GAGs- Final Paper

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_disorder


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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

GAGs- Final Paper

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