MONTANO, Elisa B. MONTANO, Ma. Sheena-Day D. MORALES, MORZO, MUKSAN, NAPA, Reina Lyria C. Dan Israel B.

Ufyla Nashrene M. Christa Rosemary Faith D.M.

LEARNING OBJECTIVES:

Define what are glycosaminoglycans and proteoglycans and their biologic importance. Know the different mucopolysaccharidoses, identify the deficient enzyme in each type and its clinical characteristics. Know the role of glycosaminoglycans in cancer, atherosclerosis and arthritis.

Glycosaminoglycans (GAGs)
Long, unbranched heteropolysaccharide chains Repeating Disaccharide Units Amino Sugar D-Glucosamine D-Galactosamine Acidic Sugar (Uronic Acid) D-Glucuronic Acid L-Iduronic Acid All GAGs, except Hyaluronic Acid, contains Sulfur in atleast one of its sugars Essential components of the ECM

Disaccharide Units
A. Amino Sugars
May either be:
1. D-Glucosamine 2. D-Galactosamine

Contains an Amino group (-NH2)

Usually acetylated

May be Sulfated on C4, C6, or on a nonacetylated Nitrogen

Disaccharide Units
B. Acidic Sugars
May either be:
1. D-Glucuronic Acid 2. L-Iduronic Acid
C5 epimer

Contain carboxyl group (-COOH)

Negative at physiologic pH

May contain Sulfur Exception:

Keratan Sulfate
Galactose in place of Acidic Sugar

Major GAGs
CHONDROITIN SULFATE DERMATAN SULFATE KERATAN SULFATE HEPARIN HEPARAN SULFATE HYALURONIC ACID

Chondroitin Sulfate
Most abundant GAG in the body Disaccharides:

Acidic Sugar: Glucuronic Acid (GlcUA) Amino Sugar: N-Acetylgalactosamine (GalNAC)

 

C4 Chondroitin 4-Sulfate C6 Chondroitin 6-Sulfate

Function: Form proteoglycan aggregates with Keratan Sulfate In Cartilage, bind Collagen and hold fibers in a tight, strong network Localization: Cartilage Tendons Ligaments Bone Aorta

Dermatan Sulfate
Disaccharides:
Acidic Sugar: L-Iduronic Acid (IdUA) Amino Sugar: N-Acetylgalactosamine (GalNAC)

Localization:

Skin Blood Vessels Heart Valves

Keratan Sulfate
Most Heterogeneous GAG Sulfate content is variable Disaccharides:
Acidic Sugar: Galactose (Gal) Amino Sugar: N-Acetylglucosamine (GlcNAC)

Function:

Form proteoglycan aggregates with Chondroitin Sulfate. Cartilage Cornea

Localization:

Heparin
Only intracellular GAG Almost all Glucosamine residues are Sulfated Disaccharides:

Acidic Sugar: Glucuronic Acid (GlcUA) or Iduronic Acid (IdUA) Amino Sugar: Glucosamine (GlcN)

Function: Anticoagulant Localization: Mast Cells that line arteries

  

Liver Lungs Skin

Heparan Sulfate
Difference from Heparin: Extracellular Some Glucosamines are acetylated Fewer Sulfate Groups Disaccharides:

Acidic Sugar: Glucuronic Acid (GlcUA) or Iduronic Acid (IdUA) Amino Sugar: Glucosamine (GlcN)

Localization: Basement Membranes Cell Surfaces Skin Fibroblasts Aortic Wall

Hyaluronic Acid
Difference from other GAGs: Unsulfated Not covalently attached to protein Only GAG not limited to animal tissue, also found in bacteria. Disaccharides:

Acidic Sugar: Glucuronic Acid (GlcUA) Amino Sugar: N-Acetylglucosamine (GlcNAC) Lubricant Shock Absorber

Function:

Localization: Synovial fluid of joints Vitreous humor of the eye Umbilical cord Lose Connective Tissue

Proteoglycans
Core Proteins containing covalently linked GAG chains Major components of Ground Substance CHON-CHO Ratio
Protein : around 5%  Carbohydrates : up to about 95% of its weight


All GAGs, except for Hyaluronic Acid, are found covalently attached to proteins, forming proteoglycan monomers.

