ECB-ART-47357
Molecules
2019 Aug 01;2415:. doi: 10.3390/molecules24152803.
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Galactosaminoglycans: Medical Applications and Drawbacks.
Pomin VH
,
Vignovich WP
,
Gonzales AV
,
Vasconcelos AA
,
Mulloy B
.
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Galactosaminoglycans (GalAGs) are sulfated glycans composed of alternating N-acetylgalactosamine and uronic acid units. Uronic acid epimerization, sulfation patterns and fucosylation are modifications observed on these molecules. GalAGs have been extensively studied and exploited because of their multiple biomedical functions. Chondroitin sulfates (CSs), the main representative family of GalAGs, have been used in alternative therapy of joint pain/inflammation and osteoarthritis. The relatively novel fucosylated chondroitin sulfate (FCS), commonly found in sea cucumbers, has been screened in multiple systems in addition to its widely studied anticoagulant action. Biomedical properties of GalAGs are directly dependent on the sugar composition, presence or lack of fucose branches, as well as sulfation patterns. Although research interest in GalAGs has increased considerably over the three last decades, perhaps motivated by the parallel progress of glycomics, serious questions concerning the effectiveness and potential side effects of GalAGs have recently been raised. Doubts have centered particularly on the beneficial functions of CS-based therapeutic supplements and the potential harmful effects of FCS as similarly observed for oversulfated chondroitin sulfate, as a contaminant of heparin. Unexpected components were also detected in CS-based pharmaceutical preparations. This review therefore aims to offer a discussion on (1) the current and potential therapeutic applications of GalAGs, including those of unique features extracted from marine sources, and (2) the potential drawbacks of this class of molecules when applied to medicine.
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Genes referenced: LOC100887844 LOC100893907
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Figure 1. (A) Representative repeating disaccharide unit of chondroitin sulfate (CS) structures. CSs are composed of alternating 4-linked β-d-glucuronic acid (GlcA) and 3-linked β-d-N-acetylgalactosamine (GalNAc) units. While CS-A is mostly 4-sulfated at the GalNAc units, CS-C is predominantly 6-sulfated [7]. While CS-D is composed of 2-sulfated GlcA and 6-sulfated GalNAc, CS-E is composed of 4,6-di-sulfated GalNAc. CS-K, CS-L and CS-M are all sulfated at C3 position of GlcA, and respectively sulfated at positions C4, C6, and simultaneously at C4 and C6. Oversulfated chondroitin sulfate (OSCS) is fully sulfated. Dermatan sulfate (DS) also known as CS-B is composed of alternating 4-linked α-L-iduronic acid (IdoA) and 3-linked β-d-GalNAc units. (B) Representative repeating trisaccharide unit of the fucosylated chondroitin sulfate (FucCS). Besides consisting of the regular CS disaccharide unit as shown at panel A, the FucCS also exhibits branching units of α-l-fucopyranose (Fucp) 3-linked to the GlcA unit as highlighted with the box in dashed lines. The detailed structure of the Fucp unit varies according to the holothurian species. In all panels the glycosidic bonds are indicated in ellipses whereas monosaccharide types are indicated in continuous black rectangles. For fast notation of the sulfation patterns, sulfation sites are highlighted by light-grey rectangles. |
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Figure 2. Representative disaccharide unit, GlcA(β1−3)GalNAc, of CS backbones in the 3D stick model. Hydrogens, carbons, oxygens and nitrogens are respectively represented in light grey, dark grey, red and blue. Carbon atoms are numbered according to their positions in the ring. Monosaccharides are indicated accordingly. Model created by the online AMBER/GLYCAM-based carbohydrate builder [40]. |
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Figure 3. Representative disaccharide units of CS types, (A) CS-A, (B) CS-C, (C) CS-D, (D) CS-E, and (E) CS-K in their 3D stick models. Table 1 displays the structural description of these disaccharides. Hydrogens, carbons, oxygens and nitrogens are respectively represented in light grey, dark grey, red and blue. The carbon numbering and monosaccharide units are the same as shown in Figure 2, since all structures are the GlcA(β1−3)GalNAc disaccharide backbone. Models created by the online AMBER/GLYCAM-based carbohydrate builder [40]. |
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Figure 4. Representative disaccharide unit, IdoA(α1−3)GalNAc, of DS backbones in the 3D stick model. Hydrogens, carbons, oxygens and nitrogens are respectively represented in light grey, dark grey, red and blue. Carbon atoms are numbered according to their positions in the ring. Monosaccharides are indicated accordingly. Model created by the online AMBER/GLYCAM-based carbohydrate builder [40]. |
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Figure 5. Representative disaccharide units, (A) IdoA2S(α1−3)GalNAc4S and (B) IdoA2S(α1−3)GalNAc6S, of the DS backbones from three ascidian species in their 3D stick models. These ascidian DS are highly sulfated at the C2 position of the α-L-IdoA units but differ in the pattern of sulfation at the β-d-GalNAc units. (A) In the species S. plicata and H. pyriformis the GalNAc moieties are heavily 4-O-sulfated, (B) whereas in A. nigra, they are 6-O-sulfated. Percentage of sulfation/site/species is shown in the table. Hydrogens, carbons, oxygens and nitrogens are respectively represented in light grey, dark grey, red and blue. Carbon atoms are numbered according to their positions in the ring. Monosaccharides are indicated accordingly. Model created by the online AMBER/GLYCAM-based carbohydrate builder [40]. |
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Figure 6. Representative trisaccharide unit {→4)-[α-L-Fucp-(1→3)]-β-d-GlcA-(1→3)-β-d-GalNAc-(1→} of the FucCS backbone from sea cucumber in its 3D stick models. The sites of possible substitution by sulfate groups are C2, C3 and C4 of Fucp unit and C4 and C6 of GalNAc as indicated in the structure. Hydrogens, carbons, oxygens and nitrogens are represented in light grey, dark grey, red and blue, respectively. Carbon atoms are numbered according to their positions in the ring. Monosaccharides are indicated accordingly. Model created by the online AMBER/GLYCAM-based carbohydrate builder [40]. |
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