Glycoconjugates

Glycoconjugates

1. Introduction

   • include
     • Proteoglycans
     • Glycolipids
     • Glycoproteins
   • the
     • Glycosylation is the main enzymatic modification of proteins in the body
     • Animal cells have two main types of proteins that contain sugars
       • which are
         • Glycoproteins
         • Proteoglycans
     • Glycoproteins have short glycan chains
       • they can have
         • Up to 20 sugars
     • Glycoproteins
       • generally
         • Do not contain uronic acids
       • often
         • Contain much smaller amounts of carbohydrates than proteins
       • are
         • Most cell surface membrane proteins

2. Glycoproteins

   • Structures and links
     • General structures of glycoproteins
       • the
         • LDL receptor has two N-glucans located near the LDL-binding domain
           • and
             • A group of O-glucans near the membrane-spanning region
         • A glycoprotein can have a single N-glucan chain
           • or it can have
             • Several types of oligosaccharides
         • Microheterogeneity of the oligosaccharide structures
           • is due to
             • Incomplete processing in some chains during their biosynthesis
         • N-glucans exposed on the surface of a folded protein are more vulnerable to processing enzymes
           • while
             • Those protected behind the protein structure are inaccessible to enzymes
         • Glycoproteins with N-glycosidic bonds also contain O-glucans
     • Structure-function relationships in mucin glycoproteins
       • the
         • Mucins are glycoproteins secreted by epithelial cells
           • that line the
             • Respiratory
             • Gastrointestinal
             • Genitourinary systems
         • Oligosaccharides carry a negatively charged sialic acid
           • preventing
             • The protein from folding, causing it to remain extended
       • there
         • Are many complex linear and branched oligosaccharide structures on mucins
           • including
             • Blood group antigens
       • about
         • A third of the amino acids in mucins are serines or threonines
           • most of them
             • Are replaced by the O-glycosidic linked oligosaccharide
     • the
       • Sugars can bind to proteins
         • either
           • N-glycosidic bonds
           • O-glycosidic bonds
       • Oligosaccharides with N-glycosidic bonds (N-glucans) are widely distributed in nature
         • they are characteristic of
           • The membrane and secretory proteins
       • Union of the oligosaccharides with the proteins involved a glucosamine union
         • between
           • N-acetylglucosamine residue (GlcNAc)
           • The amide nitrogen of an asparagine residue
       • O-glycosidic linked oligosaccharides (O-glucans)
         • are found
           • In proteins of mucosal fluids
       • O-glucans generally contain three or more sugars in straight or branched chains
         • linked to proteins by
           • A glycosidic bond between an N-acetylgalactosamine (GalNAc) residue
           • The hydroxyl group of a serine or threonine residue in the protein
       • Glucosyl-galactose disaccharide is often attached to the hydroxyl group of hydroxylysine residues
         • in
           • The fibrous protein, collagen
       • Procollagens are usually synthesized as glycoproteins with N-glycosidic bonds
         • but
           • N-glucan is eliminated as part of this peptide
       • Only disaccharides with O-glycosidic bonds
         • remain in the
           • Mature collagen molecule
       • GlcNAC modification (O-GlcNAcylation) may represent a mechanism
         • that allows cells to
           • Block the phosphorylation of specific serine threonine residues in specific proteins
       • Donor substrate for O-GlcNAcylation
         • is
           • UDP-GlcNAc derived from glucose
       • Mannose O-glucans serve as links
         • between
           • The intracellular cytoskeleton
           • The extracellular matrix to maintain myocyte function
       • Glycogenin is a self-glycosylated protein that binds a glucose
         • to the
           • Hydroxyl group of one of its tyrosine residues
       • N-glucans have oligosaccharide chains that are branched structures
         • with
           • A common center of three mannose residues
           • Two GlcNAC residues
       • Oligosaccharides give rise to a wide group of structures
         • that are called
           • Mannose rich chains
           • Complex chains
       • N-glucans have rich structures in hands as built from a common nucleus
       • O-GlcNAcylation of proteins involved in the insulin signaling pathway
         • causes
           • Insulin resistance
             • in
               • Skeletal muscle
               • Adipose tissue
               • Pancreatic B cells
   • Interconversions of sugars in the diet
     • Formation of galactose, mannose and fucose from glucose
       • the
         • GDP-Man is the form of mannose
           • that is used in the
             • Formation of oligosaccharides with N-glycosidic bond
         • Glucose is phosphorylated
           • by
             • Hexokinase (or glucokinase in the liver) when it enters the cell
         • Glucose-6-phosphate (Glc-6-P) can then be converted by a mutase (phosphoglucose mutase)
           • to form
             • Glc-1-P, which reacts with uridine triphosphate (UTP) to form UDP-Glc
               • catalyzed by
                 • UDP-Glc pyrophosphorylase enzyme
         • UDP-Glc is epimerized to UDP-galactose (UDP-Gal)
           • by
             • UDP-Gal 4-epimerase, providing UDP-Gal for the synthesis of glycoconjugates
         • Glc-6-P can also be converted to fructose-6-phosphate (Fru-6-P) by the glycolytic enzyme phosphoglucose isomerase
           • and
             • Fru-6-P can be isomerized to mannose-6-phosphate (Man-6 -P) by phosphomannose isomerase
         • Man-6-P is then converted by a mutase (phosphomannose mutase) to Man-1-P
           • which
             • Is condensed with GTP to form GDP-Man
     • Galactose metabolism
       • the
         • UDP-Gal 4-epimerase., this enzyme catalyzes the balance between UDP-Glc and UDP-Gal
           • providing
             • A constant source of UDP-Glc during galactose metabolism
         • Galactose from the diet is transported to the liver
           • where
             • It is phosphorylated by a specific kinase, galactokinase
         • Enzyme Gal-1-P uridyltransferase catalyzes an exchange between UDP-Glc and Gal-1-P
           • to form
             • UDP-Gal Glc-1-P
     • Fructose metabolism
       • the
         • Cleavage products of fructose by aldolase B are dihydroxyacetone phosphate and glyceraldehyde
           • after which
             • Glyceraldehyde must be phosphorylated by triose kinase to be metabolized by glycolysis
         • Fructose is a component of sucrose
           • and
             • Makes up about half the sugar in high-fructose corn syrup
         • Fructose can be phosphorylated
           • by
             • Hexokinase, an enzyme present in all cells
         • Main pathway of fructose metabolism, which is especially important in the liver after a meal involves fructokinase
           • this enzyme
             • Is a very specific kinase that phosphorylates fructose at carbon 1 to fructose phosphate (Fru-1-P )
     • the
       • Cells can use glucose to form the rest of the sugars they need
       • Sugars need to make glycoconjugates
         • can be
           • Synthesized from blood sugar
   • Other pathways of sugar nucleotide metabolism
     • UDP-GIcUA
       • the
         • Two-stage oxidation by the enzyme UDP-Glc dehydrogenase leads to the formation of the activated
           • form of
             • Glucuronic acid (UDP-GlcUA), this sugar nucleotide is the glucuronic acid donor for the formation of proteoglycans
         • UDP-Glc is the precursor to several other sugars, such as glucuronic acid, xylose and galactose
           • which
             • Are required for the synthesis of proteoglycans and / or glycoproteins
         • UDP-GlcUA is also the precursor to UDP-xylose. a pentose sugar nucleotide
     • GDP-Man and GDP-Fuc
       • the
         • Resulting depletion of GDP-Fuc in the Golgi lumen blocks the biosynthesis
           • of the
             • Leukocyte recognition signal, the Lewis-X sialyl structure
         • Guanosine diphosphate-mannose (GDP-Man) is the donor substrate for most mannosyltransferases
         • Conversion of GDP-Man to GDP-fucose involves a complex series of oxidative
           • and
             • Reductive steps, in addition to epimerization
     • Amino sugars
       • the
         • UDP-GlcNAc can be epimerized to UDP-GalNAc
         • Fru-6-P is the precursor of amino sugars
         • Acetyl group is transferred from acetyl-CoA to the amino group of GlcN-6-P
           • to form
             • GlcNAc-6-P, which is converted to its activated form, UDP-GlcNAc
