Lec1 Glucosamineglycans PDF

# Extra Cellular matrix "Glycosaminoglycans" ## **Dr. Uzma Naseeb** ## **YOUR PATIENT** - A 5 year old boy was brought to the Paeds OPD with the following symptoms - severe structural abnormalities - mental retardation - On examination he had:- - Abnormal facial features - Abnormal...

# Extra Cellular matrix "Glycosaminoglycans" ## **Dr. Uzma Naseeb** ## **YOUR PATIENT** - A 5 year old boy was brought to the Paeds OPD with the following symptoms - severe structural abnormalities - mental retardation - On examination he had:- - Abnormal facial features - Abnormalities in hearing, vision and cardiovascular system. - alpha-L-iduronidase enzyme deficiency - **What is wrong with him?** ## **Learning Objectives** - Composition & function of the extra cellular matrix (ECM). - Glycosaminoglycans:- - Classification - Biochemical functions - Disease related with the GAGS. ## **Extra cellular matrix (ECM)** ### **Definition** - A collection of extra cellular molecules secreted by the cells which provide structural and biochemical support to the surrounding cells. - Composition of ECM varies between multicellular structures. - Functions are cell adhesion and cell-to-cell communication. ### **Composition of ECM** - An interlocking mesh of fibrous proteins and glycosaminoglycans (GAGS). - Contains three major classes of biomolecules: - **Structural proteins:** - Collagen - Elastin - Fibrillin - **Specialized proteins** - Fibrillin - Fibronectin - Laminin - **Proteoglycans:** compound consisting of a protein bonded to mucopolysaccharide ## **Introduction to GAGs** - Extracellular matrix - Extracellular spaces - Connective tissues - Basement membrane - Fibrous proteins - Gel-like matrix - Collagen and elastin fibers - GAGS - Free or linked to proteins to form proteoglycans ## **Glycosaminoglycans** - Large complexes of negatively charged heteropolysaccharide chains. - Have special ability to bind with large amount of water - Producing a gel like matrix that forms the basis of the body ground substance (amorphous gel like substance surrounding the cells) ## **Structure of GAGs** - Linear polymers - Heteropolysaccharides.... repeating disaccharide units, (AB) - Uronic acid - Glycosamine ## **Glycosaminoglycans** ### **Structure** - Long unbranched polysaccharide consisting of repeating disaccharide units (amino sugar + uronic sugar) - N-acetylglucosamin or N-acetylgalactosamine - glucuronic acid or iduronic acid. ## **Classification of GAGs** - **Sulphate free** - Hyaluronic acid - **Sulphate containing** - Chondroitin sulfate - Keratan sulfate I - Keratan sulfate II - Heparin - Heparan sulfate - Dermatan sulfate ## **1. CHONDROITIN SULFATE** - Contains D-Glucoronic acid + Galactosamine. - Most abundant GAG in body ### **Found in cartilage, tendons, ligaments & aorta** - Form proteoglycans aggregates - In cartilage binds with collagen & hold fibers in a tight, strong network - Role in compressibility of cartilage in weight bearing along with hyaluronic acid. ## **Keratan sulfate** - contains - Only GAG with no uronic acid. - Most heterogenous GAG - KSII found in loose connective tissues - KSI found in cornea - Maintans the corneal transparency. ## **HEPARIN** - Contains D-Glucuronic acid + Glucosamine - It is the only intracellular GAG. - Intracellular component of mast cells it line arteries in liver, lung & skin. - Serves as anticoagulant, strongly acidic sulfate group. - Help in releasing lipoprotein lipase, so help in clearing lipidemia after fatty meal---clearing factors. ### **Uses of Heparin** - Thromboembolism - In vitro - (anticoagulant) to take plasma/whole blood samples ## **Dermatan sulfate** - Contains L-iduronic acid + Glucosamine - Found in skin, cardiac valve & blood vessels - Main function is maintaining the shape of the eye (present in sclera of eye). ## **Heparan sulfate** - Same as heparin except some glycosamines are acetylated have few sulfate group - Extracellular GAG found in basement membrane as a ubiquitous component of cell surface. ## **2. HYALURONIC ACID** - Contains D-Glucoronic acid + Glucosamine. - It is sulphate free GAG. - Greek "Hyalos" means "glass" - Viscous clear solutions ### **Structure** - GIcA and GlcNAc - β (1→3) and ẞ (1→4) linkages - 50,000 repeats.. - Mol. wt. 105-107 KDa - Highly hydrated - Degradation by hyaluronidase - breaks... ẞ(1→4) linkages - Ground substance of synovial fluid of joints, vitreous humor of eyes and connective tissues, tendon. - Hyaluronidase is an enzyme that breaks ẞ-1 - 4 linkages. - Present in high concentration in testes, seminal fluid, & in certain snake and insect venoms. ### **Functions of Hyaluronic acid** - Serves as a lubricant and shock absorbant in joints. - Determines charge selectiveness of renal glomerulus. - Acts as seives in extracelluar matrix. - Permits cell migration during morphogenesis & wound repair. - Hyaluronidase enzyme of semen degrades the gel around ovum & allows effective penetration of sperm into ovum. ### **Hyaluronic acid differs from other GAGS** | Hyaluronic Acid | Other GAGS | |-------------------|---------------------------------| | Disaccharide