Textbook - BIOLOGICAL CHEMISTRY - Hubsky Y.I. - 2000

Chapter I. BIOMOLECULES AND CELLULAR STRUCTURES

CHAPTER 4. CARBOHYDRATES AND THEIR DERIVATIVES

4.3. HETEROPOLYSACCHARIDES. PROTEOGLYCANS. GLYCOPROTEINS

Class="center">Heteropolysaccharides

Heteropolysaccharides are polymers composed of A wide variety of different monosaccharide units and their derivatives. In Human and Animal biochemistry and physiology, The most significant heteropolysaccharides are glycosaminoglycans.

Glycosaminoglycans are heteropolysaccharides built from repeating disaccharide units. The monosaccharide components of glycosaminoglycan disaccharide units are most commonly hexuronic acids (glucuronic or sometimes iduronic acid, etc.) and N-acetyl derivatives of hexosamines (glucosamine, galactosamine).

Glycosaminoglycans include numerous animal Biopolymers that form the Extracellular matrix of Connective Tissue, filling the spaces between individual Cells. The outdated term for these compounds, mucopolysaccharides, indicates that substances of this class were first isolated from mucin—a component of mucus that acts as a physiological lubricant. The most thoroughly studied glycosaminoglycans are hyaluronic acid, chondroitin sulfates, dermatan sulfates, keratan sulfates, and heparan sulfates, which are found in the Skin, tendons, and joint cartilages, providing mechanical strength, structural resilience, and joint elasticity. The glycosaminoglycan heparin serves as a natural anticoagulant.

Glycosaminoglycans are polyanionic molecules. At least one of the monosaccharide components in glycosaminoglycan molecules bears an acidic group—a carboxyl or sulfate group—which ensures their high hydrophilicity, meaning The ability to retain a significant amount of Water within biological Tissues.

All glycosaminoglycans perform their biochemical and physiological Functions while bound to Proteins. Covalent complexes of connective tissue glycosaminoglycans (such as hyaluronic acid and chondroitin sulfates) with proteins are termed Proteoglycans, which represent a class of mixed biopolymers (Glycoconjugates).

Table 4.1. Structural components of glycosaminoglycans

Hyaluronic acid is a linear heteropolysaccharide in which D-glucuronic acid and N-acetyl-D-glucosamine are linked by a β-1,3-glycosidic bond, with individual disaccharide fragments joined by β-1,4-glycosidic bonds:

Hyaluronic acid possesses the highest molecular weight among all glycosaminoglycans, ranging from 10⁵ to 10⁷. A large number of —COO^- groups creates a significant negative charge on the molecule, facilitating the retention of water and Na⁺ cations. Hyaluronic acid is present in loose connective tissue, the synovial fluid of joints, and the vitreous body of the eye.

Chondroitin sulfates are glycosaminoglycans that, as part of respective proteoglycans (see below), serve as vital structural components of Cartilage tissue. The Molecular Weight of chondroitin sulfates is 10-60 kDa. Their disaccharide fragments consist of glucuronic acid and sulfated N-acetylgalactosamine linked by a β-1,3-glycosidic bond. A —SOO^- group is present at the 4th or 6th positions of the N-acetylgalactosamine residue (chondroitin-4- and chondroitin-6-sulfates, respectively):

Keratan sulfates are glycosaminoglycans sulfated at the 6th position of the N-acetylglucosamine residue. Similar to chondroitin sulfates, keratan sulfates are linked to proteins in the form of proteoglycans. There are two main types: keratan sulfate I, found in the Cytology/practical/76.html">Cornea of the eye, and keratan sulfate II, a component of Bone tissue.

Heparan sulfates are glycosaminoglycans present on the outer surfaces of animal cells. The uronic acid components within the disaccharide units of heparan sulfates are glucuronic and iduronic acids, which are linked by β-1,4-glycosidic bonds to sulfated N-acetylglucosamine residues.

Heparin is a glycosaminoglycan synthesized by mast cells of connective tissue that acts as an anticoagulant by enhancing the inhibitory activity of antithrombin III, thereby preventing intravascular Blood clotting.

Similar to heparan sulfates, heparin chains contain disaccharide units incorporating iduronic and glucuronic acids (with iduronic acid predominating in heparin, unlike heparan sulfates, accounting for up to 90% of the total uronic acid content), linked via β(1→4) bonds to N- or O-sulfated residues of glucosamine and N-acetylglucosamine:

The three presented disaccharide fragments (A), (B), and (C) (in brackets) include:

(A) O- and N-sulfated glucosamine (a) linked to sulfated iduronic acid (b);

(B) O- and N-sulfated glucosamine (c) linked to glucuronic acid (d);

(C) O-sulfated N-acetylglucosamine (e) linked to sulfated iduronic acid (f).

