Glycosaminoglycans and Glycoproteins: Structure, Synthesis, and Clinical Correlates

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Glycosaminoglycans and Glycoproteins

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Overview of Glycosaminoglycans

Glycosaminoglycans (GAGs) are large complexes of negatively charged heteropolysaccharide chains. Generally, they are associated with a small amount of protein to form structures known as proteoglycans. These proteoglycans typically consist of greater than $95\,\%$ carbohydrate (CHO).

Comparison: GAGs vs. Glycoproteins

• Proteoglycans (GAG-based): Consist of > $95\,\%$ carbohydrate with a small amount of protein.

• Glycoproteins: Consist primarily of protein with a small amount of carbohydrate.

Physical Properties

• Water Binding: GAGs possess the unique ability to bind large amounts of water. This produces the gel-like matrix that serves as the basis for the body's "ground substance."

• Viscosity and Lubrication: The viscous and lubricating properties of mucous secretions are a direct result of the presence of GAGs. This led to the original nomenclature for these compounds: mucopolysaccharides.

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Structure of GAGs

GAGs are characterized as long, unbranched, heteropolysaccharide chains usually composed of a repeating disaccharide unit represented by the formula $[\text{acidic sugar}-\text{amino sugar}]_n$.

Component Sugars

1. Amino Sugar: Either D-glucosamine or D-galactosamine.     - The amino group is usually acetylated, which eliminates its positive ($+\text{ve}$) charge.     - The amino sugar may be sulfated at carbon-$4$ ($C-4$), carbon-$6$ ($C-6$), or on a non-acetylated nitrogen.

2. Acidic Sugar: Either D-glucuronic acid or its $C-5$ epimer, L-iduronic acid.     - Exception: Keratan sulfate is the single exception to this rule; it contains Galactose rather than an acidic sugar.

Charge Properties

These acidic sugars contain carboxyl groups ($-COOH$) that are negatively charged ($-\text{ve}$) at physiologic $pH$. Together with the sulfate groups, these carboxyl groups give GAGs their strongly negative nature.

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Molecular Components of the Repeating Disaccharide Unit

• Acidic Sugar: Contains a carboxyl group ($COOH$).

• N-Acetylated Amino Sugar: Contains a $CH_2OH$ group and an acetyl group ($NH-C=O-CH_3$).

• Repeating Unit ($n$): The structure consists of these two units linked together in long chains.

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Specific Monosaccharide Units in GAGs

• Glucosamine: Characterized by a $CH_2OH$ group and an amino group ($NH_2$).

• D-Glucuronic Acid: A sugar with a carboxyl group ($COOH$) at $C-6$ in the D-configuration.

• L-Iduronic Acid: The $C-5$ epimer of glucuronic acid, featuring the $COOH$ group in the L-configuration.

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Relationship Between GAG Structure and Function

Solvation and Repulsion

Due to the large number of negative ($-\text{ve}$) charges, heteropolysaccharide chains tend to be extended in solution. They repel one another and are surrounded by a "shell" of water molecules.

Lubrication: The "Magnet" Analogy

When brought together, GAG chains "slip" past each other. This is comparable to two magnets with identical polarity which seem to slip past each other. This physical property produces the slippery consistency found in:

• Mucous secretions.

• Synovial fluid.

Resilience and Hydration

When a solution of GAGs is compressed, water is "squeezed out," forcing the GAGs to occupy a smaller volume. Upon releasing the compression, the GAGs spring back to their original hydrated volume due to the repulsion of the negative charges. This property is vital for the resilience of:

• Synovial fluid.

• The vitreous humor of the eye.

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Visual Model of Resilience

• Under Compression: Water ($H_2O$) molecules are forced out of the GAG matrix as the negatively charged chains are pushed together.

• During Relaxation: Repulsion between negative charges draws water back in, restoring the original volume.

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Classification of GAGs

The six major classes of GAGs are categorized based on:

1. Monomeric composition.

2. Type of glycosidic linkages.

3. Degree and location of sulfate units.

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Detailed Classification and Distribution

Chondroitin 4- and 6-Sulfates

• Disaccharide Unit: N-acetylgalactosamine ($GalNAc$) with sulfate on $C-4$ or $C-6$ and glucuronic acid ($GlcUA$).

