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8/4/2019 GAGs- Final Paper
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1.) What are glycosaminoglycans and proteoglycans? Give their biologic
importance/significance.
Glycosaminoglycans (GAGs) is a type of polysaccharide based on a repeating disaccharide
in which one of the sugar is an amino acid sugar and at least one of them has a negative charge
owing to the presence of a sulphate group or a carboxyl group. This is the most abundant
heteropolysaccharide in the body. These polysaccharides are involved in a wide variety of
cellular functions and tissues including blood plasma, joints and the mucosal (mucous
membrane) lining of a variety of organs, including the GIT and the bladder.
Characteristics of GAGs
GAG Localization Comments
Hyaluronatesynovial fluid, vitreous humor,
ECM of loose connective tissue
large polymers, shock
absorbing
Chondroitin
sulfatecartilage, bone, heart valves most abundant GAG
Heparan sulfatebasement membranes, components of cell
surfaces
contains higher acetylated
glucosamine than heparin
Heparin
component of intracellular granules of mast
cellslining the arteries of the lungs, liver and skin
more sulfated than heparan
sulphates
Dermatan sulfate skin, blood vessels, heart valves
Keratan sulfatecornea, bone, cartilage aggregated with
chondroitin sulphates
GAG Biological Significance
Hyaluronate Chief components of the extracellular matrix ,
contributes to cell proliferation and migration,
may also be involved in the progression of
some malignant tumors.
Chondroitin Sulfate Dietary supplement for treatment of
osteoarthritis, maintaining the structural
integrity of the tissue, regulates the growth and
development as well as the nervous system
response to injury.
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Heparan Sulfate Regulates developmental processes,
angiogenesis, blood coagulation and tumour
metastasis.
Heparin Act as an anticoagulant
Dermatan Sulfate May have roles in coagulation, cardiovascular
disease, carcinogenesis, infection, wound
repair, and fibrosis
Keratan Sulfate Supporting functional roles in cellular
recognition of protein ligands, axonal
guidance, cell motility, and embryo
implantation.
Hyaluronates:
composed of D-glucuronate +
GlcNAc
linkage is (1, 3)
Dermatan sulfates:
composed of L-iduronate (many are
sulfated)
+ GalNAc-4-sulfate
linkages is (1, 3)
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Chondroitin 4- and 6-sulfates :
composed of D-glucuronate
and GalNAc-4- or 6-sulfatelinkage is (1, 3)
(the figure contains GalNAc 4-
sulfate)
Heparin and Heparan sulfates:
composed of iduronate-2-sulfate
(D-glucuronate-2-sulfate)
andN-sulfo-D-glucosamine-6-
sulfate
linkage is (1, 4)
(heparans have less sulfate than
heparins)
Keratan sulfates:
composed of galactose + GlcNAc-
6-sulfate
linkage is (1, 4)
Proteoglycans are glycoproteins with an extremely high carbohydrate content
approximately 85% to 95% by weight. The majority of GAGs in the body are linked to core
proteins, forming proteoglycans (also known as mucopolysaccharides). Proteoglycans make up a
major part of the extracellular matrix, the material between cells that provides structural support.
Proteoglycan s are heavily glycosylated glycoprotein which means that they are protein with
chains of polysaccharide. The specific type of polysaccharides attached to proteoglycans are
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called glycosaminoglycans. The GAG chains of proteoglycan may be made of chondroitin
sulphate, dermatan sulphate, heparin sulphate, heparan sulphate, or keratin sulphate.
Structure of the GAG Linkage to Protein in Proteoglycans
2.) What are the different mucopolysaccharides? Identify the defect/deficient enzyme in
each type. Give the clinical characteristics of each type
Mucopolysaccharides are proteins covalently linked to glycosaminoglycans. Types of
proteoglycans vary from each other in terms of tissue distribution, nature of protein core,
attached glycosaminoglycans and functions.
Linkages of glycosaminoglycans to the core protein involves specific trisaccharidestructure composed of two galactose residues and a xylose residue (Galactose-Galactose-
Xylose). An O-glycosidic bond is formed between the xylose and serine residue of the protein.
There are about six types of glycosaminoglycans (GAGs): hyaluronate, chondrotin
sulfate, heparin sulfate, heparan, dermatan sulfate, keratin sulfate I and II.
Hyaluronate is composed of N-acetylglucosamine and glucoronic acid. It is usually non-sulfonated and non-covalently attached to proteins. Hyaluronate is found in synovial fluid of
joints, vitreous humor or eye, umbilical cord, loose connective tissue and cartilage. This
compound serves as lubricant and shock absorber.
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Chondroitin sulfate is composed of N-acetylgalactosamine with sulfate (on either
carbon 4 or carbon 6) and glucoronic acid dissacharide units. It is said to be the most abundant
GAG in the body. Also, it is usually found in cartilage, tendons, ligaments and aorta.
Heparan sulfate is almost the same with heparin, however, it has less sulfate groups.
The disaccharide unit is composed of N-glucosamine and mainly glucoronic acid.
Dermatan sulfate is composed of N-acetylgalactosamine and L-iduronic acid. This is
mainly found in skin, blood vessels and heart valves.
Lastly, Keratan sulphates I and II are composed of the same disaccharide unit N-
acetylglucosamine and galactose (no uronic acid). However, they differ in their protein linkages:
GlcNAc-Asn for Keratan sulfate I and GlcNAc-Thr for Keratan sulfate II. The first one is mainlyfound in the cornea and the second one is found in loose connective tissue.
Table 1 shows the summary of each glycosaminoglycans mentioned above.
Table 1: Summary of GAGs (attachments, localization and special features)
GAGs Sugar
attachment
Sulfate Protein
linkages
Localization Special
features
Hyaluronate Glucoronic acid
and N-
acetlyglucosamin
e
Glucosamine None Synovial fluid,
loose
connective
tissue,
cartilage and
vitreous body
of eye
-Present in
bacteria
-Shock
absorbers
Chondroitin
sulphate
Glucoronic acid
and N-
acetylgalactogluc
-osamine
N-acetylgalactogl-
ucosamine
Xyl-Ser O-
glycosidic
bond
Cartilage,
bone, cornea,
heart valve
Most
abundant
GAG
Heparan
sulphate
Glucoronic acid
and N-
glucosamine
N-Glucosamine Xyl-Ser Skin
fibroblast,
aortic wall
Contains
higher
acetylated
glucosaminethan heparin
Dermatan
sulfate
N-Glucosamine
and Iduronic acid
N-Glucosamine
N-Glucosamine
Iduronic acid
Ser Mast cells,
lining the
arteries of the
lungs, liver
More
sulfated than
heparin
sulfates
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and skin
Keratan
sulfate I
N-acetlygalactos-
amine and
galactose
N-
acetylgalactosamine
GlcNAc-Asn Cornea --
Keratan
sulfate II
N-acetlygalactos-
amine and
galactose
N-
acetylgalactosamine
GlcNAc-Thr Loose
connective
tissue
--
(A) (B)
(C) (D)
(E)
Figure 1: Structures of different GAGs: (A) Hyaluronate, (B) Chondroitin sulfate, (C) Heparan
sulfate, (D) Dermatan sulfate and (E) Keratan sulfate. Note that Sulfate groups (labelled as S=)
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are shown in all possible positions. Also, structure of Keratan sulfate I differs from Keratan
sulfate II via protein attachments. (Images taken from Champe et al., 2008)
Mucopolysaccharidoses are hereditary disorders that are characterized by accumulation
of GAGs on various tissues. Basically, it is caused by deficiency of any lysosomal hydrolases.Incomplete lysosomal degradation of GAGs results in the presence of oligosaccharides in urine.
Few of the disorders are summarized in Table 2.