Proteoglycans

Proteoglycans
Aggrecan
Major

type of proteoglycan in cartilage Very large proteoglycan Bottle brush structure Components:
    

Core Protein Keratan Sulfate Chondroitin Sulfate Link Proteins Hyaluronic Acid

Mucopolysaccharidoses

Mucopolysaccharidoses is a collection of metabolic disorders that arise when mucopolysaccharides are unable to break down, causing a fault in the production of a particular gene. This results from abnormalities of specific enzymes.

Types of Mucopolysaccharidoses
Hurler Scheie Hurler- Scheie Hunter Sanfilippo A/B/C/D Morquio A/B Maroteaux-Lamy Sly

Hurlers syndrome/ Mucopolysaccharidosis type I (MPS I - H)

Enzyme defect: -L-iduronidase Affected GAG: dermatan sulfate, heparan sulfate s/s: Corneal clouding  Abnormal bones in the spine  Claw hand  Halted growth / dwarfism  Heart valve disease  Joint stiffness  Mental retardation  Thick, coarse facial features with low nasal bridge  Early mortality It is the most severe of the MPS I subtypes.


Scheie (MPS I S)
Enzyme defect : -L-iduronidase Affected GAG: dermatan sulfate, heparan sulfate s/s:

corneal clouding  broad mouth with full lips  hirsutism  prognathism  joint stiffening


Children born with this form normal intelligence and may live to adulthood.

Hurler-Scheie (MPS I-HS)

Enzyme defect: -L-iduronidase Affected GAG: dermatan sulfate, heparan sulfate s/s:
Dwarfism Progressive blindness Deafness Heart failure Normal/ near normal intelligence

Hunters Syndrome (MPS II)

Enzyme defect: L-iduronate-2-sulfatase Affected GAG: dermatan sulfate, heparan sulfate s/s:
       

mild and severe forms only X-linked MPS (usually seen in males) slowly progressive valvular disease organomegaly facial and physical deformities no corneal clouding mental retardation death before 15 yrs except in mild form then survival to 20 - 60 yrs

Sanfilippo (MPS III)

Sanfilippo A
Enzyme

defect: heparan N-sulfatase Affected GAG: heparan sulfate s/s

marked with severe neurological symptoms profound mental deterioration coarse facial features walking problems fairly normal height skin, brain, lungs and skeletal muscle are affected in all 4 types of MPSIII

Sanfilippo
Sanfilippo B
Enzyme

defect: -N-acetyl-D-glucosaminidase affected GAG: heparan sulfate s/s:



phenotype similar to III A

Sanfilippo
Sanfilippo C
enzyme defect: acetylCoA: -glucosaminideacetyltransferase affected GAG: heparan sulfate s/s:

phenotype similar to III A

Sanfilippo
Sanfilippo D
enzyme

defect: N-acetylglucosamine-6-sulfatase Affected GAG: heparan sulfate s/s:



phenotype similar to III A

Morquio
Morquio A
Enzyme defect: galactose-6-sulfatase Affected GAG: keratan sulfate, chondroitin 6-sulfate s/s:

corneal clouding,  odontoid hypoplasia,  aortic valve disease,  distinctive skeletal abnormalities short stature, short trunk  widely spaced teeth  large head  intelligence is normal unless hydrocephalus develops and not treated


Morquio
Morquio B
Enzyme

defect: -galactosidase Affected GAG : keratan sulfate s/s:



severity of disease similar to IV A

Maroteaux-Lamy (MPS VI)

Enzyme defect: arylsulfatase B also called Nacetylgalactosamine-4-sulfatase Affected GAG: dermatan sulfate s/s:
 

  

aortic valve disease shortened trunk, crouched stance, and restricted joint movement by age 10 normal intelligence corneal clouding coarse facial features

Sly Syndrome (MPS VII)

Enzyme defect: -glucuronidase Affected GAG: heparan sulfate, dermatan sulfate, chondroitin 4-, 6-sulfates s/s:
hepatosplenomegaly dystosis

multiplex wide spectrum of severity hydrops fetalis

Type:Syndrome

Enzyme Defect

Affected GAG

Symptoms

Hurler MPSIH (MPS1H)

-L-iduronidase

dermatan sulfate, heparan sulfate

corneal clouding, dystosis multiplex, organomegaly, heart disease, dwarfism, mental retardation; early mortality

Scheie MPSIS (MPS1S)

-L-iduronidase

dermatan sulfate, heparan sulfate

corneal clouding; aortic valve disease; joint stiffening; normal intelligence and life span intermediate between I H and I S

Hurler-Scheie MPSIHS (MPS1HS)