Heparin and heparan sulfates share a common precursor: an unsulfated polysaccharide chain of a heparin proteoglycan. Modification of the polysaccharide within the proteoglycan involves the action of an epimerase, which converts a portion of the glucuronic acid residues into iduronic acid, followed by O- and N-sulfonation reactions.

Proteoglycans

Proteoglycans are hybrid molecules (glycoconjugates) in which proteins are covalently linked to polysaccharide chains called glycosaminoglycans. In proteoglycans, proteins account for 5-10% of the molecular mass, while the carbohydrate moiety makes up 90-95%.

The polysaccharide chains are attached to the polypeptide backbone of the proteoglycan molecules, forming:

1) O-glycosidic bonds between the hydroxyl groups of Monosaccharides and the OH groups of Serine or Threonine;

2) N-glycosylamide bonds between the acetyl group of N-acetylglucosamines and the amide nitrogen of asparagine in the polypeptide.

A typical proteoglycan molecule consists of a central polypeptide backbone—the core protein (or core)—to the sides of which glycosaminoglycan chains are attached.

Due to electrostatic repulsion between individual polyanionic polysaccharide chains, the overall Structure of a proteoglycan resembles a bottle brush or a fir tree.

When proteoglycans interact with hyaluronic acid molecules in the extracellular matrix of connective tissue, complex structural arrangements are formed, featuring a central hyaluronic acid molecule with proteoglycan side chains radiating outward (a "tree-of-trees" structure). Research has shown that up to 150 sulfated proteoglycan molecules can associate with a single molecule of hyaluronic acid (Fig. 4.1).

Fig. 4.1. SCHEMATIC STRUCTURE OF a proteoglycan aggregate consisting of a hyaluronic acid molecule (a), core Polypeptides (b), and glycosaminoglycans (c).

Proteoglycans bound to hyaluronic acid form a gel-like matrix—the "ground substance" of connective tissue—which impedes the diffusion of foreign molecules and microorganisms into the tissues. Acting as polyvalent anions, the glycosaminoglycan components of proteoglycans bind significant amounts of extracellular Na⁺ and, consequently, H₂O, which underlies The Role of tissue proteoglycans in the Regulation of Water-salt balance.

Glycoproteins

Glycoproteins are hybrid molecules classified as complex proteins in which oligosaccharide (glycan) chains are covalently linked to a polypeptide backbone.

Glycoproteins represent a large and functionally diverse group of proteins. Broadly speaking, the majority of extracellular proteins are glycoproteins. These include structural proteins of Introduction/36.html">Biological Membranes and the extracellular matrix, particularly connective tissue (Collagen, Elastin, mucins, mucous secretions, and bone matrix proteins); blood proteins, including clotting factors, vitamin, hormone, and mineral carriers; Hormones (such as chorionic gonadotropin and thyrotropin); immune system proteins (IMMUNOGLOBULINS, interferons, and Complement components); Enzymes (proteases, Nucleases, glycosidases), and more.

Glycoproteins, along with structurally similar Glycolipids, form The Cell surface glycocalyx, whose components participate in cell-cell interactions and the Regulation of Cell division, as well as its disruption during malignant growth. Cell-surface glycoproteins mediate mutual Cell Recognition, which is particularly crucial for immune processes: cell membrane Polysaccharides act as Antigens that trigger cell-mediated immune responses, notably during Organ and tissue transplantation.

The carbohydrate content in most glycoproteins is relatively low, but can occasionally reach 50-80% of the molecular mass. The number of carbohydrate chains in individual glycoprotein molecules ranges from one to several dozen. In turn, each oligosaccharide chain of a glycoprotein contains from 1 to 15 monosaccharide residues. These chains can be either linear or branched.

The most common sugars found in the carbohydrate moiety of human glycoproteins include galactose (Gal), glucose (Glc), mannose (Man), fucose (Fuc), N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), and N-acetylneuraminic (sialic) acid (NeuAc).

Similar to proteoglycans, the oligosaccharide chains in glycoprotein molecules are attached to the polypeptide portion through:

1) An O-glycosidic bond between the sugar and the OH group of serine or threonine;

2) An N-glycosidic bond between the sugar and the amide group of asparagine.

Examples of O-linked glycoproteins include mucins (mucus proteins) as well as certain blood and biomembrane proteins. In these glycoproteins, the sugar directly attached to Ser or Thr of the peptide chain is GalNAc.

N-linked glycoproteins feature a pentasaccharide core, (Man)₃(GlcNAc)₂, attached directly to the NH group of asparagine, to which structurally diverse outer oligosaccharide branches are connected. These outer branched oligosaccharide chains resemble molecular "antennas" that play a key role in cell-cell interactions as well as binding to other protein and polysaccharide structures.

Examples of The structure of O- and N-linked oligosaccharide components of glycoproteins: