Glycosaminoglycan

class=skin-invert-image|thumb|240px|right|The repeating disaccharide unit (GlcUA(1β→3)GalNAc(1β→4))n of [[chondroitin sulfate. For polysaccharide nomenclature see here. R1, R2, R3 may have different values.]]

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units (i.e., two-sugar units). The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria.

Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

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

Production

Glycosaminoglycans vary greatly in molecular mass, disaccharide structure, and sulfation. This is because GAG synthesis is not template driven, as are proteins or nucleic acids, but is constantly altered by processing enzymes.

GAGs are classified into four groups, based on their core disaccharide structures:

Heparin/heparan sulfate (HSGAGs)
Chondroitin sulfate/dermatan sulfate (CSGAGs) which along with HSGAGs are synthesized in the Golgi apparatus, where core proteins, made in the rough endoplasmic reticulum, are post-translationally modified via O-linked glycosylation by glycosyltransferases, thus forming proteoglycans.
Keratan sulfate which may modify core proteins through N-linked glycosylation or O-linked glycosylation of the proteoglycan
Hyaluronic acid (also known as hyaluronan), which is synthesized by integral membrane synthases, which immediately secrete the dynamically elongated disaccharide chain.

HSGAG and CSGAG

HSGAG and CSGAG modified proteoglycans first begin with a consensus Ser-Gly/Ala-X-Gly motif in the core protein. 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. The first modification of the tetrasaccharide linker determines whether the HSGAGs or CSGAGs will be added. Addition of a GlcNAc promotes the addition of HSGAGs while addition of GalNAc to the tetrasaccharide linker promotes CSGAG development.

Keratan sulfate types

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

Hyaluronic acid class

The fourth class of GAG, hyaluronic acid (HA), is not sulfated and is synthesized by three transmembrane synthase proteins HAS1, HAS2, and HAS3. 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 105 to 107 Da. Each HAS enzyme is capable of transglycosylation when supplied with UDP-GlcA and UDP-GlcNAc. HAS2 is responsible for very large hyaluronic acid polymers, while smaller sizes of HA are synthesized by HAS1 and HAS3. While each HAS isoform catalyzes the same biosynthetic reaction, each HAS isoform is independently active. HAS isoforms have also been shown to have differing Km values for UDP-GlcA and UDPGlcNAc. 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.

Pharmacodynamics

HSGAGs

Endogenous heparin is localized and stored in secretory granules of mast cells. Histamine that is present within the granules is protonated (H2A2+) 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. while interactions with hepatic growth factor/scatter factor (HGF/SF) activate the HGF/SF signaling pathway (c-Met) through its receptor. CSGAGs are important in providing support and adhesiveness in bone, skin, and cartilage. 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.

Keratan sulfates

One of the main functions of the third class of GAGs, keratan sulfates, is the maintenance of tissue 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 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. The viscoelasticity of hyaluronic acid makes 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.

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| Heparin || GlcUA or IdoUA(2S) || GlcNAc or GlcNS or GlcNAc(6S) or GlcNS(6S) || -IdoUA(2S)α1-4GlcNS(6S)α1-4 || Highest negative charge density of any known biological molecule

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| Heparan sulfate || GlcUA or IdoUA or IdoUA(2S) || GlcNAc or GlcNS or GlcNAc(6S) or GlcNS(6S) || -GlcUAβ1-4GlcNAcα1-4 || Highly similar in structure to heparin, however heparan sulfate's disaccharide units are organised into distinct sulfated and non-sulfated domains.

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| Hyaluronan || GlcUA || GlcNAc || -GlcUAβ1-3GlcNAcβ1-4 || The only GAG that is exclusively non-sulfated

Abbreviations

GlcUA = β-D-glucuronic acid
GlcUA(2S) = 2-O-sulfo-β-D-glucuronic acid
IdoUA = α-L-iduronic acid
IdoUA(2S) = 2-O-sulfo-α-L-iduronic acid
Gal = β-D-galactose
Gal(6S) = 6-O-sulfo-β-D-galactose
GalNAc = β-D-N-acetylgalactosamine
GalNAc(4S) = β-D-N-acetylgalactosamine-4-O-sulfate
GalNAc(6S) = β-D-N-acetylgalactosamine-6-O-sulfate
GalNAc(4S,6S) = β-D-N-acetylgalactosamine-4-O, 6-O-sulfate
GlcNAc = α-D-N-acetylglucosamine
GlcNAc(6S) = α-D-N-acetylglucosamine-6-O-sulfate
GlcNS = α-D-N-sulfoglucosamine
GlcNS(6S) = α-D-N-sulfoglucosamine-6-O-sulfate

References

External links

King M. 2005. Glycosaminoglycans . Indiana University School of Medicine Accessed December 31, 2006.
MRI evaluation of glycosaminoglycan loss (dGEMRIC evaluation)

Production

HSGAG and CSGAG

Keratan sulfate types

Hyaluronic acid class

Pharmacodynamics

HSGAGs

Keratan sulfates

Abbreviations

See also

References

External links