glycosaminoglycan and proteoglycans

GLYCOSAMINOGLYCAN and

PROTEOGLYCANS

GLYCOSAMINOGLYCAN and

PROTEOGLYCANS

CHUA, Ma. AureaCIRILO, Gerry Marc

CLARITO, Eunice LovelleCLARITO, Kristy Ann

Group 6, MD-I A2

CHUA, Ma. AureaCIRILO, Gerry Marc

CLARITO, Eunice LovelleCLARITO, Kristy Ann

Group 6, MD-I A2

LEARNING OBJECTIVES:

At the end of the clinical conference, the students will be able to:

Define what are glycosaminoglycans and proteoglycans and their biologic importance.Understand the biosynthesis of glycosaminoglycans and differentiate each type.Know the different mucoplysaccharidoses, identify the deficient enzyme in each type and its clinical characteristics.Know the role of glycosaminoglycans in Cancer, Atherosclerosis and Arthritis.

At the end of the clinical conference, the students will be able to:

Define what are glycosaminoglycans and proteoglycans and their biologic importance.Understand the biosynthesis of glycosaminoglycans and differentiate each type.Know the different mucoplysaccharidoses, identify the deficient enzyme in each type and its clinical characteristics.Know the role of glycosaminoglycans in Cancer, Atherosclerosis and Arthritis.

GLYCOSAMINOGLYCANS and their biologic importance

GAGs are long unbranched polysaccharides containing a repeating dissacharide unitsAmino sugars –

N-acetylgalactosamine (Gal NAc) or N-acetylglucosamine (Glc NAc)

Uronic acids – glucuronic acid (Glc UA) or iduronic acid (Id UA)

GAGs are long unbranched polysaccharides containing a repeating dissacharide unitsAmino sugars –

N-acetylgalactosamine (Gal NAc) or N-acetylglucosamine (Glc NAc)

Uronic acids – glucuronic acid (Glc UA) or iduronic acid (Id UA)

GLYCOSAMINOGLYCANS and their biologic importance

Sulfate groups Hyaluronic acid, chondroitin sulfates, keratin sulfates I and II, heparin and heparin sulfates and dermatan sulfateThe majority of GAGs in the body are linked to core proteins forming proteoglycans

Sulfate groups Hyaluronic acid, chondroitin sulfates, keratin sulfates I and II, heparin and heparin sulfates and dermatan sulfateThe majority of GAGs in the body are linked to core proteins forming proteoglycans

Functions of GAGs and Proteoglycans

Acts as structural component of the ECMHave specific interactions with collagen, elastin, fibronectin, laminin and other proteins such as growth factorsAs polyanions, bind polycations and cationsContribute to characteristic turgor of various tissues

Acts as structural component of the ECMHave specific interactions with collagen, elastin, fibronectin, laminin and other proteins such as growth factorsAs polyanions, bind polycations and cationsContribute to characteristic turgor of various tissues

Functions of GAGs and Proteoglycans

Acts as sieves in the ECMFacilitate cell migration (HA)Have role in compressibility of cartilage in weight-bearing (HA, CS)Play a role in corneal transparency (KS1 and DS)Have structural role in sclera (DS)

Acts as sieves in the ECMFacilitate cell migration (HA)Have role in compressibility of cartilage in weight-bearing (HA, CS)Play a role in corneal transparency (KS1 and DS)Have structural role in sclera (DS)

Functions of GAGs and Proteoglycans

Act as anticoagulant (heparin)Component of plasma membranes (HS)Determine charge-selectiveness of renal glumerulus (HS)Components of synaptic and other vesicles

Act as anticoagulant (heparin)Component of plasma membranes (HS)Determine charge-selectiveness of renal glumerulus (HS)Components of synaptic and other vesicles

Biosynthesis of GAGs

A. Attachment to core proteins:1. O-glycosidic bond between xylose

(Xyl) and Ser through UDP-xylose

A. Attachment to core proteins:1. O-glycosidic bond between xylose

(Xyl) and Ser through UDP-xylose

Gal Gal Xyl O-Ser1,3 1,4

Link trisaccharide

Biosynthesis of GAGs

2. O- glycosidic bond between GalNAC (N-acetylgalactosamine) and Ser (Thr) through UDP-GalNAC

3. N-glycosylamine bond between GlcNAc (N-acetylglucosamine) and the amide nitrogen of Asn through dolichol-P-P-oligosaccharide

2. O- glycosidic bond between GalNAC (N-acetylgalactosamine) and Ser (Thr) through UDP-GalNAC

3. N-glycosylamine bond between GlcNAc (N-acetylglucosamine) and the amide nitrogen of Asn through dolichol-P-P-oligosaccharide