Table 2: Few known mucopolysaccharidoses and their specific enzyme defects, urinary
metabolites and symptoms
Mucopolysaccharidoses Enzyme defect Urinary
metabolites
Symptoms
Hurler (MPS1H) -L-iduronudase Dermatan
sulfate
Heparan
sulfate
Heart disease, dwarfism, corneal
clouding, dystosis, mentalretardation, early mortality
Schele (MPS1S) -L-iduronudase Dermatan
sulfate
Heparan
sulfate
Corneal clouding, aortic valve
disease, joint stiffening
Hurler-Schele(MPS1HS)
-L-iduronudase Dermatansulfate
Heparan
sulfate
Intermediate between H and S
Hunter (MPS II) Iduronate sulfatase Dermatansulfate,
Heparan
sulfate
Physical deformity, mentalretardation, dystosis multiplex,
only X-linked MPS
Sanfilippo A (MPS IIIA) Heparan sulfate N-sulfatase (sulfamidase)
Heparansulfate
Severe nervous systemdisorders, profound mental
retardation, hyperactivity, skin,
brains, lungs
Sanfilippo B (MPS IIIB) -N-
Acetylglucosaminidase
Heparan
sulfate
Severe nervous system
disorders, profound mentalretardation, hyperactivity, skin,
brains, lungs
Sanfilippo C (MPS IIIC) Acetyltransferase Heparan Severe nervous system
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sulfate disorders, profound mental
retardation, hyperactivity, skin,brains, lungs
Sanfilippo D (MPS IIID) -N-
Acetylglucosamine-6-
sulfatase
Heparan
sulfate
Severe nervous system
disorders, profound mental
retardation, hyperactivity, skin,brains, lungs
Morquio A (MPS IVA) Galactose-6-sulfatase Keratan sulfate
Chondroitin-6
sulfate
Corneal clouding, odontoidhypoplasia, aortic valve disease,
distinctive skeletal abnormalities
Morquio B (MPS IVB) -galactosidase Keratan sulfate Corneal clouding, odontoidhypoplasia, aortic valve disease,
distinctive skeletal abnormalities
Maroteaux-Lamy
(MPS VI)
Arylsulfatase B
(N-Acetylgalactosamine-
4-sulfatase)
Dermatan
sulfate
Aortic valve disease, dystosis
multiplex, normal intelligence,
corneal clouding, coarse facialfeatures
Sly (MPS VII) -glucoronidase Heparan
sulfate
Dermatan
sulfate
Chondroitin-4,6-sulfates
Hepatosplenomegaly, dystosis
multiplex, hydrops fetalis
3.) What is the role of glycosaminoglycans in:
a.) Cancer:
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Hyaluronic acid localized in the synovial fluid, vitreous humor and extracellular matrix
of loose connective tissue is significant since they are involved in the progression of cancer.Exposure of the said glycosaminoglycan with that of the cancer cells will activate series of
activities which in turn will result in cell migration.
Heparan sulphate glycosaminoglycans (HSGAGs), which are complex polysaccharides
also regulate aspects of cancer life process (metastasis, tumor progressing, tumorgenesis). Theyare found on the cell surfaces and extracellular matrix. HSGAGs are part of the
glycosaminoglycan family that are complex polysaccharides having repeating disaccharide units
of uronic acid linked to a glucosamine. These can be found at the cell-tissue-organ interface of
every eukaryotic cell and are shown play roles in physiological processes including tumorprogression and onset.
The structure of HSGAGs enables binding and interaction with different proteins (growth
factors, chemokines, morphogens, and enzymes). The binding of these proteins to the HSGAGscan affect cancer cells. The growth factors involved in tumor development are the Fibroblast
Growth Factors (FGF1 and FGF2), Vascular Endothelial Growth Factor (VEGF), Hepatocyte
Growth Factor (HGF), Transforming Growth factor , and Platelet-derived Growth Factor.Although the presence of HSGAGs contributes to the metastasis of cells, studies have
indicated that heparin might interfere with tumor progression and metastasis by means of several
mechanisms:
1. Anticoagulation Heparin interferes with fibrin clot formation that surrounds the tumor
cells.
2. Immune modulation Heparin inhibit metastasis by making circulating cancer cells more
vulnerable to immune response. It also regulated the activities of several cytokines.Heparin binds to granulocytes and macrophages to promote destruction of tumors.
3. Cell adhesion Heparin inhibit tumor metastasis by blocking P selectin mediated
interaction between platelates and sialylated, fucosylated mucins that reside on thesurface of the circulating cancer cells
B.) Atherosclerosis
The intima of the arterial wall contains hyaluronic acid and chondroitin sulfate, dermatan
sulfate, and heparan sulfate proteoglycans. Immunohistochemistry reveals that versican, which is
the principal chondroitin sulfate proteoglycans in the blood vessels, is prominent in the intimaadventitia of most arteries and veins. The accumulation of versician in the normal arterial intima
is mainly responsible for the proteoglycan-rich nature of this layer. Versician interacts with
hyaluronan and link protein to form higher molecular weight stable aggregates that fill the ECM
space not occupied by the other fibrous proteins such as collagens and elastic fibers. Thesecomplexes create a reversibly compressive compartment and provide a swelling pressure within
the ECM that is offset by collagen and elastic fibers.