• Linkage: $GlcUA\, \beta1,3\, GalNAc$.

• Prevalence: Most abundant GAG in the body.

• Location: Found in cartilage, tendons, ligaments, and the aorta.

• Function: In cartilage, they bind collagen and hold fibers in a tight, strong network. They form proteoglycan aggregates, often noncovalently with hyaluronic acid.

Keratan Sulfates I and II

• Disaccharide Unit: N-acetylglucosamine ($GlcNAc$) and Galactose ($Gal$). Note: No uronic acid.

• Linkage: $Gal\, \beta1,4\, GlcNAc$.

• Sulfate: Variable; may be on $C-6$ of either sugar.

• Complexity: Most heterogeneous GAGs; contain additional monosaccharides (L-fucose, N-acetylneuraminic acid, mannose).

• Location: KS I is in the cornea; KS II is in loose connective tissue proteoglycan aggregates with chondroitin sulfate.

Dermatan Sulfate

• Disaccharide Unit: N-acetylgalactosamine ($GalNAc$) and L-iduronic acid ($IdUA$), with variable amounts of glucuronic acid.

• Linkage: $IdUA\, \alpha1,3\, GalNAc$.

• Location: Skin, blood vessels, and heart valves.

Heparin

• Disaccharide Unit: Glucosamine ($GlcN$) and glucuronic or iduronic acid.

• Sulfate: Most glucosamine residues have sulfamide linkages. Sulfation also occurs at $C-3$ or $C-6$ of glucosamine and $C-2$ of uronic acid (average of $2.5$ sulfates per disaccharide unit).

• Location: Unlike other GAGs, heparin is intracellular, found in mast cells lining arteries (especially in liver, lungs, skin).

• Function: Serves as an anticoagulant.

Hyaluronic Acid

• Disaccharide Unit: N-acetylglucosamine ($GlcNAc$) and glucuronic acid ($GlcUA$).

• Linkage: $GlcUA\, \beta1,3\, GlcNAc$.

• Unique Features: Unsulfated, not covalently attached to protein, and found in both animal tissues and bacteria.

• Location: Synovial fluid, vitreous humor, umbilical cord, loose connective tissue, and cartilage.

• Function: Lubricant and shock absorber.

Heparan Sulfate

• Disaccharide Unit: Identical to heparin, except some glucosamines are acetylated and there are fewer sulfate groups.

• Location: Extracellular GAG; found in the basement membrane and as a ubiquitous component of cell surfaces.

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Structure of Proteoglycans

With the exception of hyaluronic acid, all GAGs are found covalently attached to proteins, forming proteoglycan monomers.

The Proteoglycan Monomer

• Consists of a core protein with linear GAG chains attached covalently.

• Each GAG chain may consist of greater than $100$ monosaccharides.

• The chains extend from the core protein and remain separated by charge repulsion, resulting in a "bottle brush" structure.

• In cartilage, the GAG species are primarily chondroitin sulfate and keratan sulfate.

Examples of Named Proteoglycans

• Syndecan: An integral membrane proteoglycan.

• Versican and Aggrecan: Predominant extracellular proteoglycans.

• Neurocan and Cerebrocan: Found primarily in the Nervous System (NS).

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Bottle-Brush Model

• Side View: Shows the core protein as a central stem with GAG chains (chondroitin sulfate and keratan sulfate) branching out like bristles.

• Top View: Shows the radial extension of GAG chains around the core protein.

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Linkage Between the Carbohydrate Chain and Protein

• Trihexoside Linkage: The connection is most commonly made through a trihexoside bridge consisting of Galactose-Galactose-Xylose.

• Amino Acid Attachment: The xylose residue forms an O-glycosidic bond with the hydroxyl ($-OH$) group of a Serine (Ser) residue on the core protein.

• General Chain Sequence: Core protein $\rightarrow$ Serine side chain $\rightarrow$ Xylose $\rightarrow$ Galactose $\rightarrow$ Galactose $\rightarrow$ [Acidic sugar - Amino sugar]$_n$.

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Proteoglycan Aggregates

Proteoglycan monomers associate with a single molecule of hyaluronic acid to form large aggregates.

• Nature of Association: Not covalent. Occurs primarily through ionic interactions between the core protein and the hyaluronic acid.

• Stabilization: The association is stabilized by additional small proteins called link proteins.

