Glycosaminoglycan

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Glycosaminoglycans (GAGs) or mucopolysaccharides are long linear polysaccharides consisting of repeating disaccharide units (i.e. two-sugar units). Glycosaminoglycan_sentence_0

The repeating two-sugar unit consists of a uronic sugar and an amino sugar, with the exception of keratan, where in the place of the uronic sugar it has galactose. Glycosaminoglycan_sentence_1

Because GAGs are highly polar and attract water, they are used in the body as a lubricant or shock absorber. Glycosaminoglycan_sentence_2

Mucopolysaccharidoses are a group of metabolic disorders in which abnormal accumulations of glycosaminoglycans occur because of enzyme deficiencies. Glycosaminoglycan_sentence_3

Production Glycosaminoglycan_section_0

Glycosaminoglycans vary greatly in molecular mass, disaccharide construction, and sulfation. Glycosaminoglycan_sentence_4

This is because GAG synthesis is not template driven like proteins or nucleic acids, but constantly altered by processing enzymes. Glycosaminoglycan_sentence_5

GAGs are classified into four groups based on core disaccharide structures. Glycosaminoglycan_sentence_6

Heparin/heparan sulfate (HSGAGs) and chondroitin sulfate/dermatan sulfate (CSGAGs) are synthesized in the Golgi apparatus, where protein cores made in the rough endoplasmic reticulum are post-translationally modified with O-linked glycosylations by glycosyltransferases forming proteoglycans. Glycosaminoglycan_sentence_7

Keratan sulfate may modify core proteins through N-linked glycosylation or O-linked glycosylation of the proteoglycan. Glycosaminoglycan_sentence_8

The fourth class of GAG, hyaluronic acid is synthesized by integral membrane synthases which immediately secrete the dynamically elongated disaccharide chain. Glycosaminoglycan_sentence_9

HSGAG and CSGAG Glycosaminoglycan_section_1

HSGAG and CSGAG modified proteoglycans first begin with a consensus Ser-Gly/Ala-X-Gly motif in the core protein. Glycosaminoglycan_sentence_10

Construction of a tetrasaccharide linker that consists of -GlcAβ1–3Galβ1–3Galβ1–4Xylβ1-O-(Ser)-, where xylosyltransferase, β4-galactosyl transferase (GalTI),β3-galactosyl transferase (GalT-II), and β3-GlcA transferase (GlcAT-I) transfer the four monosaccharides, begins synthesis of the GAG modified protein. Glycosaminoglycan_sentence_11

The first modification of the tetrasaccharide linker determines whether the HSGAGs or CSGAGs will be added. Glycosaminoglycan_sentence_12

Addition of a GlcNAc promotes the addition of HSGAGs while addition of GalNAc to the tetrasaccharide linker promotes CSGAG development. Glycosaminoglycan_sentence_13

GlcNAcT-I transfers GlcNAc to the tetrasaccahride linker, which is distinct from glycosyltransferase GlcNAcT-II, the enzyme that is utilized to build HSGAGs. Glycosaminoglycan_sentence_14

EXTL2 and EXTL3, two genes in the EXT tumor suppressor family, have been shown to have GlcNAcT-I activity. Glycosaminoglycan_sentence_15

Conversely, GalNAc is transferred to the linker by the enzyme GalNAcT to initiate synthesis of CSGAGs, an enzyme which may or may not have distinct activity compared to the GalNAc transferase activity of chondroitin synthase. Glycosaminoglycan_sentence_16

With regard to HSGAGs, a multimeric enzyme encoded by EXT1 and EXT2 of the EXT family of genes, transfers both GlcNAc and GlcA for HSGAG chain elongation. Glycosaminoglycan_sentence_17

While elongating, the HSGAG is dynamically modified, first by N-deacetylase, N-sulfotransferase (NDST1), which is a bifunctional enzyme that cleaves the N-acetyl group from GlcNAc and subsequently sulfates the N-position. Glycosaminoglycan_sentence_18

Next, C-5 uronyl epimerase coverts d-GlcA to l-IdoA followed by 2-O sulfation of the uronic acid sugar by 2-O sulfotransferase (Heparan sulfate 2-O-sulfotransferase). Glycosaminoglycan_sentence_19

Finally, the 6-O and 3-O positions of GlcNAc moities are sulfated by 6-O (Heparan sulfate 6-O-sulfotransferase) and 3-O (3-OST) sulfotransferases. Glycosaminoglycan_sentence_20

Chondroitin sulfate and dermatan sulfate, which comprise CSGAGs, are differentiated from each other by the presence of GlcA and IdoA epimers respectively. Glycosaminoglycan_sentence_21

Similar to the production of HSGAGs, C-5 uronyl epimerase converts d-GlcA to l-IdoA to synthesize dermatan sulfate. Glycosaminoglycan_sentence_22

Three sulfation events of the CSGAG chains occur: 4-O and/or 6-O sulfation of GalNAc and 2-O sulfation of uronic acid. Glycosaminoglycan_sentence_23

Four isoforms of the 4-O GalNAc sulfotransferases (C4ST-1, C4ST-2, C4ST-3, and D4ST-1) and three isoforms of the GalNAc 6-O sulfotransferases (C6ST, C6ST-2, and GalNAc4S-6ST) are responsible for the sulfation of GalNAc. Glycosaminoglycan_sentence_24

Keratan sulfate types Glycosaminoglycan_section_2

Unlike HSGAGs and CSGAGs, the third class of GAGs, those belonging to keratan sulfate types, are driven towards biosynthesis through particular protein sequence motifs. Glycosaminoglycan_sentence_25

For example, in the cornea and cartilage, the keratan sulfate domain of aggrecan consists of a series of tandemly repeated hexapeptides with a consensus sequence of E(E/L)PFPS. Glycosaminoglycan_sentence_26

Additionally, for three other keratan sulfated proteoglycans, lumican, keratocan, and mimecan (OGN), the consensus sequence NX(T/S) along with protein secondary structure was determined to be involved in N-linked oligosaccharide extension with keratan sulfate. Glycosaminoglycan_sentence_27

Keratan sulfate elongation begins at the nonreducing ends of three linkage oligosaccharides, which define the three classes of keratan sulfate. Glycosaminoglycan_sentence_28

Keratan sulfate I (KSI) is N -linked via a high mannose type precursor oligosaccharide. Glycosaminoglycan_sentence_29

Keratan sulfate II (KSII) and keratan sulfate III (KSIII) are O-linked, with KSII linkages identical to that of mucin core structure, and KSIII linked to a 2-O mannose. Glycosaminoglycan_sentence_30

Elongation of the keratan sulfate polymer occurs through the glycosyltransferase addition of Gal and GlcNAc. Glycosaminoglycan_sentence_31

Galactose addition occurs primarily through the β-1,4-galactosyltransferase enzyme (β4Gal-T1) while the enzymes responsible for β-3-Nacetylglucosamine have not been clearly identified. Glycosaminoglycan_sentence_32

Finally, sulfation of the polymer occurs at the 6-position of both sugar residues. Glycosaminoglycan_sentence_33

The enzyme KS-Gal6ST (CHST1) transfers sulfate groups to galactose while N-acetylglucosaminyl-6-sulfotransferase (GlcNAc6ST) (CHST2) transfers sulfate groups to terminal GlcNAc in keratan sulfate. Glycosaminoglycan_sentence_34

Hyaluronic acid Glycosaminoglycan_section_3

The fourth class of GAG, hyaluronic acid, is not sulfated and is synthesized by three transmembrane synthase proteins HAS1, HAS2, and HAS3. Glycosaminoglycan_sentence_35

HA, a linear polysaccharide, is composed of repeating disaccharide units of →4)GlcAβ(1→3)GlcNAcβ(1→ and has a very high molecular mass, ranging from 10 to 10 Da. Glycosaminoglycan_sentence_36

Each HAS enzyme is capable of transglycosylation when supplied with UDP-GlcA and UDP-GlcNAc. Glycosaminoglycan_sentence_37

HAS2 is responsible for very large hyaluronic acid polymers, while smaller sizes of HA are synthesized by HAS1 and HAS3. Glycosaminoglycan_sentence_38

While each HAS isoform catalyzes the same biosynthetic reaction, each HAS isoform is independently active. Glycosaminoglycan_sentence_39

HAS isoforms have also been shown to have differing Km values for UDP-GlcA and UDPGlcNAc. Glycosaminoglycan_sentence_40

It is believed that through differences in enzyme activity and expression, the wide spectrum of biological functions mediated by HA can be regulated, such as its involvement with neural stem cell regulation in the subgranular zone of the brain. Glycosaminoglycan_sentence_41

Function Glycosaminoglycan_section_4

Glycosaminoglycan_description_list_0

  • CSGAGs: Endogenous heparin is localized and stored in secretory granules of mast cells. Histamine that is present within the granules is protonated (H2A) at pH within granules (5.2–6.0), thus it is believed that heparin, which is highly negatively charged, functions to electrostatically retain and store histamine. In the clinic, heparin is administered as an anticoagulant and is also the first line choice for thromboembolic diseases. Heparan sulfate (HS) has numerous biological activities and functions, including cell adhesion, regulation of cell growth and proliferation, developmental processes, cell surface binding of lipoprotein lipase and other proteins, angiogenesis, viral invasion, and tumor metastasis.Glycosaminoglycan_item_0_0

CSGAGs interact with heparin binding proteins, specifically dermatan sulfate interactions with fibroblast growth factor FGF-2 and FGF-7 have been implicated in cellular proliferation and wound repair while interactions with hepatic growth factor/scatter factor (HGF/SF) activate the HGF/SF signaling pathway (c-Met) through its receptor. Glycosaminoglycan_sentence_42

CASGAGs are important in providing support and adhesiveness in bone, skin, and cartilage. Glycosaminoglycan_sentence_43

Other biological functions for which CSGAGs are known to play critical functions in include inhibition of axonal growth and regeneration in CNS development, roles in brain development, neuritogenic activity, and pathogen infection. Glycosaminoglycan_sentence_44

Glycosaminoglycan_description_list_1

  • Keratan sulfates: One of the main functions of the third class of GAGs, keratan sulfates, is the maintenance of tissue hydration. Keratan sulfates are in the bone, cartilage, and the cornea of the eye. Within the normal cornea, dermatan sulfate is fully hydrated whereas keratan sulfate is only partially hydrated suggesting that keratan sulfate may behave as a dynamically controlled buffer for hydration. In disease states such as macular corneal dystrophy, in which GAGs levels such as KS are altered, loss of hydration within the corneal stroma is believed to be the cause of corneal haze, thus supporting the long-held hypothesis that corneal transparency is a dependent on proper levels of keratan sulfate. Keratan sulfate GAGs are found in many other tissues besides the cornea, where they are known to regulate macrophage adhesion, form barriers to neurite growth, regulate embryo implantation in the endometrial uterine lining during menstrual cycles, and affect the motility of corneal endothelial cells. In summary, KS plays an anti-adhesive role, which suggests very important functions of KS in cell motility and attachment as well as other potential biological processes.Glycosaminoglycan_item_1_1

Dermatan sulfates Glycosaminoglycan_sentence_45

Dermatan sulfates function in the skin, tendons, blood vessels, and heart valves. Glycosaminoglycan_sentence_46

Glycosaminoglycan_description_list_2

  • Hyaluronic acid: Hyaluronic acid is a major component of synovial tissues and fluid, as well as the ground substance of other connective tissues. Hyaluronic acid binds cells together, lubricates joints, and helps maintain the shape of the eyeballs.:The viscoelasticity of hyaluronic acid make it ideal for lubricating joints and surfaces that move along each other, such as cartilage. A solution of hyaluronic acid under low shear stress has a much higher viscosity than while under high shear stress. Hyaluronidase, an enzyme produced by white blood cells, sperms cells, and some bacteria, breaks apart the hyaluronic acid, causing the solution to become more liquid.Glycosaminoglycan_item_2_2
  • In vivo, hyaluronic acid forms randomly kinked coils that entangle to form a hyaluronan network, slowing diffusion and forming a diffusion barrier that regulates transport of substances between cells. For example, hyaluronan helps partition plasma proteins between vascular and extravascular spaces, which affects solubility of macromolecules in the interstitium, changes chemical equilibria, and stabilizes the structure of collagen fibers.Glycosaminoglycan_item_2_3
  • Other functions include matrix interactions with hyaluronan binding proteins such as hyaluronectin, glial hyaluronan binding protein, brain enriched hyaluronan binding protein, collagen VI, TSG-6, and inter-alpha-trypsin inhibitor. Cell surface interactions involving hyaluronan are its well-known coupling with CD44, which may be related to tumor progression, and also with RHAMM (Hyaluronan-mediated motility receptor), which has been implicated in developmental processes, tumor metastasis, and pathological reparative processes. Fibroblasts, mesothelial cells, and certain types of stem cells surround themselves in a pericellular "coat", part of which is constructed from hyaluronan, in order to shield themselves from bacteria, red blood cells, or other matrix molecules. For example, with regards to stem cells, hyaluronan, along with chondroitin sulfate, helps to form the stem cell niche. Stem cells are protected from the effects of growth factors by a shield of hyaluronan and minimally sulfated chondroitin sulfate. During progenitor division, the daughter cell moves outside of this pericellular shield where it can then be influenced by growth factors to differentiate even further.Glycosaminoglycan_item_2_4

Classification Glycosaminoglycan_section_5

Members of the glycosaminoglycan family vary in the type of hexosamine, hexose or hexuronic acid unit they contain (e.g. glucuronic acid, iduronic acid, galactose, galactosamine, glucosamine). Glycosaminoglycan_sentence_47

They also vary in the geometry of the glycosidic linkage. Glycosaminoglycan_sentence_48

Examples of GAGs include: Glycosaminoglycan_sentence_49

Glycosaminoglycan_table_general_0

NameGlycosaminoglycan_header_cell_0_0_0 Hexuronic acid or

hexose (for keratan)Glycosaminoglycan_header_cell_0_0_1

HexosamineGlycosaminoglycan_header_cell_0_0_2 Linkage geometry between predominant monomeric unitsGlycosaminoglycan_header_cell_0_0_3 Unique featuresGlycosaminoglycan_header_cell_0_0_4
Chondroitin sulfateGlycosaminoglycan_cell_0_1_0 GlcUA or

GlcUA(2S)Glycosaminoglycan_cell_0_1_1

GalNAc or

GalNAc(4S) or GalNAc(6S) or GalNAc(4S,6S)Glycosaminoglycan_cell_0_1_2

GlcUAβ(1→3)GalNAcβ(1→4)Glycosaminoglycan_cell_0_1_3 Most prevalent GAGGlycosaminoglycan_cell_0_1_4
Dermatan sulfateGlycosaminoglycan_cell_0_2_0 GlcUA or

IdoUA or IdoUA(2S)Glycosaminoglycan_cell_0_2_1

GalNAc or

GalNAc(4S) or GalNAc(6S) or GalNAc(4S,6S)Glycosaminoglycan_cell_0_2_2

'IdoUAβ1-3'GalNAcβ1-4Glycosaminoglycan_cell_0_2_3 Distinguished from chondroitin sulfate by the presence of iduronic acid, although some hexuronic acid monosaccharides may be glucuronic acid.Glycosaminoglycan_cell_0_2_4
Keratan sulfateGlycosaminoglycan_cell_0_3_0 Gal or