         • Amino sugars in glycoconjugates are acetylated
           • therefore
             • They are neutral and do not contribute to the ionic charge of the glycoconjugates
         • Transfer of an amino group from the amide nitrogen of glutamine
           • to
             • Fru-6-P to produce glucosamine-6-P (GlcN-6-P)
     • Sialic acid
       • the
         • CMP-sialic acid is the only sugar donor nucleoside monophosphate
           • in the
             • Metabolism of glycoconjugates
         • UDP-GIcNAc is the precursor of N-acetylneuraminic acid (NeuAc)
           • also called
             • Sialic acid
         • Sialic acid, a 9-carbon N-acetylamino-ketodeoxygluconic acid
           • is produced by
             • Condensation of an amino sugar with phosphoenolpyruvate
   • Oligosaccharide biosynthesis
     • Oligosaccharides with O-glycosidic bonds (O-glucans)
       • the
         • Glycosyltransferases of the Golgi apparatus
           • are
             • Involved in the stepwise biosynthesis of mucin oligosaccharides
         • O-glycosidic linked oligosaccharides
           • are
             • Synthesized in the Golgi apparatus
         • Synthesis of the oligosaccharides with O-glycosidic bonds takes place only in the Golgi apparatus
           • by
             • The addition in stages of sugars from the nucleotide derivatives of sugar the protein
         • GalNAc is transferred from the UDP-GalNAc to serine or threonine residues in the protein
           • by
             • Means of a GalNAc transferase in the Golgi apparatus
     • the
       • Final structure of the oligosaccharide chains
         • depends on
           • The complement of glycosyltransferases in the cell
       • Assembly of oligosaccharides with N-glycosidic bonds
         • begins
           • In the endoplasmic reticulum
       • First sugar to be added to dolichol-P from UDP-GIcNAc is GlcNAc-1-P
         • by
           • A GlcNAc-1-P transferase to produce dolichol-P-P-GIcNAc
       • Second GlcNAc binds to the first GlcNAc
         • followed by
           • The addition of 4-5 mannose residues from GDP-Man
       • Presence of glucose in lipid-bound oligosaccharides
         • has been shown to
           • Accelerate the transfer of oligosaccharides from lipids to proteins
       • Glucose is important in directing protein folding in the endoplasmic reticulum
         • the
           • Intermediate processing continues in the endoplasmic reticulum (ER) and the Golgi apparatus
       • Final modifications of the N-glycosidic bond oligosaccharides
         • occur
           • In the Golgi apparatus
       • Mannose and glucose residues are added
         • to construct
           • A lipid-linked oligosaccharide intermediate
       • Following ER cleavage reactions and proper folding
         • the protein
           • GlcNAc, is transported to the Golgi apparatus, where further modification reactions occur
   • Functions of the oligosaccharide chains of glycoproteins
     • the
       • Glycoprotein ZP3, which is present in the zona pellucida of the mouse ovum
         • functions as
           • A receptor for sperm during fertilization
       • Proteins resident in the endoplasmic reticulum
         • known as chaperones
           • Help newly synthesized proteins to fold into their proper conformations
       • Oligosaccharides containing Man-6-P direct lysosomal enzymes to lysosomes
         • most of these lysosomal enzymes
           • Are glycoproteins with N-glycosidic bonds that are synthesized and glycosylated in the endoplasmic reticulum and in the Golgi apparatus
       • Oligosaccharide chains of glycoproteins
         • frequently
           • Increase the solubility and stability of proteins
       • Oligosaccharides are hydrophilic, so they increase the solubility of proteins in the aqueous medium
       • Sugars are involved in chemical recognition interactions with lectins
       • Glycoproteins with N-glycosidic bonds found on the cell surface of mammals
         • this process is a key factor in
           • Fertilization
           • Inflammation
           • Infection
           • Development
           • Differentiation
         • play
           • A key role in cell-cell interactions and other recognition processes
       • Gram-negative enteric bacteria have short hair-like projections called pili on their surfaces
         • these pili have
           • Mannose-binding lectins at their end that can recognize and bind to mannose-rich oligosaccharides on membranes

