MONTANO, Elisa B.

MONTANO, Ma. Sheena-Day D.

MORALES, Reina Lyria C.

MORZO, Dan Israel B.

MUKSAN, Ufyla Nashrene M.

NAPA, 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 UnitsAmino Sugar

D-GlucosamineD-Galactosamine

Acidic Sugar (Uronic Acid)D-Glucuronic AcidL-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-Glucosamine2. D-Galactosamine

Contains an Aminogroup (-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 Acid2. 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.

Localization: Cartilage Cornea

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)

Function: Lubricant Shock Absorber

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

Hurler’s syndrome/ Mucopolysaccharidosis type I (MPS I - H)

Enzyme defect: α-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 mortalityIt is the most severe of the MPS I subtypes.

Scheie (MPS I – S)

Enzyme defect :α-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: α-L-iduronidase Affected GAG: dermatan sulfate, heparan

sulfate s/s:

Dwarfism Progressive blindness Deafness Heart failure Normal/ near normal intelligence

Hunter’s 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 MPS-III

Sanfilippo

Sanfilippo B Enzyme defect: α-N-acetyl-D-

glucosaminidase affected GAG: heparan sulfate s/s:

phenotype similar to III A

Sanfilippo

Sanfilippo C enzyme defect: acetylCoA:α-

glucosaminide-acetyltransferase 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: β-galactosidase Affected GAG : keratan sulfate s/s:

severity of disease similar to IV A

Maroteaux-Lamy (MPS VI)

Enzyme defect: arylsulfatase B also called N-acetylgalactosamine-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: β-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

HurlerMPSIH (MPS1H)

α-L-iduronidasedermatan sulfate, heparan sulfate

corneal clouding, dystosis multiplex,

organomegaly, heart disease, dwarfism, mental retardation;

early mortality

ScheieMPSIS (MPS1S)

α-L-iduronidasedermatan sulfate, heparan sulfate

corneal clouding; aortic valve disease; joint stiffening; normal

intelligence and life span

Hurler-ScheieMPSIHS (MPS1HS)

α-L-iduronidasedermatan sulfate, heparan sulfate

intermediate between I H and I S

HunterMPSII (MPS2)

L-iduronate-2-sulfatasedermatan sulfate, heparan sulfate

mild and severe forms, only X-linked 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

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

CANCERATERHOSCLEROSISARTHRITIS

Roles of Glycosaminoglycans in

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.

Dermatan sulfate may play an important role in the development of the atherosclerotic plaque.

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 Harper’s Illustrated Biochemistry 27th and 28th Edition Lippincott Illustrated Reviews Biochemistry 4th Edition Murray, Robert K. et al: Harper’s 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 heparan-sulphate 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! =)