D-Gal-(1→3)-β-D-GlcNAc-(1→3)-β-D-Gal-(1→4)-D-Glc; LNT C26H45NO21 FW 707.63 [14116‑68‑8] α2,6 β1,4 from human milk, ≥95% (HPAE/PAD) store at: 2-8°C β 3 β 3 β from human milk, ≥95% (HPAE/PAD) 4 store at: −20°C L6770-1MG 1 mg L6770-5MG 5 mg Lacto-N-neo-tetraose 1 mg A9204-5MG 5 mg from bovine colostrum, ≥97% (HPAE/PAD) 8 β-D-Gal-(1→4)-β-D-GlcNAc-(1→3)-β-D-Gal-(1→4)-D-Glc; LNnT C26H45NO21 FW 707.63 [13007‑32‑4] A9204-1MG store at: −20°C A8556-1MG 1 mg A8556-5MG 5 mg from synthetic, ≥85% (HPLC) store at: 2-8°C L6543-2MG 16 sigma.com/glycobiology 2 mg BioFiles, your gateway to Life Science products, services, and more, visit sigma.com/biofiles GLY FINAL 1207 PGD cleanxrefs2 O-Glycans Globotriose Sialyllactose sodium salt 4‑O-(4‑O-α-D-Galactopyranosyl-β-D-galactopyranosyl)-D-glucopyranose; α-DGal-(1→4)-β-D-Gal-(1→4)-D-Glc C18H32O16 FW 504.44 [66580‑68‑5] Mixture of (2→6′) and (2→3′) isomers. store at: 2-8°C α2 3/6 β1 α1 4 β1 4 4 G9287-.5MG ~80% (HPAE/PAD), from bovine colostrum iso-A-Pentasaccharide store at: −20°C A3307-5MG 5 mg A3307-25MG 25 mg α-GalNAc-(1→3)-(α-Fuc-[1→2])-β-Gal-(1→3)-(α-Fuc-[1→4])-Glc; A-LebPentasaccharide C32H55NO24 FW 837.77 [128464‑25‑5] from human milk, ≥97% store at: −20°C A0828-5MG 5 mg A0828-25MG 25 mg 0.5 mg Glycan Component Classes N-Acetylneuraminyl-lactose; α-NeuNAc-(2→3)- and -(2→6)-β-D-Gal-(1→4)D-Glc; Neuramin-lactose C23H38NO19Na FW 655.53 from human urine, ≥90% store at: 2-8°C α1 Blood Group Antigens α1 3 4β-Galactobiose 4‑O-β-D-Galactopyranosyl-D-galactopyranose; β-D-Gal-(1→4)-D-Gal C12H22O11 FW 342.30 [2152‑98‑9] ≥90% 2 α1 4 β1 3 20 μg A7560-20UG B-Pentasaccharide store at: 2-8°C α-Fuc-(1→2)-α-Gal-(1→3)-β-Gal-(1→4)(α-Fuc-[1→3])-Glc C30H52O24 FW 796.72 [72468‑43‑0] β1 4 G9662-2MG 2 mg G9662-10MG 10 mg from human urine, ≥85% store at: 2-8°C Galacto-N-biose α1 2 2‑Acetamido-2‑deoxy-3‑O-β-D-galactopyranosyl-D-galactopyranose; T Antigen; β-D-Gal-(1→3)-D-GalNAc C14H25NO11 FW 383.35 [20972‑29‑6] A substrate for N-acetylglucosaminyltransferase,1 fucosyl- and sialyltransferase,2,3 and galactosidase.4 Also used in lectin inhibition studies.5 Lit. cited: 1. Williams, D., et al., J. Biol. Chem. 255, 11253 (1980) 2. Beyer, T.A. and Hill, R.L., J. Biol. Chem. 255, 5373 (1980) 3. Rearick, J.I., et al., J. Biol. Chem. 254, 4444 (1979) 4. Distler, J.J. and Jourdian, G.W., J. Biol. Chem. 248, 6772 (1973) 5. Tollefsen, S.E. and Kornfeld, R., J. Biol. Chem. 258, 5172 (1983) α1 3 α1 3 β1 4 50 μg B3791-50UG Key to Monosaccharide Symbols store at: −20°C β1 3 A0167-1MG 1 mg A0167-5MG 5 mg β-D-Glucose (Glc) β-D-Xylose (Xyl) β-D-Mannose (Man) α-N-Acetylneuraminic acid; Sialic acid (NeuNAc) β-D-Galactose (Gal) β-D-Glucuronic acid (GlcA) β-D-N-Acetylglucosamine (GlcNAc) α-L-Iduronic acid (IdoA) β-D-N-Acetylgalactosamine (GalNAc) α-L-Fucose (Fuc) Proteomics, glycosylation and other post-translational