Biosynthesis of GAGs

B. CHAIN ELONGATION

Nucleotide sugars (UDP-xylose, UDP-GalNAC)Highly specific glucosyltransferases“one enzyme, one linkage”

B. CHAIN ELONGATION

Nucleotide sugars (UDP-xylose, UDP-GalNAC)Highly specific glucosyltransferases“one enzyme, one linkage”

Biosynthesis of GAGs

C. CHAIN TERMINATION

Sulfation ( certain positions of sugar)Progression of the growing GAG chain away from the membrane site where catalysis occurs

C. CHAIN TERMINATION

Sulfation ( certain positions of sugar)Progression of the growing GAG chain away from the membrane site where catalysis occurs

Biosynthesis of GAGs

D. FURTHER MODIFICATIONS

Introduction of sulfate groups unto GalNAc and other moieties through sulfotransferases and the use of 3’-phosphoadenosine-5’-phosphosulfate (PAPS)

Conversion of GlcUA to IdUA residues through epimerase

D. FURTHER MODIFICATIONS

Introduction of sulfate groups unto GalNAc and other moieties through sulfotransferases and the use of 3’-phosphoadenosine-5’-phosphosulfate (PAPS)

Conversion of GlcUA to IdUA residues through epimerase

Major Properties of GAGs

GAG SUGARS SULFATE LINKAGE OF PROTEIN

HA GlcNAc, GlcUA Nil No firm evidence

CS GalNAc, GlcUA GalNAc Xyl-Ser; associated with HA via link proteins

KS I GlcNAc, Gal GlcNAc GlcNAc-Asn

KS II GlcNAc, Gal GlcNAc GalNAc- Thr

Heparin GlcN, IdUA GlcNGlcNIdUA

Ser

Heparan sulfate GlcN, GlcUA GlcN Xyl-Ser

Dermatan sulfate GalNAc, IdUA, (GlcUA)

GalNAcIdUA

Xyl-Ser

Synthesis of Choindroitin Sulfate Proteoglycan

Xyl, xylose; Gal, galactose; GlcUA, glucuronic acid; GalNAC, N-acetylgalactosamine; PAPS, 3’-phosphoadenosine-5’-phosphosulfate*-( UDP-GalNAc, UDP-GlcUA, PAPS)n

Xyl, xylose; Gal, galactose; GlcUA, glucuronic acid; GalNAC, N-acetylgalactosamine; PAPS, 3’-phosphoadenosine-5’-phosphosulfate*-( UDP-GalNAc, UDP-GlcUA, PAPS)n

Structures of GAGs

Hyaluronic AcidHyaluronic Acid

Hyaluronic Acid GlcUA GlcNAc GlcUA GlcNAc β 1,4 β 1,3 β 1,4 β 1,3 β 1,4

Structures of GAGs

Dermatan sulfateDermatan sulfate

β 1, 4 α 1, 3 β 1, 4 β 1, 3 β 1, 4 β 1, 3 β 1, 3 β 1, 4 β

2- Sulfate 4-Sulfate

Dermatan IdUA GalNAc GlcUA GalNAc GlcUA Gal Gal Xyl SerSulfate

Structures of GAGs

HeparinHeparin

Heparin IdUA GlcN GlcUA GlcNAC GlcUA Gal Gal Xyl Ser

α 1, 4 α 1, 4 α 1, 4 β 1, 4 α 1, 4 β 1, 3 β 1, 3 β 1, 4 β

2-Sulfate S03-

6-Sulfate

Structures of GAGs

Heparan sulfateHeparan sulfate

Heparan: IdUA GlcN GlcUA GlcNAC GlcUA Gal Gal Xyl Ser Sulfate

α 1, 4 α 1, 4 α 1, 4 β 1, 4 α 1, 4 β 1, 3 β 1, 3 β 1, 4 β

Ac

6-Sulfate

Structures of GAGs

Keratan Sulfate IKeratan Sulfate I

Keratan Sulfate I GlcNAc Gal GlcNAc Gal GlcNAc Asnβ 1,4 β 1,3 β 1,4 β 1,3 (GlcNAc, Man) β

6-Sulfate 6-Sulfate

Structures of GAGs

Keratan Sulfate IIKeratan Sulfate II

Keratan Sulfate I GlcNAc Gal GlcNAc Gal GalNAc Thr (Ser)

β 1,4 β 1,3 β 1,4 β 1,3 1, 6 α

6-Sulfate 6-Sulfate Gal-NeuAC

Mucopolysaccharidoses

Mucopolysaccharidoses

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin and connective tissue.Depending on the specific enzyme deficiency, the catabolism of one or more GAGs may be blocked. Clinical features vary depending on the tissue distribution of the affected substrate and the degree of enzyme deficiency.`

Mucopolysaccharidoses are a group of metabolic disorders caused by the absence or malfunctioning of lysosomal enzymes needed to break down molecules called glycosaminoglycans - long chains of sugar carbohydrates in each of our cells that help build bone, cartilage, tendons, corneas, skin and connective tissue.Depending on the specific enzyme deficiency, the catabolism of one or more GAGs may be blocked. Clinical features vary depending on the tissue distribution of the affected substrate and the degree of enzyme deficiency.`

In Morquio syndrome (mucopolysaccharidosis type IV), the degradation of KS is defective because of deficiency of either N -acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in Morquio syndrome type IVA or β –galactosidase (GLB1 gene) in Morquio syndrome type IVB.

