Chapter: Chemistry of Carbohydrates

Focus: Structural Biochemistry, Clinical Correlations, and Metabolic Integration.

1. Introduction and Biomedical Importance

Carbohydrates are polyhydroxy aldehydes or ketones, or substances that yield these upon hydrolysis. They are the most abundant organic molecules in nature.

Biomedical Significance:

• Energy Source: Glucose is the primary fuel for the brain, erythrocytes, and renal medulla.

• Structural Elements: Glycosaminoglycans (GAGs) in the Extracellular Matrix (ECM).

• Cell Recognition: Glycocalyx (glycoproteins/glycolipids) acts as a cellular ID card (e.g., Blood group antigens).

2. Classification of Carbohydrates

[Insert Image: Flowchart of Carbohydrate Classification]

A. Monosaccharides

Simple sugars that cannot be hydrolyzed further.

• Aldoses: Glucose, Galactose, Mannose, Ribose.

• Ketoses: Fructose, Ribulose, Xylulose.

B. Disaccharides

Two monosaccharides linked by a glycosidic bond.

• Maltose: Glucose + Glucose (α-1,4).

• Lactose: Galactose + Glucose (β-1,4).

• Sucrose: Glucose + Fructose (α-1, β-2). Note: This is a non-reducing sugar.

C. Polysaccharides

• Homopolysaccharides: Starch, Glycogen, Cellulose, Dextran.

• Heteropolysaccharides: Glycosaminoglycans (GAGs), Agar.

3. Isomerism: The High-Yield Zone

Enzymes are stereospecific; therefore, understanding isomerism is critical for metabolism.

A. D and L Isomerism (Enantiomers)

• Mirror images of each other.

• Determined by the orientation of the -OH group on the penultimate carbon (C5 in Glucose).

• Clinical Note: Human metabolic enzymes are specific for D-sugars (unlike proteins, which use L-amino acids).

B. Epimers

Isomers differing in configuration around one specific carbon atom.

• C2 Epimers: Glucose and Mannose.

• C4 Epimers: Glucose and Galactose.

Mnemonic: "Galactose is C4 (Go Forth), Mannose is C2 (Man has 2 feet)."

C. Anomers (α and β)

Formed during cyclization (Ring formation). The carbonyl carbon becomes the Anomeric Carbon (C1 in aldoses, C2 in ketoses).

• α-anomer: -OH group is below the plane.

• β-anomer: -OH group is above the plane.

• Mutarotation: The spontaneous change in optical rotation when an anomer is dissolved in water, reaching an equilibrium mixture (approx. 36% α and 63% β).

[Insert Image: Alpha vs Beta D-Glucose Haworth Projection]

4. Key Reactions and Derivatives

A. Oxidation

1. Aldonic Acid: Oxidation of C1 (Aldehyde) → Gluconic Acid.

2. Uronic Acid: Oxidation of C6 (Primary Alcohol) → Glucuronic Acid.

   • Significance: Essential for conjugation reactions (Bilirubin, Steroids, Drugs) to make them water-soluble for excretion.

3. Saccharic Acid: Oxidation of both C1 and C6.

B. Reduction (Formation of Polyols)

Aldehyde/Ketone groups are reduced to alcohols.

• Glucose → Sorbitol (Glucitol).

• Galactose → Dulcitol (Galactitol).

• Mannose → Mannitol.

Clinical Correlation: Diabetic Cataract

In hyperglycemia, the Polyol Pathway is activated.

Glucose + NADPH + H+ → Sorbitol + NADP+ (Enzyme: Aldose Reductase)

Sorbitol cannot cross cell membranes easily. It accumulates in the lens, causing osmotic overhydration which leads to opacity (Cataract).

C. Glycosidic Bond Formation

Formed between the anomeric carbon of one sugar and a hydroxyl group of another.

• N-Glycosidic Bond: Sugar + Amine (e.g., ATP, DNA, RNA).

• O-Glycosidic Bond: Sugar + Hydroxyl (e.g., Disaccharides).

• Cardiac Glycosides: (e.g., Digoxin) contain a sugar + steroid nucleus. They inhibit the Na+/K+ ATPase pump.

5. Polysaccharides of Medical Importance

A. Glycogen (Animal Starch)

• Structure: Highly branched homopolymer of α-D-glucose.

• Bonds:

  • α(1→4) linkage: Linear chain.

  • α(1→6) linkage: Branch points (every 8-12 residues).

• Significance: Liver glycogen maintains blood glucose; Muscle glycogen provides local energy.

B. Heteropolysaccharides (Glycosaminoglycans - GAGs)

Unbranched chains of repeating disaccharide units: [Amino Sugar + Acidic Sugar].

They carry a heavy negative charge (carboxyl/sulfate groups), allowing them to bind water and act as lubricants/shock absorbers.

GAG

Location/Function

Clinical Relevance

Hyaluronic Acid

Synovial fluid, Vitreous humor

Only GAG not sulfated; Facilitates cell migration.

Heparin

Mast cells, Liver

Anticoagulant; Activates Antithrombin III.

Chondroitin Sulfate

Cartilage, Bone

Most abundant GAG.

Dermatan Sulfate

Skin, Heart Valves

Accumulates in Hurler's Syndrome (MPS I).

Keratan Sulfate

Cornea

Only GAG without Uronic Acid; Maintains corneal transparency.

6. Clinical Integration: Carbohydrate Disorders

A. Glycosuria and Diabetes Mellitus

• Glycosylated Hemoglobin (HbA1c): Non-enzymatic addition of glucose to N-terminal valine of the β-chain of hemoglobin. Indicates glucose control over the past 3 months.

• Benedict’s Test: Detects reducing sugars in urine.

  • Positive: Glucose, Fructose, Galactose, Lactose, Maltose.

  • Negative: Sucrose (Non-reducing).

B. Lactose Intolerance

• Defect: Deficiency of Lactase (β-galactosidase).

• Mechanism: Undigested lactose reaches the colon → Bacterial fermentation → Gas (H2, CO2) + Organic acids → Osmotic diarrhea + Bloating.

C. Galactosemia

• Classic Galactosemia: Deficiency of Galactose-1-Phosphate Uridyltransferase (GALT).

• Biochemistry: Galactose-1-P accumulates → Depletes inorganic phosphate → Liver failure.

• Feature: Accumulation of Galactitol causes "Oil-drop" cataracts.

D. Mucopolysaccharidoses (MPS)

Genetic defects in lysosomal enzymes that degrade GAGs.

• Hurler Syndrome (MPS I): Deficiency of α-L-Iduronidase. Corneal clouding present.

• Hunter Syndrome (MPS II): Deficiency of Iduronate Sulfatase. X-linked recessive. No corneal clouding.

7. Summary of Key PG Entrance Points

1. Reference Carbon: The highest numbered asymmetric carbon (penultimate) determines D or L series.

2. Sweetest Sugar: Fructose.

3. Inulin: Polymer of fructose; used for GFR estimation.

4. Dextran: Glucose polymer produced by bacteria (dental plaque); used as a plasma expander.

5. Smallest Monosaccharide: Dihydroxyacetone (no asymmetric carbon).

8. References

1. Harper’s Illustrated Biochemistry, 32nd Edition.

2. Lippincott Illustrated Reviews: Biochemistry, 8th Edition.

3. Vasudevan DM, Textbook of Biochemistry for Medical Students, 10th Edition.