modifications, visit sigma.com/proteomics 17 GLY FINAL 1207 PGD cleanxrefs2 O-Glycans Lewis and Cell Adhesion Glycans Glycan Component Classes iso-B-Pentasaccharide BLeb-Pentasaccharide; α-Gal-(1→3)-(α-Fuc-[1→2])-β-Gal-(1→3)-(α-Fuc[1→4])-Glc C30H52O24 FW 796.72 [128464‑26‑6] from human urine, ≥85% Lewis-b tetrasaccharide α-Fuc(1→2)-β-Gal-(1→3)-(α-Fuc-[1→4])-GlcNAc; Leb glycan C26H45NO19 FW 675.63 Lewis-b human blood group determinant. store at: 2-8°C store at: −20°C α1 2 α1 3 α1 4 3 β1 20 μg B0799-20UG A-Trisaccharide α1 2 β1 3 α1 4 L7659-1MG 1 mg Lewis-Y hexasaccharide Blood group A trisaccharide; α-D-GalNAc-(1→3)-(α-L-Fuc-[1→2])-D-Gal C20H35NO15 FW 529.49 [49777‑13‑1] store at: room temp α-Fuc-(1→2)-β-Gal-(1→4)(α-Fuc-[1→3])-β-GlcNAc-(1→3)-β-Gal-(1→4)-Glc; Lacto-N-neo-difucohexaose I; Ley-lactose C38H65NO29 FW 999.91 [62469‑99‑2] from human urine store at: 2-8°C α1 2 α1 3 α1 2 250 μg A7911-250UG β1 4 α1 3 β1 3 B-Trisaccharide 20 μg L7401-20UG Blood group B trisaccharide; α-D-Gal-(1→3)-(α-L-Fuc-[1→2])-D-Gal C18H32O15 FW 488.44 [49777‑14‑2] store at: 2-8°C β1 4 Lewis-Y tetrasaccharide α-Fuc-(1→2)-β-Gal-(1→4)-(α-Fuc-[1→3])-GlcNAc C26H45NO19 FW 675.63 Lewis-Y blood group antigenic determinant. α1 2 α1 3 B1422-1MG store at: 2-8°C α1 2 1 mg β1 4 α1 3 H-Trisaccharide Blood group H trisaccharide; α-Fuc-(1→2)-β-Gal-(1→4)-GlcNAc; 2′-FucosylN-acetyllactosamine C20H35NO15 FW 529.49 L7784-1MG synthetic Human blood group H type trisaccharide. store at: 2-8°C α1 2 F7297-1MG 18 sigma.com/glycobiology β1 4 1 mg For Technical Service, call your local office or visit sigma.com/techinfo 1 mg GLY FINAL 1207 PGD cleanxrefs2 O-Glycans α-Gal-(1→3)-Gal Antigens 3′-Sialyl-Lewis-a tetrasaccharide α-NeuNAc-(2→3)-β-D-Gal-(1→3)-(α-L-Fuc-[1→4])-D-GlcNAc; 3'-SLea C31H52N2O23 FW 820.74 [92448‑22‑1] 3‑O-α-D-Galactopyranosyl-D-galactose; α-D-Gal-(1→3)-D-Gal C12H22O11 FW 342.30 [13168‑24‑6] synthetic, ≥90% α2 3 β1 3 store at: 2-8°C α1 4 α1 S2279-.2MG 0.2 mg S2279-1MG 1 mg G7522-5MG 5 mg 3α,4β,3α-Galactotetraose 3′-Sialyl-Lewis-X tetrasaccharide α-NeuNAc-(2→3)-β-D-Gal-(1→4)(α-L-Fuc-[1→3])-D-GlcNAc; 3'-SLeX C31H52N2O23 FW 820.74 [98603‑84‑0] store at: −20°C 3 Glycan Component Classes store at: −20°C 3‑α-Galactobiose 3‑O-(4‑O-[3‑O-α-D-Galactopyranosyl-β-D-galactopyranosyl]-α-D-galactopyranosyl)-D-galactopyranose; α-D-Gal-(1→3)-β-D-Gal-(1→4)-α-D-Gal-(1→3)D-Gal C24H42O21 FW 666.58 [56038‑38‑1] ≥90% store at: −20°C α2 3 β1 4 α1 α1 3 3 G9912-2MG S1782-.2MG 0.2 mg S1782-1MG 1 mg β1 4 α1 3 2 mg Key to Monosaccharide Symbols β-D-Glucose (Glc) β-D-Xylose (Xyl) β-D-Mannose (Man) α-N-Acetylneuraminic acid; Sialic acid (NeuNAc) β-D-Galactose (Gal) β-D-Glucuronic acid (GlcA) β-D-N-Acetylglucosamine (GlcNAc) α-L-Iduronic acid (IdoA) β-D-N-Acetylgalactosamine (GalNAc) α-L-Fucose (Fuc) Your Favorite Gene™, Your Comprehensive Gene Search Tool, visit sigma.com/yfg 19