In Morquio syndrome (mucopolysaccharidosis type IV), the degradation of KS is defective because of deficiency of either N -acetyl-galactosamine-6-sulfate sulfatase (GALNS gene) in Morquio syndrome type IVA or β –galactosidase (GLB1 gene) in Morquio syndrome type IVB.

Type Main diseases Deficient enzyme Accumulated products

Symptoms Incidence

MPS I Hurler syndrome α-L-iduronidase Heparan sulfateDermatan sulfate

Mental retardation, Micrognathia, Coarse facies,Macroglossia,Retinal degeneration,Corneal clouding,Cardiomyopathy,Hepatosplenomegaly

1 in 100.000

MPS II Hunter syndrome Iduronate sulfatase Heparan sulfateDermatan sulfate

Mental retardation 1 in 250.000

MPS III

Sanfilippo syndrome A Heparan sulfamidase Heparan sulfate Developmental delaySevere hyperactivitySpasticityMotor dysfunctionDeath by the second decade

1 in 280,000to1 in 50,000Sanfilippo syndrome B N-acetylglucosaminidase

Sanfilippo syndrome C Acetyl-CoA:alpha-glucosaminide acetyltransferase

Sanfilippo syndrome D N-acetylglucosamine 6-sulfatase

MPS IV

Morquio syndrome A Galactose-6-sulfate sulfatase

Keratan sulfateChondroitin 6-sulfate

Severe skeletal dysplasiaShort statureMotor dysfunction

1 in 75,000

Morquio syndrome B Beta-galactosidase Keratan sulfate

MPS VI

Maroteaux-Lamy syndrome

N-acetylgalactosamine-4-sulfatase

Dermatan sulfate Severe skeletal dysplasia, Short stature,Motor dysfunction,Kyphosis,Heart defects

MPS VII

Sly syndrome β-glucuronidase Heparan sulfateDermatan sulfateChondroitin 4,6-sulfate

Hepatomegaly,Skeletal dysplasia,Short stature,Corneal cloudingDevelopmental delay

Less than 1 in 250,000

Types of Mucopolysaccharidoses

Hurler syndrome(MPS I)-is the most severe of the MPS I subtypes-Developmental delay is evident by the end of the

first year, and patients usually stop developing between ages 2 and 4

-followed by progressive mental decline and loss of physical skills

-Language may be limited due to hearing loss and an enlarged tongue

Hurler syndrome(MPS I)-is the most severe of the MPS I subtypes-Developmental delay is evident by the end of the

first year, and patients usually stop developing between ages 2 and 4

-followed by progressive mental decline and loss of physical skills

-Language may be limited due to hearing loss and an enlarged tongue

Hunter syndrome(MPS II) -share many of the same clinical

features associated with Hurler syndrome (MPS I H) but with milder symptoms

-Onset of the disease is usually between ages 2 and 4

-Developmental decline is usually noticed between the ages of 18 and 36 months, followed by progressive loss of skills

Hunter syndrome(MPS II) -share many of the same clinical

features associated with Hurler syndrome (MPS I H) but with milder symptoms

-Onset of the disease is usually between ages 2 and 4

-Developmental decline is usually noticed between the ages of 18 and 36 months, followed by progressive loss of skills

Sanfilippo syndrome(MPS III) -marked by severe neurological

symptoms -progressive dementia -aggressive behavior

-hyperactivity-seizures -deafness and -loss of vision-and an inability to sleep for

more than a few hours at a time

Sanfilippo syndrome(MPS III) -marked by severe neurological

symptoms -progressive dementia -aggressive behavior

-hyperactivity-seizures -deafness and -loss of vision-and an inability to sleep for

more than a few hours at a time

Morquio syndrome(MPS IV) -Onset is between ages 1 and 3 -Neurological complications include spinal

nerve and nerve root compression resulting from extreme, progressive skeletal changes, particularly in the ribs and chest

-conductive and neurosensitive loss of hearing and clouded corneas

-Intelligence is normal unless hydrocephalus develops and is not treated

-Physical growth slows and often stops between the ages of 4-8. Skeletal abnormalities include a bell-shaped chest, a flattening or curvature of the spine, shortened long bones, and dysplasia of the hips, knees, ankles, and wrists. The bones that stabilize the connection between the head and neck can be malformed.