3. Proteoglycans

   • Hyaluronate
     • the
       • Hyaluronate is very different from the others
         • because
           • It is not sulfated
           • It is not covalently bound to a protein
           • It is the only glycosaminoglycan that is not limited to animal tissues
     • it
       • Is found predominantly
         • in the
           • Synovial fluid
           • Vitreous humor
           • Umbilical cord
       • Consists solely of repeating disaccharide units
         • of
           • N-acetylglucosamine
           • Glucuronic acid
   • Chondroitin sulfates
     • the
       • Chondroitin sulfate proteoglycans have been shown to aggregate noncovalently
         • with
           • Hyaluronate, forming much larger structures
       • Most abundant glycosaminoglycans in the body are chondroitin sulfates
       • Polysaccharide chains are linked to specific core protein serine residues of varying molecular mass
         • via a
           • Trisaccharide binding region
       • Characteristic disaccharide repeating units formed by N-acetylgalactosamine and glucuronic acid
         • are
           • Covalently linked to this binding region
       • Disaccharides can be sulfated at the 4 or 6 position of N-acetylgalactosamine
   • Dermatan sulfate
     • the
       • Dermatan sulfate
         • is found in the
           • Skin
           • Blood vessels
           • Heart valves
       • Dermatan sulfate differs from chondroitin 4 and 6 sulfates
         • in that its
           • Predominant uronic acid is L-iduronic acid
       • Glycosidic bonds are the same in position and configuration as in chondroitin sulfates
         • with
           • Average polysaccharide chains of molecular mass
   • Heparin and heparan sulfate
     • the
       • Heparan sulfate
         • is found in the
           • Walls of blood vessels
           • Brain
           • Amyloid
       • Heparin contains α-glycosidic bonds
         • can also contain
           • The C-2 of uronic acid
           • Sulfate on the C-3 of hexosamine
       • Heparin is an intracellular component of mast cells
         • and
           • Functions predominantly as an anticoagulant and lipid clarifying agent
       • Heparan sulfate contains a similar disaccharide repeating unit
         • but
           • Has more N-acetyl groups, fewer N-sulfate groups, and a lower degree of O-sulfate groups
     • in
       • Heparin, the characteristic repeating disaccharide unit is formed
         • by
           • Glucosamine and D-glucuronic acid
           • L-iduronic acid
   • Keratan sulfate
     • the
       • Keratan sulfate is composed primarily of a repeating disaccharide unit
         • of
           • N-acetylglucosamine and galactose
     • there are
       • Two types of keratin sulfate
         • the
           • Keratan sulfate II, isolated from cartilage, is bound to protein through an O-glycosidic bond
             • between
               • Serine or threonine
               • N-acetylgalactosamine
           • Keratan sulfate I, isolated from the cornea, is bound to the protein
             • by
               • An N-acetylglucosamine-asparagine bond
   • Chondroitin sulfate biosynthesis
     • the
       • Predominant extracellular species
         • are
           • Thrombomodulin
           • Versican
           • CD44
           • Sirdecan
           • Aggrecan
       • Best-known biosynthesis is that of chondroitin sulfates
         • it is the
           • Prototype pathway for the formation of glycosaminoglycans
       • Formation of the core proteoglycan chondroitin sulfate protein
         • followed by
           • The formation of polysaccharide chains catalyzed by six different glucosyltransferases
       • Polymerization then occurs
         • by two glucosyltransferases
           • An N-acetylgalactosaminyltransferase
           • A glucuronosyltransferase
       • Synthesis of the other glycosaminoglycans requires additional specific transferases
         • for the
           • Sugars and bonds found in these molecules
       • Epimerization of D-glucuronic acid to L-iduronic acid occurs after incorporation
         • into
           • The polymer chain and occurs simultaneously with the sulfation process
       • Synthesis of both proteoglycans and glycoproteins
         • is regulated by
           • The same mechanism, at the level of hexosamine synthesis
       • Proteoglycans, like glycoproteins
         • are degraded by
           • The sequential action of proteases and glycosidases
             • as well as
               • Deacetylases and sulphatases
       • Mucopolysaccharidosis is a group of human genetic diseases
         • that are characterized by
           • The accumulation in the tissues and the excretion in the urine of oligosaccharide
             • products derived from
               • The incomplete breakdown of proteoglycans
                 • which is due to
                   • The lack of one or more lysosomal hydrolases
       • More proteoglycans are being defined
         • based primarily on
           • Their functional properties or their location
   • Introduction
     • the
       • Common constituents of glycosaminoglycans
         • are
           • Sulfate groups linked by ester bond to certain monosaccharides or by amide bond to the amino group of glucosamine
       • Glycosaminoglycans are the carbohydrate chains of proteoglycans
       • Proteoglycans are high molecular mass polyanionic substances
         • that are composed of
           • Many different chains of glycosaminoglycans covalently attached to a protein core
       • Long linear heteropolysaccharide chains are largely made up of repeating disaccharide units
         • in which
           • One sugar is a hexosamine
           • The other is a uronic acid
       • Glycosaminoglycans are components of extracellular matrices and cell surfaces