Gal(6S)Glycosaminoglycan_cell_0_3_1

GlcNAc or

GlcNAc(6S)Glycosaminoglycan_cell_0_3_2

-Gal(6S)β1-4GlcNAc(6S)β1-3Glycosaminoglycan_cell_0_3_3 Keratan sulfate type II may be fucosylated.Glycosaminoglycan_cell_0_3_4
HeparinGlycosaminoglycan_cell_0_4_0 GlcUA or

IdoUA(2S)Glycosaminoglycan_cell_0_4_1

GlcNAc or

GlcNS or GlcNAc(6S) or GlcNS(6S)Glycosaminoglycan_cell_0_4_2

-IdoUA(2S)α1-4GlcNS(6S)α1-4Glycosaminoglycan_cell_0_4_3 Highest negative charge density of any known biological moleculeGlycosaminoglycan_cell_0_4_4
Heparan sulfateGlycosaminoglycan_cell_0_5_0 GlcUA or

IdoUA or IdoUA(2S)Glycosaminoglycan_cell_0_5_1

GlcNAc or

GlcNS or GlcNAc(6S) or GlcNS(6S)Glycosaminoglycan_cell_0_5_2

-GlcUAβ1-4GlcNAcα1-4Glycosaminoglycan_cell_0_5_3 Highly similar in structure to heparin, however heparan sulfate's disaccharide units are organised into distinct sulfated and non-sulfated domains.Glycosaminoglycan_cell_0_5_4
HyaluronanGlycosaminoglycan_cell_0_6_0 GlcUAGlycosaminoglycan_cell_0_6_1 GlcNAcGlycosaminoglycan_cell_0_6_2 -GlcUAβ1-3GlcNAcβ1-4Glycosaminoglycan_cell_0_6_3 The only GAG that is exclusively non-sulfatedGlycosaminoglycan_cell_0_6_4

Abbreviations Glycosaminoglycan_section_6

Glycosaminoglycan_unordered_list_3

  • GlcUA = β-D-glucuronic acidGlycosaminoglycan_item_3_5
  • GlcUA(2S) = 2-O-sulfo-β-D-glucuronic acidGlycosaminoglycan_item_3_6
  • IdoUA = α-L-iduronic acidGlycosaminoglycan_item_3_7
  • IdoUA(2S) = 2-O-sulfo-α-L-iduronic acidGlycosaminoglycan_item_3_8
  • Gal = β-D-galactoseGlycosaminoglycan_item_3_9
  • Gal(6S) = 6-O-sulfo-β-D-galactoseGlycosaminoglycan_item_3_10
  • GalNAc = β-D-N-acetylgalactosamineGlycosaminoglycan_item_3_11
  • GalNAc(4S) = β-D-N-acetylgalactosamine-4-O-sulfateGlycosaminoglycan_item_3_12
  • GalNAc(6S) = β-D-N-acetylgalactosamine-6-O-sulfateGlycosaminoglycan_item_3_13
  • GalNAc(4S,6S) = β-D-N-acetylgalactosamine-4-O, 6-O-sulfateGlycosaminoglycan_item_3_14
  • GlcNAc = α-D-N-acetylglucosamineGlycosaminoglycan_item_3_15
  • GlcNS = α-D-N-sulfoglucosamineGlycosaminoglycan_item_3_16
  • GlcNS(6S) = α-D-N-sulfoglucosamine-6-O-sulfateGlycosaminoglycan_item_3_17

See also Glycosaminoglycan_section_7

Glycosaminoglycan_unordered_list_4


Credits to the contents of this page go to the authors of the corresponding Wikipedia page: en.wikipedia.org/wiki/Glycosaminoglycan.