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Aggregate Visualization

• Central filament: Hyaluronic acid.

• Attached components: Link proteins and proteoglycan monomers (core protein + GAG bristles).

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Synthesis of Glycosaminoglycans

• Elongation: Polysaccharide chains are elongated by the sequential addition of alternating acidic and amino sugars.

• Donors: Sugars are donated by their UDP-derivatives (e.g., UDP-xylose, UDP-glucuronic acid).

• Catalysts: Specific transferases catalyze these reactions.

• Localization: Unlike glycogen synthesis (cytosol), GAG synthesis occurs in the Endoplasmic Reticulum (ER) and the Golgi because GAGs are produced for export from the cell.

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Synthesis of Amino Sugars

Amino sugars are essential for GAGs, glycoproteins, glycolipids, and certain antibiotics. In connective tissues, up to $20\,\%$ of glucose flows through this pathway.

N-acetylglucosamine (GlcNAc) and N-acetylgalactosamine (GalNAc)

• Precursor: Fructose 6-phosphate ($F-6-P$).

• Amino Donor: The amino acid Glutamine.

• Acetylation: Amino groups are almost always acetylated.

• Activation: UDP-derivatives of GlcNAc and GalNAc are synthesized similarly to UDP-glucose to provide activated forms for chain elongation.

• Sialic Acids: $F-6-P$ is also the precursor for N-acetylneuraminic acid ($NANA$), a nine-carbon acidic monosaccharide.

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N-Acetylneuraminic Acid (NANA)

NANA is part of the sialic acid family. These compounds are typically terminal carbohydrate residues in oligosaccharide side chains.

• Composition: Carbons and nitrogens come from N-acetylmannosamine and Phosphoenolpyruvate (PEP).

• Activation: Before addition to a chain, NANA must react with Cytidine Triphosphate (CTP).

• Enzyme: N-acetylneuraminate-CMP-pyrophosphorylase removes pyrophosphate from CTP and attaches CMP to NANA.

• Note: This is the only nucleotide sugar in human metabolism where the carrier is a monophosphate ($CMP$) rather than a diphosphate.

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Amino Sugar Synthetic Pathway (Figure 14.8)

1. $Glucose \rightarrow Glucose\, 6-phosphate \rightarrow Fructose\, 6-phosphate$.

2. $Fructose\, 6-phosphate + Glutamine \xrightarrow{\text{Aminotransferase}} Glucosamine\, 6-phosphate + Glutamate$.

3. $Glucosamine\, 6-phosphate + Acetyl-CoA \rightarrow N-acetylglucosamine\, 6-phosphate + CoA$.

4. $N-acetylglucosamine\, 6-phosphate \rightarrow N-acetylglucosamine\, 1-phosphate$.

5. $N-acetylglucosamine\, 1-phosphate + UTP \rightarrow UDP-N-acetylglucosamine + PPi$.

6. Diversion: $UDP-N-acetylglucosamine$ can be converted to $UDP-N-acetylgalactosamine$ or used in GAGs/glycoproteins.

7. Sialic Acid pathway: $UDP-GlcNAc \rightarrow \dots \rightarrow CMP-NANA$.

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Synthesis of Acidic Sugars

• D-glucuronic acid: Structure is glucose with an oxidized carbon-$6$ ($CH_2OH \rightarrow COOH$).

• L-iduronic acid: The $C-5$ epimer of D-glucuronic acid.

Roles of Glucuronic Acid

1. GAG component.

2. Detoxification: Required for detoxifying insoluble compounds like bilirubin, steroids, and drugs.

3. Ascorbic Acid Precursor: In plants and most mammals, it is a precursor to Vitamin C. Note: Humans, primates, and guinea pigs cannot synthesize Vitamin C from glucuronic acid.

4. D-xylulose entry: Provides a mechanism for dietary D-xylulose to enter central metabolic pathways.

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Glucuronic and Iduronic Acid Detail

1. Glucuronic Acid

• Sources: Diet (small amounts), lysosomal degradation of GAGs, or the uronic acid pathway.

• End-product in Humans: D-xylulose 5-phosphate ($5-P$), which enters the Hexose Monophosphate Pathway to produce glyceraldehyde 3-phosphate ($GA-3P$) and $F-6-P$.

