Chemical Properties of Monosaccharides

1. Classification by Carbon Number

2. Carbonyl Group: Aldoses vs. Ketoses

• Aldoses - contain an aldehyde group (e.g., glyceraldehyde, glucose). The carbonyl is at C-1.
• Ketoses - contain a keto group (e.g., dihydroxyacetone, fructose). The carbonyl is at C-2.

3. Stereoisomerism

D- and L-Isomers (Enantiomers)

• D-form: -OH is on the right in Fischer projection
• L-form: -OH is on the left

Optical Activity

• Dextrorotatory (+): rotates light to the right (e.g., glucose is D(+), also called dextrose)
• Levorotatory (-): rotates light to the left (e.g., fructose is D(-))

Epimers

• Glucose and galactose are C-4 epimers (differ only at carbon 4)
• Glucose and mannose are C-2 epimers (differ only at carbon 2)
• Galactose and mannose differ at two carbons (C-2 and C-4), so they are simply isomers, not epimers

4. Cyclization (Ring Formation)

• Pyranose rings: 6-membered (similar to pyran) - e.g., glucopyranose. For glucose in solution, >99% is in the pyranose form.
• Furanose rings: 5-membered (similar to furan) - common for fructose in some glycosides.

5. Anomers (α and β Forms)

• α-anomer: -OH on the anomeric carbon projects to the same side as the ring in Fischer projection; it is trans to the -CH₂OH group in Haworth projection.
• β-anomer: -OH projects to the opposite side.

Mutarotation

6. Reducing Sugar Property

• Benedict's test (alkaline copper reduction - turns brick red/orange)
• Fehling's test
• Old clinical urine glucose testing

7. Glycoside Formation

• If the aglycone (second group) is another sugar: O-glycosidic bond forms - this is how disaccharides and polysaccharides are built.
• If the second group is an amine (e.g., adenine): an N-glycosidic bond forms (as in nucleotides like ATP).

8. Important Monosaccharide Derivatives

Summary of Key Chemical Properties

Glycosaminoglycans (GAGs) and Their Amino Sugar Components

1. Overview

• Forming the gel-like ground substance of the extracellular matrix (ECM)
• Binding large amounts of water, acting as a flexible support
• Acting as a molecular sieve, influencing movement of materials through the ECM
• Providing viscous lubrication in synovial fluid and mucous secretions

2. The Repeating Disaccharide Unit - Core Structure

• One sugar = an N-acetylated amino sugar (either GlcNAc or GalNAc)
• Other sugar = an acidic sugar (D-glucuronic acid or L-iduronic acid)
• Exception: Keratan sulfate uses galactose instead of an acidic sugar

3. Amino Sugar Components

What are amino sugars?

Additional modification - sulfation

• Carbon 4 (C-4)
• Carbon 6 (C-6)
• On a non-acetylated nitrogen (as in heparin - N-sulfamate linkage)

4. Acidic Sugar Components

• D-Glucuronic acid (GlcUA) - glucose with C-6 oxidized (-CH₂OH → -COOH)
• L-Iduronic acid (IdUA) - the C-5 epimer of glucuronic acid (produced post-incorporation by uronosyl 5-epimerase)

5. The Six Major Classes of GAGs

Key features of each:

• Not sulfated
• Not covalently attached to a protein core
• Found in bacteria as well as animal tissues
• Serves as the backbone of proteoglycan aggregates (many monomers non-covalently bind to one hyaluronate chain via link proteins)

• An intracellular compound (stored in mast cell granules)
• The most highly sulfated GAG (avg 2.5 sulfate groups per disaccharide)
• A clinical anticoagulant - binds and activates antithrombin III; also releases lipoprotein lipase from capillary walls

6. Proteoglycans - GAG-Protein Complexes

Monomer structure (Bottle-brush model)

• A core protein
• Up to 100 linear GAG chains radiating outward
• Each GAG chain: up to 200 disaccharide units long
• Mutual charge repulsion keeps chains separated

GAG-protein linkage

• Xylose (attached to GAG chain) → hydroxyl of serine in core protein
• The full linker: Xylose-Galactose-Galactose (trihexoside) bridging GAG to serine
• Exception: Keratan sulfate I attaches to asparagine (N-linkage)

Aggregate formation

7. Synthesis of GAGs

1. Amino sugar synthesis: Fructose 6-phosphate → (glutamine amidotransferase, acetylation, isomerization, activation) → UDP-GlcNAc. UDP-GalNAc is formed by epimerization of UDP-GlcNAc.
2. Acidic sugar synthesis: UDP-Glucose → (2 NAD+-dependent oxidations) → UDP-Glucuronic acid. L-Iduronic acid is formed by epimerization of glucuronic acid after it has been incorporated into the chain.
3. Core protein synthesis: Ribosome → RER → Golgi, where glycosylation occurs.
4. Chain elongation: Sequential addition of alternating acidic + amino sugars via specific glycosyltransferases, using their UDP-activated nucleotide sugar donors. The chain is initiated by a xylose-serine O-glycosidic linkage.
5. Sulfation: After incorporation, sulfate groups are added from PAPS (3'-phosphoadenosyl-5'-phosphosulfate, "active sulfate") by sulfotransferases. This is the same sulfate donor used in glycosphingolipid synthesis.

8. Degradation of GAGs

1. Phagocytosis and delivery to lysosomes
2. Endoglycosidases cleave long chains into shorter oligosaccharides
3. Exoglycosidases and sulfatases sequentially remove residues from the non-reducing end (last group added is first removed)

9. Clinical Relevance - Mucopolysaccharidoses (MPS)

Summary Diagram of Key Relationships

GAG Core Structure:
[Acidic sugar — Amino sugar]n
   ↓                ↓
GlcUA or IdUA    GlcNAc or GalNAc
(COOH at C6)     (NH-acetyl or NH-sulfonate)
+ Sulfate groups on C4/C6 of amino sugar, C2 of uronic acid
= Strongly polyanionic chain

↓ Covalently linked to core protein (via Xyl-Gal-Gal-Ser)
= PROTEOGLYCAN MONOMER (bottle brush)

↓ Non-covalently associated with hyaluronic acid via link proteins
= PROTEOGLYCAN AGGREGATE