4. Glycolipids

   • Structure and nomenclature of gangliosides
     • the
       • Nomenclature used to identify the various gangliosides
         • is based on the
           • Number of sialic acid residues contained in the molecule and on the sequence of carbohydrates
       • Gangliosides are glycosphingolipids that contain sialic acid (N-acetylneuraminic)
       • Term ganglioside is applied to glycolipids that were originally identified
         • in high concentrations in
           • Ganglion cells of the central nervous system
   • Lysosomal storage diseases secondary to defects in glycolipid breakdown
     • the
       • Defects in the sequential breakdown of glycolipids
         • cause
           • Various lysosomal storage diseases, known as sphingolipidosis and gangliosides
       • Complex oligosaccharides of glycolipids are formed
         • by
           • Adding a sugar residue, in the Golgi apparatus
             • and
               • Are degraded in the same sequential way, but in the opposite direction, by a series of deglycosylases in lysosomes
       • Sphingolipidoses, like inclusion cell disease
         • are characterized by
           • The accumulation of undigested lipids in inclusion bodies in cells
   • Introduction
     • the
       • Sulfatides are formed by adding sulfate
         • from the
           • Sulfate donor, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), yielding, GalCer 3-sulfate
       • Sphingolipids that contain sugars linked by covalent bonds
         • are known as
           • Glycosphingolipids or glycolipids
       • Glycolipids can be classified
         • into 3 groups
           • In all these compounds the polar head group
             • comprising the sugars
               • Is attached to the ceramide by a glycosidic bond at the terminal hydroxyl group of sphingosines
           • Neutral glycolipids
           • Gangliosides
           • Sulphatides
       • Neutral glycolipids contain only neutral sugars and amino sugars
         • like
           • Glucosylceramide (GlcCer)
           • Galactosylceramide (GalCer)
       • Glycolipids that contain sialic acid (N-acetylneuraminic acid NeuAc) are called gangliosides

5. Made by: David Leonado López Sánchez

6. ·

   • Took from: Baynes, J., & Dominiczak, M. (2015). Bioquímica médica. En J. Baynes, & M. Dominiczak, Bioquímica médica (págs. 353-376). Barcelona: Elsevier Saunders.

7. ·

   • Took from: Schwartz, N. (2015). Metabolismo glucídico II: rutas especiales y glucoconjugados. En T. Devlin, Bioquímica libro de texto con aplicaciones clínicas (págs. 666 - 691). Reverté.

8. ·

   • Took from: Baynes, J., & Dominiczak, M. (2015). Bioquímica médica. En J. Baynes, & M. Dominiczak, Bioquímica médica (págs. 353-376). Barcelona: Elsevier Saunders.

9. ·

   • Took from: Baynes, J., & Dominiczak, M. (2015). Bioquímica médica. En J. Baynes, & M. Dominiczak, Bioquímica médica (págs. 353-376). Barcelona: Elsevier Saunders.

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