• Active Form for Synthesis: UDP-glucuronic acid, produced by the oxidation of UDP-glucose.

2. L-Iduronic Acid Synthesis

• Occurs after D-glucuronic acid is already incorporated into the carbohydrate chain.

• Enzyme: Uronosyl 5-epimerase catalyzes the epimerization from the D- to L-sugar.

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Uronic Acid Pathway and Clinical Notes (Figure 14.9)

• Pathway: $UDP-glucose \xrightarrow{\text{UDP-glucose dehydrogenase}} UDP-glucuronate \rightarrow D-glucuronic acid \rightarrow L-gulonate \rightarrow \dots \rightarrow D-xylulose\, 5-P$.

• Essential Pentosuria: Deficiency in NADP-dependent xylitol dehydrogenase; causes L-xylulose to appear in urine. Clinically asymptomatic; common in Ashkenazi Jews.

• Ascorbic Acid: Humans lack L-Gulonolactone oxidase, making Vitamin C an essential dietary nutrient.

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Oxidation of UDP-Glucose

Reaction: $UDP\text{-Glucose} + 2\,NAD^+ + H_2O \xrightarrow{\text{UDP-Glucose dehydrogenase}} UDP\text{-Glucuronic acid} + 2\,NADH + 2\,H^+$

• Functions of UDP-Glucuronic acid: GAG synthesis and conjugation to less polar compounds (bilirubin/steroids).

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Core Protein and Chain Synthesis

C. Synthesis of the Core Protein

• Synthesized on and enters the rough ER (rER).

• Glycosylated by membrane-bound transferases during movement through the ER.

D. Synthesis of the Carbohydrate Chain

1. Linkage Region: Short region synthesized on the core protein.

2. Xylose Transfer: UDP-xylose transfers xylose to a Serine (or Threonine) hydroxyl group via xylosyltransferase.

3. Trihexoside Completion: Two galactose molecules are added.

4. Elongation: Sequential addition of alternating acidic and amino sugars.

5. Modification: Conversion of some D-glucuronyl to L-iduronyl residues.

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Synthesis of Chondroitin Sulfate (Figure 14.11)

• Step 1: Xylose addition.

• Step 2-3: Galactose additions.

• Step 4-5: Alternating GlcUA and GalNAc additions.

• Step 6: Sulfation of the chain.

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Addition of Sulfate Groups

• Timing: Sulfation occurs after the monosaccharide is incorporated into the growing chain.

• Sulfate Source: 3'-phosphoadenosyl-5'-phosphosulfate (PAPS). PAPS is a molecule of AMP with a sulfate attached to the $5'$-phosphate.

• Enzymes: Sulfotransferases.

• Disorders: Defects in sulfation lead to autosomal recessive disorders affecting skeletal development and maintenance.

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Degradation of Glycosaminoglycans

• Localization: Occurs in lysosomes.

• Enzymes: Acid hydrolases (most active at $pH \approx 5$). The low $pH$ optimum protects the cell from accidental leakage into the neutral cytosol ($pH \approx 7$).

• Half-lives:     - Hyaluronic acid: $\approx 3$ days.     - Chondroitin and Dermatan sulfate: $\approx 10$ days.     - Keratan sulfate: > 120 days.

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Phagocytosis and Lysosomal Degradation

• Entry: GAGs are engulfed via phagocytosis (invagination of the cell membrane) to form an internal vesicle.

• Fusion: The vesicle fuses with a lysosome.

• Process:     1. Endoglycosidases cleave the long polysaccharide chains into smaller oligosaccharides.     2. Sequential Degradation: Sugars/sulfates are removed one by one from the non-reducing end. The "last group added during synthesis is the first to be removed" (Last-In, First-Out principle).

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Mucopolysaccharidosis (MPS)

• Definition: Hereditary, clinically progressive disorders characterized by the accumulation of GAGs in various tissues.

• Symptoms: Skeletal/ECM deformities, mental retardation.

• Cause: Deficiency of any one of the lysosomal hydrolases involved in the degradation of heparan sulfate and/or dermatan sulfate.

• Diagnosis: Presence of oligosaccharides in urine. The specific structure at the non-reducing end identifies the missing enzyme (as it would have been the substrate).

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Clinical Features and Genetics of MPS

• Diagnosis Details: Measuring cellular levels of lysosomal hydrolases.