Analysis of binding constants of Chondroitin Sulfate Proteoglycans from lesions reveals
that multiple LDL particles can bind to a single CS chain. Thus, GAG chain length is a
determining factor in lipid binding. Vascular injury produces elongated GAG chains on the largevascular CSPG promoting LDL binding. Conditions that promote CS chain elongation in Arterial
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Smooth Muscle Cells such as cell proliferation, treatment of the cells with oxidized LDL and
transforming growth factor (TGF) also cause increased binding of versican to LDL. In addition,
exposure of human ASMCs to nonesterified free acids, as occurs in diabetes, increases theproduction of proteoglycans including versican, which then binds LDL more effectively
Inflammation, infection, or physical damage to the intima of the arterial wall can lead tothe release of soluble GAGs. This, in turn, promotes binding of LDL to the large vascular CSPG.
Buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall
results to Atherosclerosis.
C.) Arthritis
Arthritis is a form ofjoint disorderthat involves inflammation of one or more joints. The
most common form, osteoarthritis (degenerative joint disease) is a result of trauma to the joint,
infection of the joint, or age. Other arthritis forms are rheumatoid arthritis,psoriatic arthritis, and
related autoimmune diseases.
Although many infectious agents can cause inflammatory arthritis, the actual antigen behind
autoimmunity may be GAGs. According to a study conducted by Roehrl and Wang, circulating
or locally released GAGs induce the clonal expansionof various GAG-binding cells, for example,T and B cells and macrophages. These cells, because of their enhanced or matured binding to
GAGs, preferentially migrate and adhere to connective tissue where GAGs are abundant. GAGs
expressed on endothelial and synovial lining cells facilitate the extravasations and adherence of
GAG-binding cells from the bloodstream into GAG-rich environments, such as connective tissueand cartilage. Excessive and prolonged accumulation of these abnormal cells eventually leads to
pathological symptoms, including damage of joint cartilage and bone erosion.
Development of arthritis, especially osteoarthritis, is due to the changes brought about by the
amount of chondroitin sulfate in cartilage diminishing and amounts of keratan sulfate and
hyaluronic acid increasing along with age.
http://en.wikipedia.org/wiki/Arthropathyhttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Osteoarthritishttp://en.wikipedia.org/wiki/Rheumatoid_arthritishttp://en.wikipedia.org/wiki/Psoriatic_arthritishttp://en.wikipedia.org/wiki/Autoimmune_disorderhttp://en.wikipedia.org/wiki/Arthropathyhttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Osteoarthritishttp://en.wikipedia.org/wiki/Rheumatoid_arthritishttp://en.wikipedia.org/wiki/Psoriatic_arthritishttp://en.wikipedia.org/wiki/Autoimmune_disorder8/4/2019 GAGs- Final Paper
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Changes in the amounts of certain GAGs in the skin are also observed with aging and help to
account for the characteristic changes noted in this organ in elderly.
Hands affected by Rheumatoid Arthritis, an autoimmune form of arthritis
Sources:
Champe, et. al. (2008). Biochemistry: 4 th ed. Lippincott Williams & Wilkins. Philadelphia,PA.
Merrilees & Wright. (2004).Proteoglycans in Atherosclerosis and Restenosis : Key Roles for
American Heart Association. Circulation Research 2004, 94:1158-1167
Roehrl & Wang. (2002). Glycosaminoglycans are a potential cause of rheumatoidarthritis.
Channing Laboratory, Department of Medicine, Brigham and Womens Hospital, andDepartment of Biological Chemistry and Molecular Pharmacology. Harvard Medical School,
Boston.
Sasisekharan, et. al. (2002).Roles of Heparan-Sulphate Glycosaminoglycans in Cancer.
Biological Engineering Division and Center for Biomedical Engineering, Massachusetts Instituteof Technology, Division of Hematology and Oncology,New England Medical Center,Tufts
University School of Medicine.Nature, July 2002: Vol 2
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GLYCOSAMINOGLYCANS
(GAGs)
1D-2
Members:
PERALTA, JP
QUE, Arbie
QUESADA, Gab
RABAGO, Gian
RENDON, Katrina
ROBERTO, Kathleen
ROBLES, Kristine