Morquio syndrome(MPS IV) -Onset is between ages 1 and 3 -Neurological complications include spinal

nerve and nerve root compression resulting from extreme, progressive skeletal changes, particularly in the ribs and chest

-conductive and neurosensitive loss of hearing and clouded corneas

-Intelligence is normal unless hydrocephalus develops and is not treated

-Physical growth slows and often stops between the ages of 4-8. Skeletal abnormalities include a bell-shaped chest, a flattening or curvature of the spine, shortened long bones, and dysplasia of the hips, knees, ankles, and wrists. The bones that stabilize the connection between the head and neck can be malformed.

Maroteaux-Lamy syndrome (MPS VI) -usually have normal intellectual

development but share many of the physical symptoms found in Hurler syndrome

-Growth is normal at first but stops suddenly around age 8

-shortened trunk, crouched stance, and restricted joint movement by age 10

-In more severe cases, children also develop a protruding abdomen and forward-curving spine

Maroteaux-Lamy syndrome (MPS VI) -usually have normal intellectual

development but share many of the physical symptoms found in Hurler syndrome

-Growth is normal at first but stops suddenly around age 8

-shortened trunk, crouched stance, and restricted joint movement by age 10

-In more severe cases, children also develop a protruding abdomen and forward-curving spine

Sly syndrome (MPS VII)

-Sly syndrome causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body.

-Survival is usually a few months or less

Sly syndrome (MPS VII)

-Sly syndrome causes children to be born with hydrops fetalis, in which extreme amounts of fluid are retained in the body.

-Survival is usually a few months or less

Genetics

Mucopolysaccharidoses are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children.

Mucopolysaccharidoses are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected. (The exception is MPS II, or Hunter syndrome, in which the mother alone passes along the defective gene to a son.) When both people in a couple have the defective gene, each pregnancy carries with it a one in four chance that the child will be affected. The parents and siblings of an affected child may have no sign of the disorder. Unaffected siblings and select relatives of a child with one of the mucopolysaccharidoses may carry the recessive gene and could pass it to their own children.

Is there any treatment?

Currently there is no cure for these disease syndromes.  Medical care is directed at treating systemic conditions and improving the person's quality of life.

-Physical therapy and daily exercise may delay joint problems and improve the ability to move. 

-Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea. 

-Surgery can also correct hernias, help drain excessive cerebrospinal fluid from the brain, and free nerves and nerve roots compressed by skeletal and other abnormalities.

-Corneal transplants for significant corneal clouding. 

-Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain

Currently there is no cure for these disease syndromes.  Medical care is directed at treating systemic conditions and improving the person's quality of life.

-Physical therapy and daily exercise may delay joint problems and improve the ability to move. 

-Surgery to remove tonsils and adenoids may improve breathing among affected individuals with obstructive airway disorders and sleep apnea. 

-Surgery can also correct hernias, help drain excessive cerebrospinal fluid from the brain, and free nerves and nerve roots compressed by skeletal and other abnormalities.

-Corneal transplants for significant corneal clouding. 

-Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain

ROLE OF GAGs

In cancer:Hyaluronic acid may be important in permitting in tumor cells to migrate through the extracellular matrix.Glycosaminoglycans from normal cells are completely inactive. However, glycosaminoglycans from cancer cells are very active. They are quickly taken up by both normal and cancer cells and transported to the cell nuclei where they affect gene transcription and induce an antiproliferative effect, accompanied by apoptosis (cell death).

In cancer:Hyaluronic acid may be important in permitting in tumor cells to migrate through the extracellular matrix.Glycosaminoglycans from normal cells are completely inactive. However, glycosaminoglycans from cancer cells are very active. They are quickly taken up by both normal and cancer cells and transported to the cell nuclei where they affect gene transcription and induce an antiproliferative effect, accompanied by apoptosis (cell death).

ROLE OF GAGs

In atherosclerosis:Dermatan sulfate binds plasma

LDL and it is the major GAG synthesized by the arterial smooth muscle cells.

In atherosclerosis:Dermatan sulfate binds plasma

LDL and it is the major GAG synthesized by the arterial smooth muscle cells.

ROLE OF GAGs

In arthritis:In various types of arthritis,

proteoglycans may act as autoantigens.The amount of chondroitin sulfate

in cartilage diminishes with age while keratan sulfate and hyaluronic acid increases. These changes may contribute to development of osteoarthritis.

In arthritis:In various types of arthritis,

proteoglycans may act as autoantigens.The amount of chondroitin sulfate

in cartilage diminishes with age while keratan sulfate and hyaluronic acid increases. These changes may contribute to development of osteoarthritis.