• Progression: Children appear normal at birth; gradual deterioration follows. Severe cases result in childhood death.

• Inheritance: Most are autosomal recessive.

• Hunter Syndrome Exception: X-linked inheritance.

• Treatment: Bone marrow transplants are being used for Hunter syndrome; transplanted macrophages provide the missing sulfatase to degrade extracellular GAGs.

• Overlapping Disorders: Some enzymes also degrade glycolipids and glycoproteins; hence, an individual may have combined lipidosis or glycoprotein-oligosaccharidosis.

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Specific Mucopolysaccharidoses

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Clinical Comparison: Hurler vs. Hunter

• Hurler: Developmental delay, hirsutism, skeletal anomalies, airway obstruction, clouded cornea, hepatosplenomegaly. Deficiency: $\alpha\text{-L-iduronidase}$. Inheritance: AR.

• Hunter: Mild Hurler symptoms plus aggressive behavior, no corneal clouding. Deficiency: Iduronate-2-sulfatase. Inheritance: XR.

• Mnemonic: "Hunters see clearly (no corneal clouding) and aggressively aim for the X (X-linked recessive)."

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Overview of Glycoproteins

Glycoproteins are proteins with covalently attached oligosaccharides.

Comparisons to Proteoglycans

• Chain Length: Glycoprotein carbohydrate chains are short ($2\text{--}10$ residues), whereas GAG chains are very long.

• Repeats: Glycoproteins do not have serial disaccharide repeats.

• Branching: Glycoprotein chains are often branched rather than linear.

• Charge: May or may not be negatively charged.

• Carbohydrate Content: Highly variable. IgG is < 4\,\% CHO; Mucin is > 80\,\% CHO.

Functions

• Cell surface recognition (for hormones, viruses, other cells).

• Cell surface antigenicity (e.g., Blood group antigens).

• Extracellular matrix components.

• Protective biologic lubricants (Mucins).

• Most plasma globular proteins are glycoproteins.

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Functions Visualized

• Components of the extracellular matrix.

• Surface receptors for recognition.

• Antigenic markers on cell surfaces.

• Mucins for lubrication.

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Structure of Glycoprotein Oligosaccharides

Oligosaccharides are branched heteropolymers composed primarily of D-hexoses, neuraminic acid, and L-fucose (a 6-deoxyhexose).

Carbohydrate-Protein Linkages

1. N-glycosidic link: Sugar chain is attached to the amide group of an asparagine (Asn) side chain.

2. O-glycosidic link: Attached to the hydroxyl group of Serine (Ser) or Threonine (Thr).

3. Collagen Exception: O-glycosidic linkage occurs between Galactose/Glucose and the hydroxyl group of hydroxylysine.

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N- and O-Linked Oligosaccharides

• A single glycoprotein may contain only one type of linkage or both within the same molecule.

• O-linked characteristics: Can be linear or branched. Found in membrane glycoproteins and extracellular proteins. Provide ABO blood group determinants.

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N-Linked Oligosaccharide Classes

All N-linked oligosaccharides contain a common core pentasaccharide.

1. Complex oligosaccharides: Contain diverse additional sugars ($GlcNAc$, $Fuc$, $NANA$).

2. High-mannose oligosaccharides: Contain primarily Mannose (Man).

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Core Pentasaccharide Structure

• The core consists of three mannose and two GlcNAc residues ($Man_3GlcNAc_2$).

• This core is attached to the Asparagine ($Asn$) of the protein chain.

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Synthesis of Glycoproteins

• Site of Synthesis: Proteins destined for membranes, lysosomes, or export are synthesized on ribosomes attached to the rough ER (rER).

• Signal Sequences: N-terminal "address labels" direct the growing polypeptide into the rER lumen.

• Transport: Vesicles move proteins from the ER to the Golgi complex (the sorting center).

• Sorting:     - Secreted/Lysosomal proteins remain free in the lumen.     - Membrane proteins integrate into the Golgi membrane, with CHO portions facing the lumen.

• Exocytosis: Vesicles fuse with the Cell Membrane ($CM$); CHO portions end up on the outside of the cell.

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Precursors and Mechanism of Synthesis

• Sugar Nucleotide Donors: UDP-glucose, UDP-galactose, UDP-GlcNAc, UDP-GalNAc, GDP-mannose, GDP-L-fucose, and CMP-NANA.

