L21 GAG and Glycoproteins .pdf

L21 Glycosaminoglycans and Glycoproteins: Composition and Functions Dr. Nelofar Khan www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives: 1. 2. 3. Types and functions of Glycosaminoglycans Explain the term mucopolysaccharidoses with Examples Describe the structure and functions of glycoprotei...

L21 Glycosaminoglycans and Glycoproteins: Composition and Functions Dr. Nelofar Khan www.gmu.ac.ae COLLEGE OF MEDICINE Learning Objectives: 1. 2. 3. Types and functions of Glycosaminoglycans Explain the term mucopolysaccharidoses with Examples Describe the structure and functions of glycoproteins Reference • Reading: Satyanarayana U and Chakrapani U. Biochemistry; Elsevier; 5th Edition; 2020. ISBN- 978-8131262535. Chapter 2, pages 22-26. • Video: https://youtu.be/zkvzmf0e_nY Cells in tissues are surrounded by a complex substance called the extracellular matrix (ECM). The ECM contains three major classes of biomolecules: 1. Structural proteins: Collagen, Elastin and Fibrillin-1 2. Specialized proteins: such as Fibronectin and Laminin 3. Proteoglycans The ECM has been found to be involved in many normal and pathologic processes such as: ✔ normal development and aging ✔ inflammatory states ✔ spread of cancer cells 3 PROTEOGLYCANS & GLYCOSAMINOGLYCANS OF THE ECM • Proteoglycans are complex molecules and are found mainly in the ECM or "ground substance." • They contain large amounts of glycosaminoglycans (heteropolysaccharides) (95%) covalently linked to some proteins. • Examples are aggrecan, versican, decorin, biglycan, and fibromodulin. • They vary in tissue distribution, nature of protein, attached glycosaminoglycans and function. Proteoglycans Have Numerous Functions • They associate with each other and with collagen and elastin. • These interactions are important in determining the structural organization of the matrix. Glycosaminoglycans (GAG) • Heteropolysaccharides found in the extracellular matrix. • Unbranched polysaccharide made up of repeating disaccharide units. • One component of the disaccharide is always an amino sugar (hence the name GAG), either D-glucosamine or D-galactosamine. • The other is usually a uronic acid, either L-glucuronic acid (GlcUA) or L-iduronic acid (IdUA). • Negatively charged: Contain sulfate groups (exception is hyaluronic acid). • Generally associated with a small amount of protein, forming proteoglycans (5% Protein and 95% carbohydrate). • The seven glycosaminoglycans (GAGs) are Hyaluronic acid, Chondroitin sulfate, Keratan sulfates I and II, Heparin, Heparan sulfate, and Dermatan sulfate. Glycosaminoglycans are Large complexes of negatively charged heteropolysaccharide chains Contain two or more types of monosaccharides repeated large number of times. Have wide range of functions. For example: Hyaluronic acid (act as lubricants) (Glucuronic acid +N-acetyl glucosamine)n Heparin (an anticoagulant) (Glucuronate sulfate and Sulfoglucosamine sulfate)n Chondroitin sulfate (form the extracellular matrix in connective tissue) 7 Relationship between glycosaminoglycan structure and function • Because of their large number of negative charges, these heteropolysaccharide chains tend to be extended in solution due to repulsion of same charges. • When brought together, they “slip” past each other, much as two magnets with the same polarity seem to slip past each other. This produces the “slippery” consistency of mucous secretions and synovial fluid. 8 Structure of proteoglycans • All GAG’s, except hyaluronic acid, are found covalently attached to protein, forming proteoglycan monomers. • Structure of proteoglycan monomers: Consists of a core protein to which the linear glycosaminoglycan chains are covalently attached. • Each chains may be composed of more than 100 monosaccharides, extend out from the core protein, and remain separated from each other because of charge repulsion. The resulting structure resembles a “bottle brush”. • In cartilage proteoglycan, the species of glycosaminoglycans include chondroitin sulfate and keratan sulfate. Linkage between the carbohydrate chain and the protein: • This linkage is most commonly through a trihexoside (galactose-galactose-xylose) and a serine residue, respectively. • An O-glycosidic bond is formed between the xylose and the hydroxyl group of the serine. Proteoglycan aggregates: • The proteoglycan monomers associate with a molecule of hyaluronic acid to form proteoglycan aggregates. • The association is not covalent but occurs primarily through ionic interactions between the core protein and the hyaluronic acid. The association is stabilized by additional small proteins called link proteins. 13 Heteropolysaccharides - Dietary Fibers • Agar, mostly found in sea weeds, is a polymer of galactose sulfate and glucose. Since agar is not digested, it serves as a dietary fiber. • Agarose (with galactose and anhydrogalactose) is useful in the laboratory as a major component of microbial culture media, and in electrophoresis. • Pectins, found in apples and citrus fruits, contain galactouronate and rhamnose. Pectins, being non-digestible, are useful as dietary fiber. They are also employed in the preparation of jellies. 14 Mucopolysaccharidoses • Genetic disorders characterized by deficiencies of enzymes that degrade Glycosaminoglycans resulting in their accumulation in various tissues. • Both exo- and endoglycosidases degrade GAGs. • Like most other biomolecules, GAGs are subject to turnover, being both synthesized and degraded. • Degradation of GAGs is carried out by a battery of lysosomal hydrolases. • These include endoglycosidases, exoglycosidases, and sulfatases, generally acting in sequence to degrade the various GAGs. • They are usually inherited in an autosomal recessive manner. 16 17 Glycoproteins Vs proteoglycans Glycoproteins Proteoglycans • Proteins to which oligosaccharides are covalently attached. Variable amounts of carbohydrate. [IgG, (4%), human gastric glycoprotein mucin (80%) carbohydrate]. • They contain large amounts glycosaminoglycans (95%) covalently linked to proteins (5%). • Length of carbohydrate: usually two to ten sugar residues. • Glycosaminoglycans have Diglucosyl repeat units (Heteropolysaccharides) • Carbohydrates do not have serial repeats; often branched; and may or may not be negatively charged. • Carbohydrate can be very long in the glycosaminoglycans • Linear and Negatively charged. 18 Functions of Glycoproteins • Membrane bound glycoproteins participate in:- cell surface recognition (by other cells, hormones, and viruses), cell surface antigenicity (such as the blood group antigens). • As components of the ECM and of the mucins of the gastrointestinal and urogenital tracts, they act as protective biologic lubricants. • Almost all the globular proteins present in human plasma are glycoproteins. Types of linkages between carbohydrates and amino acids in Glycoproteins •Carbohydrates are attached to: ✔ the side chain oxygen of the amino acid Serine or Threonine by O-glycosidic bonds ✔ to the side chain Nitrogen of Asparagine residues by N-glycosidic linkages. 20 Blood Group Antigens RBC membrane and other cell membranes and secretions contain antigens based on which people can be classified into groups A, B, AB and O. The ABO substances are ∙ glycosphingolipids and glycoproteins ∙ which share common oligosaccharide chains. Summary 1. Give physiological examples of heteropolysaccharides. 2. What are Glycosaminoglycans and mucoproteins? List 7 GAGs 3. What is mucopolysaccharidoses? Give 2 examples. 4. Describe the types of linkages between oligosaccharides and the protein in glycoproteins. 5. Explain the role of carbohydrates in determination of blood group. Thank You 23