Haemoglobin & Sickle Cell Anaemia

What is haemoglobin, and what is its structure?

Haemoglobin (Hb) is a globular protein found in red blood cells that transports oxygen from the lungs to tissues and returns carbon dioxide to the lungs.

Structural features:

• Composed of four polypeptide subunits — 2 α (alpha) chains and 2 β (beta) chains.

• Each subunit has a haem group that contains an iron (Fe²⁺) ion.

• Each Fe²⁺ ion can bind one molecule of oxygen (O₂), so each haemoglobin molecule carries up to 4 oxygen molecules in total.

• The structure is quaternary, held together by hydrogen bonds, ionic bonds, and hydrophobic interactions.

How does the mutation in sickle-cell anaemia affect haemoglobin structure?

Sickle-cell anaemia is caused by a single point mutation in the gene that codes for the β-chain of haemoglobin (HBB gene).

Molecular detail:

• The normal codon GAG (for glutamic acid) is mutated to GTG, which codes for valine.

• This substitutes a polar amino acid (glutamic acid) with a non-polar amino acid (valine) at the 6th position of the β-chain.

• The new valine is hydrophobic and sticks to other hydrophobic regions on adjacent haemoglobin molecules under low oxygen conditions.

What are the consequences of sickle-shaped red blood cells?

Sickle cells cause multiple physiological problems because of their shape and rigidity:

1. Reduced oxygen transport:

   • Sickle-shaped cells carry less oxygen due to distorted haemoglobin structure.

2. Blockage of capillaries:

   • Rigid, sickled cells get stuck in small blood vessels, restricting blood flow.

   • Leads to painful vaso-occlusive crises and tissue damage.

3. Shortened lifespan of RBCs:

   • Normal RBC lifespan ≈ 120 days.

   • Sickle cells break down prematurely (≈ 20 days), leading to haemolytic anaemia.

4. Chronic fatigue and organ damage:

   • Reduced oxygen supply causes fatigue, delayed growth, and organ complications (especially in the spleen and kidneys).

What is the genetic basis of sickle-cell anaemia?

• It is caused by a point mutation in the HBB gene on chromosome 11.

• This mutation changes the sixth codon from GAG → GTG, substituting glutamic acid (hydrophilic) for valine (hydrophobic).

• The disease is autosomal recessive — two defective alleles (one from each parent) are required for full sickle-cell anaemia.

Genotypes:

Genotype	Condition	Description
HbA/HbA	Normal	No sickling
HbA/HbS	Carrier (sickle-cell trait)	Mild or no symptoms; resistant to malaria
HbS/HbS	Sickle-cell anaemia	Full symptoms, severe anaemia

How does sickle-cell anaemia demonstrate the importance of protein primary structure?

This condition perfectly illustrates that even a single amino acid substitution in the primary structure can cause a cascade of structural and functional changes:

• The substitution (Glu → Val) changes one amino acid in the β-chain.

• This alters tertiary and quaternary structure due to altered R-group interactions.

• The abnormal structure (HbS) forms fibres → distorts cell shape.

• Distorted shape reduces oxygen-carrying efficiency, cell lifespan, and flow through vessels.

How can sickle-cell anaemia be managed or treated?

Treatment strategies aim to reduce symptoms and prevent crises:

• Hydroxyurea therapy: stimulates production of fetal haemoglobin (HbF), which inhibits sickling.

• Blood transfusions: increase the number of normal RBCs.

• Bone marrow/stem cell transplant: potentially curative if matched donor is available.

• Gene therapy (emerging): attempts to correct or silence the defective HBB gene.

• Preventive care: hydration, avoiding hypoxia, vaccines, and infection control.

How does sickle-cell anaemia relate to protein denaturation and stability concepts?

While sickle-cell anaemia isn’t caused by denaturation, it exemplifies how small structural changes can destabilize a protein’s normal folding and function.
The Glu → Val mutation disrupts hydrophilic–hydrophobic balance in the β-chain, making HbS molecules aggregate under low oxygen, similar to how denatured proteins lose their normal solubility and fold.

Thus, both involve loss of proper structure = loss of proper function, but in sickle cell disease, the change is genetic, not environmental.