• Note: NANA presence gives the oligosaccharide a negative charge at physiologic $pH$.

• Protein Determination: The $3\text{-D}$ structure of the protein determines which amino acid R-groups are glycosylated.

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Synthesis of O-Linked Glycosides

1. Protein synthesis: Occurs on rER; protein enters lumen.

2. Initiation: $\text{N-acetylgalactosamine}$ is transferred from $UDP\text{-GalNAc}$ onto a Ser/Thr R-group.

3. Stepwise Addition: Glycosyltransferases bound to ER/Golgi membranes add sugars sequentially.

4. No Template: Unlike DNA, they recognize the actual structure of the growing oligosaccharide as the substrate.

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Synthesis of N-Linked Glycosides (The Dolichol Pathway)

Requires a lipid intermediate: Dolichol.

1. Dolichol-Linked Oligosaccharide Synthesis

• Dolichol: An ER membrane lipid $80\text{--}100$ carbons long.

• Process:     - A branched oligosaccharide is constructed on dolichol pyrophosphate in the ER.     - Contains $GlcNAc$, mannose, and glucose.     - Transfer: A protein-oligosaccharide transferase moves the entire branched unit from dolichol to an asparagine side chain.

2. Final Processing

• Trimming: Specific mannosyl and glucosyl residues are removed as the protein moves through the ER.

• Golgi Completion: Additional variety of sugars ($GlcNAc$, $GalNAc$, additional Mannoses, Fucose, or terminal $NANA$) are added to produce a complex glycoprotein.

• High-Mannose Path: If not processed further in the Golgi, it remains a high-mannose glycoprotein.

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N-Linked Synthesis Visualized

1. Polypeptide extrusion into ER.

2. Synthesis of oligosaccharide on dolichol pyrophosphate.

3. Transfer to $Asn$ residue.

4. Trimming in ER.

5. Further trimming/addition in Golgi.

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Lysosomal Enzyme Targeting and I-Cell Disease

Targeting Mechanism

• Lysosomal enzymes (acid hydrolases) are N-linked glycoproteins.

• Specific mannosyl residues are phosphorylated in the Golgi ($\text{Mannose 6-P}$).

• Mannose 6-P receptors in the Golgi bind these residues and facilitate translocation to the lysosomes via transport vesicles.

I-Cell Disease (Inclusion Cell Disease)

• Defect: Deficiency in the ability to phosphorylate mannose residues of potential lysosomal enzymes.

• Result: Enzymes are not targeted to lysosomes; instead, they are incorrectly secreted to extracellular sites. Plasma levels of lysosomal enzymes are very high.

• Pathology: Lysosomes lack hydrolases; substrates accumulate, forming large inclusion bodies.

• Symptoms: Skeletal abnormalities, restricted joint movement, coarse facial features, severe psychomotor impairment.

• Prognosis: Death usually occurs by age $8$ years.

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Lysosomal Degradation of Glycoproteins

• Enzymes: Exoenzymes remove groups sequentially from the non-reducing end ("last on, first off").

• Deficiency: Missing one enzyme halts the entire degradation process.

• Glycoprotein Storage Diseases (Oligosaccharidoses): Genetic deficiency of one degradative enzyme leading to accumulation of partially degraded structures in lysosomes. Fragments appear in urine after cell death.

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Summary Tables and Flowcharts

• GAG Summary: Unbranched, heteropolysaccharide, repeating disaccharide ($[\text{acidic-amino}]_n$). Found in ground substance and mucus.

• Classification: Chondroitin sulfate, KS, DS, Heparin, Heparan sulfate, Hyaluronic acid.

• Proteoglycan Summary: Core protein + GAG = Monomer; Monomer + Hyaluronic acid + Link protein = Aggregate.

• Synthesis Summary: Sequential addition from UDP-derivatives. Sulfation via PAPS.

• Glycoprotein Summary: Short, branched carbohydrate; no repeats. N-linked (Dolichol intermediate) or O-linked. Functions in recognition, antigenicity, and lubrication.

• MPS vs. Oligosaccharidoses: Both involve lysosomal enzyme deficiencies leading to excessive storage of incompletely degraded carbohydrates.