units | upto 50,000 | 50 to 1000 disaccharide units | | Sulfation | Non-sulfated | Sulfated | | Covalently bound | No | Yes | | Monomeric units | GICA and GlcNAc | Different | ## **MUCOPOLYSACCHARIDOSES (MPS)** - Rare inborn errors in the degradation of glycosaminoglycans - Hereditary disorders - autosomal recessive except Hurler's(X-linked) - Deficiency of lysosomal hydrolase for GAGS - Accumulation of GAGS - Skeletal and extracellular matrix deformities and mental retardation ## **Dysotosis Multiplex** - Major features: - (severe abnormalities in development of cartilage and bone). Chondrodystrophic (cartilage maldevelopment) skeletal changes and deposition of a lipid-like substance in many of the body tissues. mental retardation, Organomegaly - Abnormal facial features - Abnormalities in hearing, vision and cardiovascular system ## **MPS Type I** - Hurler's syndrome results from a deficiency of alpha-L-iduronidase. - Heparan sulfate and dermatan sulfate accumulate. There is growth and mental retardation with characteristic facial changes. ## **MPS Type II** - Hunters syndrome is similar to Hurler's syndrome but the enzyme deficiency is for iduronate sulfatase and the inheritance is X-linked. ## **MPS Type III** - Sanfilipo's syndrome is caused by a deficiency of one of four enzymes of which three are hydrolases and one is an N-acetyltransferase. - There is severe mental retardation but only mild structural features. - Other MPS Types are IV, V, VI and VII. | Type | Syndrome | Enzyme defect | Accumulation | | ----- | ------------------ | ------------------------------- | ------------ | | I | Hurler's | a-L-iduronidase | DS, HS | | II | Hunter's | L-iduronate-2-sulfatase | DS, HS | | III | Sanfilippo's | heparan sulfatase | HS | | IV | Morquio's | Galactosamine sulphatase | KS, CS | | V | Scheie's | L-iduronidase | DS | | VI | Maroteaux-Lamy's | N-acetylglucosamine-4-sulfatase | DS | | VII | Sly's | β-glucuronidase | DS, HS | ## **MPS I (Hurler Syndrome)** - A deficiency of L-iduronidase (degradation of GAGs in lysosomes) leads to mental retardation and structural changes due to accumulation of dermatan sulfate and heparan sulfate ## **Mucopolysaccharidosis I (MPS I)** - Disease (Hurler, Hurler-Scheie, Scheie Syndromes) - SYMPTOMES IMAGES OF KEY FEATURES - Hernia - corneal clouding - Coarse facial - Claw hand ## **MPSII(Hunter syndrome)** - X-linked disease due to a deficiency of iduronate sulfatase. Lysosomal storage disease. The lack of this enzyme causes heparan sulfate and dermatan sulfate to accumulate in all body tissues. ## **MPS III (Sanfilippo Syndrome)** - Deficiency in one of four degradative enzymes needed to break down the glycosaminoglycan (GAG) heparan sulfate (which is found in the extra-cellular matrix and on cell surface glycoproteins). leads to severe mental retardation but little structural change ## **MPS IV (Morquio Syndrome)** - Deficiency of a galactose-6-sulfatase or a beta-galactosidase leads to accumulation of keratan sulfate, with normal intelligence but severe structure deformity. ## **CHONDRODYSTROPHIES** - Autosomal recessive diseases - Affect proper development of cartilage and maintenance of skeletal system - Defect in sulphation of growing GAG chain ## **Association of GAGs with cancer** - Hyaluronic acid - tumor cell... increased production of hyaluronic acid - cell migration through ECM... aid in tumor spread - Heparan sulfate - Role in adhesiveness - Tumor cells.. less HS at their surface .... lack of adhesiveness ## **GAGS** - These long chains of sugar carbohydrates occur within the cells that help build bone, cartilage, tendons, corneas, skin and connective tissue. - They bind and hold water, acid mucopolysaccharides serve as a natural lubricant in the joints and impart elasticity to connective tissue. As a component of cartilage and ligaments, involved in support and motor functions. They also have bactericidal properties ## **Key points** | Glycosaminoglycans | |-------------------| | *composed of* | | *Proteins* | | *Core proteins* | Heteropoly-saccharide chains including | | *Link proteins* | | *physical-chemical properties include* | | *Long chains* | | *Unbranched* | | *Negatively charged* | | *Repeating disaccharide units* | | *classified as* | | *Chondroitin sulfates* | *Bind large amounts of water* | | *Keratan sulfate* | *Viscous* | | *Dermatan sulfate* | *Lubricating* | | *Hyaluronic acid* | | *Heparin* | | *Heparan sulfate* | | *degraded by* | | *Lysosomal hydrolases* | | *function to* | | *Support cellular and fibrous components of tissues* | | *Mediate cell-cell signaling and adhesion* | | *lead to* | | *Hereditary enzyme deficiencies* | | *Mucopoly-saccharidoses* | | *Hurler syndrome* | | *Hunter syndrome* | | *Sanfilippo syndrome* | | *Sly syndrome* | ## **symptoms of mucopolysaccharidosis** - Enlarged head, lips, cheeks, tongue, and nose. - Enlarged vocal cords, resulting in a deep voice. - Frequent upper respiratory infections. - Sleep apnea. - Hydrocephalus. - Hepatosplenomegaly (enlarged liver and spleen) - Umbilical hernia. - Inguinal hernia. ## **Thank you**