-L-iduronidase

dermatan sulfate, heparan sulfate

Hunter MPSII (MPS2)

L-iduronate-2-sulfatase

dermatan sulfate, heparan sulfate

mild and severe forms, only Xlinked MPS, dystosis multiplex, organomegaly, facial and physical deformities, no corneal clouding, mental retardation, death before 15 except in mild form then survival to 20 - 60

MPS VIII, a designation no longer used

Sanfilippo A MPSIIIA (MPS3A)

heparan N-sulfatase

heparan sulfate

profound mental deterioration, hyperactivity, skin, brain, lungs, heart and skeletal muscle are affected in all 4 types of MPS-III

Sanfilippo B MPSIIIB (MPS3B)

-N-acetyl-Dglucosaminidase acetylCoA: glucosaminideacetyltransferase

heparan sulfate

phenotype similar to III A

Sanfilippo C MPSIIIC (MPS3C)

heparan sulfate

phenotype similar to III A

Sanfilippo D MPSIIID (MPS3D)

N-acetylglucosamine-6sulfatase

heparan sulfate

phenotype similar to III A

Morquio A MPSIVA (MPS4A)

galactose-6-sulfatase

corneal clouding, odontoid keratan sulfate, chondroitin hypoplasia, aortic valve disease, distinctive skeletal 6-sulfate abnormalities

Morquio B MPSIVB (MPS4B)

-galactosidase

keratan sulfate

severity of disease similar to IV A

MPS V, a designation no longer used

Maroteaux-Lamy MPSVI (MPS6)

arylsulfatase Balso called Nacetylgalactosamine-4sulfatase

dermatan sulfate

3 distinct forms from mild to severe, aortic valve disease, dystosis multiplex, normal intelligence, corneal clouding, coarse facial features

Sly MPSVII (MPS7)

-glucuronidase

heparan sulfate, dermatan sulfate, chondroitin 4-, 6sulfates

hepatosplenomegaly, dystosis multiplex, wide spectrum of severity, hydrops fetalis

GENETICS
Mucopolysaccharidoses are autosomal recessive disorders, meaning that only individuals inheriting the defective gene from both parents are affected.

TREATMENT:
Currently there is no cure for these disease syndromes. Medical care is directed at treating symptomatic conditions and improving the person's quality of life. Enzyme replacement therapy has proven useful in reducing non-neurological symptoms and pain

Roles of Glycosaminoglycans in

CANCER ATERHOSCLEROSIS ARTHRITIS

Cancer
Glycosaminoglycans and proteoglycans both play major roles in multiple cancer-related processes. Changes in expression of these molecules, as well as of enzymes involved in their biosynthesis and degradation, contribute to the different steps of tumor progression.

Atherosclerosis
The

intima of the arterial wall contains hyaluronic acid, chondroitin sulfate, dermatan sulfate and heparan sulfate proteoglycans.

Dermatan

sulfate appears to be the major GAG synthesized by arterial smooth muscle cells. sulfate may play an important role in the development of the atherosclerotic plaque.

Dermatan

ARTHRITIS
Proteoglycans may act as autoantigens Amount of chondroitin sulfate diminishes with age Whereas the amount of keratan sulfate and hyaluronic acid increases. Increased in the activity of aggrecanase which acts to degrade aggrecan

References
Berg, Jeremy M. et al: Biochemistry, 6th Edition. New York: W.H. Freeman and Company, 2007. 312-313. Champe PC, Harvey RA: Biochemistry, 2nd Edition. Philadelphia: Lippincott, 1994. 147-155. http://www.ncbi.nlm.nih.gov/pubmedhealth http://themedicalbiochemistrypage.org Harpers Illustrated Biochemistry 27th and 28th Edition Lippincott Illustrated Reviews Biochemistry 4th Edition Murray, Robert K. et al: Harpers Illustrated Biochemistry, 27th Edition. McGraw-Hill Medical, 2006. 118-119, 551-564. Principles of Biochemistry By Lehninger

References:
Sasisekharan, et al. 2002. Role of heparan-sulphate glycosaminoglycans in tumour metastasis. Roles of heparansulphate glycosaminoglycans in cancer, Nature Reviews Cancer 2, 521-528. Swanson, Todd A. et al: Biochemistry and Molecular Biology, 4th Edition. Philadelphia: Lipincott Williams & Wilkins, 2007. 8, 10, 174.

THANK YOU! =)