What is the Difference Between Normal Hemoglobin and Sickle Cell Hemoglobin

The main difference between normal hemoglobin and sickle cell hemoglobin is that normal hemoglobin contains glutamate at position 6 on the surface of the beta chain. But, in sickle cell hemoglobin, valine replaces glutamate at the same position. Furthermore, in normal hemoglobin, glutamate is strongly hydrophilic, while valine makes the sickle cell hemoglobin more hydrophobic. Moreover, normal hemoglobin allows red blood cells to have a biconcave shape, freely flowing through the veins, while sickle cell hemoglobin causes sickle red blood cells to become crescent, sticking at the branching points of the veins. 

Normal hemoglobin and sickle cell hemoglobin are two structural forms of hemoglobin, the iron-containing oxygen transport metalloprotein in the red blood cells of almost all vertebrates. Generally, hemoglobin A is the most common form of normal hemoglobin, while sickle cell hemoglobin is known as hemoglobin S. 

Key Areas Covered 

1. What is Normal Hemoglobin
     – Definition, Structure, Importance
2. What is Sickle Cell Hemoglobin
     – Definition, Structure, Importance
3. What are the Similarities Between Normal Hemoglobin and Sickle Cell Hemoglobin
     – Outline of Common Features
4. What is the Difference Between Normal Hemoglobin and Sickle Cell Hemoglobin
     – Comparison of Key Differences

Key Terms

Hemoglobin A, Hemoglobin S, Normal Hemoglobin, Sickle Cell Anemia, Sickle Cell Hemoglobin

What is Normal Hemoglobin 

Normal hemoglobin is usually present in the red blood cells of vertebrates. Specifically, hemoglobin A (hemoglobin A1 or α₂β₂) is the most common type of normal hemoglobin present in 95% of red blood cells. Also, it is a tetramer with two alpha subunits and two beta subunits (α₂β₂). Apart from that, hemoglobin A2 and hemoglobin F are the other minor types of normal hemoglobin in adults. 

Figure 1: Hemoglobin Structure

Moreover, hemoglobin is an iron-containing, oxygen-transport metalloprotein in red blood cells. As it is an assembly of four globular proteins, each protein chain associates with a non-protein prosthetic heme group. Normally, the heme group consists of an iron (Fe) ion held in a heterocyclic ring, known as a porphyrin. Also, the main function of hemoglobin is to transport oxygen from the lungs throughout the body. In addition to that, it transports carbon dioxide to the lungs.  

What is Sickle Cell Hemoglobin 

Sickle cell hemoglobin is a variant of normal hemoglobin. The type of sickle cell hemoglobin is hemoglobin S with a variation in the β-chain gene, causing a change in the properties of hemoglobin, which results in the sickling of red blood cells. Here, sickle cell hemoglobin contains a single point mutation, which substitutes glutamate (E/Glu) by valine (V/Val) at position 6 (E6V substitution). Normally, glutamate is more hydrophilic while valine is more hydrophobic. Therefore, this creates a new hydrophobic spot.

Figure 2: Normal and Sickle Red Blood Cells

Furthermore, in the deoxygenated state, hydrophobic spots of both normal and sickle cell hemoglobin stick to each other, aggregating into chains. However, the amino acid composition is not exactly the same in the sickle cell hemoglobin with respect to normal hemoglobin. Therefore, this aggregation differs in sickle cell hemoglobin. Besides, valine in the beta chain binds to a different hydrophobic patch. Ultimately, this results in the sickle cell hemoglobin tetramers to stick to each other forming long fibers. On that account, it undergoes polymerization instead of remaining independent. Consequently, the polymerized sickle cell hemoglobin distorts sickle red blood cells into an abnormal sickle shape.

Importantly, under low oxygen concentrations, sickle red blood cells tend to stick together at the branching points of veins. Also, heterozygotes have a mixture of hemoglobin A and hemoglobin S. Usually, this condition is known as the ‘sickle cell trait’. In contrast, the homozygous condition leads to sickle cell anemia.  

Similarities Between Normal Hemoglobin and Sickle Cell Hemoglobin 

• Normal hemoglobin and sickle cell hemoglobin are two structural forms of hemoglobin. 
• Generally, hemoglobin is the iron-contain metalloprotein, occurring in the red blood cells of all vertebrates. 
• Also, it has a Quaternary structure made up of multi-subunit globular proteins.  
• Their function is to carry oxygen from the lungs to the rest of the body through the blood. 

Difference Between Normal Hemoglobin and Sickle Cell Hemoglobin 

Definition 

Normal hemoglobin refers to the oxygen-carrying pigment in the blood, being the predominant protein in the red blood cells while sickle cell hemoglobin refers to the most common form of abnormal hemoglobin and the basis of both sickle cell trait and sickle cell anemia. 

Type of Hemoglobin 

The normal hemoglobin types include hemoglobin A, hemoglobin A2, and hemoglobin F in adults while the type of sickle cell hemoglobin is hemoglobin S. 

The Difference in the Level of Amino Acids 

Normal hemoglobin contains glutamate at position 6 on the surface of the beta chain while in sickle cell hemoglobin, valine replaces glutamate in the same position.  

Effect of Amino Acid Replacement 

Glutamate is strongly hydrophilic in normal hemoglobin while valine makes the sickle cell hemoglobin more hydrophobic. 

Polymerization 

Under low oxygen concentrations, normal hemoglobin is less likely to polymerize while sickle cell hemoglobin tends to polymerize into crystals, distorting red blood cells into a sickle shape. 

The Shape of Red Blood Cells 

Normal hemoglobin makes red blood cells become biconcave in shape while sickle cell hemoglobin makes red blood cells to become crescent in shape. 

Solubility under Low Oxygen Concentrations 

Normal hemoglobin is more soluble under low oxygen concentrations, while sickle cell hemoglobin is less soluble. 

Flowing through Veins 

Normal hemoglobin allows red blood cells to freely flow through the veins while sickle cell hemoglobin causes sickle red blood cells to become sticky at the branching points of the veins. 

Effect 

Mutations of normal hemoglobin cause hemoglobinopathies and thalassemia while sickle cell hemoglobin causes sickle cell disease and sickle cell anemia. 

Conclusion 

Normal hemoglobin is the type of hemoglobin present in regular blood cells. Generally, hemoglobin A is the most common form of normal hemoglobin in adults. Besides, normal hemoglobin does not undergo polymerization and it allows normal red blood cells to maintain their biconcave structure. Therefore, under low oxygen concentrations, normal red blood cells freely float through the veins. In contrast, sickle cell hemoglobin is a mutation of normal hemoglobin with valine replacing the glutamate at position 6 on the surface of the beta chain. Consequently, this makes sickle cell hemoglobin to more hydrophobic, polymerizing the hemoglobin tetramers and distorting the normal biconcave shape into a sickle shape. Additionally, under low oxygen concentrations, this type of hemoglobin to become sticky at the branching points of the veins. Ultimately, sickle cell hemoglobin causes sickle cell anemia. Therefore, the main difference between normal hemoglobin and sickle cell hemoglobin is the structure and effects. 

References:

1. Driscoll, Timothy. “Sickle Hemoglobin.” Hemoglobin Tutorial, Available Here.
2. “Hemoglobin S Molecule – What Causes Sickle Cell Anemia?” World of Molecules, Available Here.

Image Courtesy:

1. “1904 Hemoglobin” By OpenStax College – Anatomy & Physiology, Connexions Web site. (CC BY 3.0) via Commons Wikimedia  
2. “Sickle cell 01” By The National Heart, Lung, and Blood Institute (NHLBI) (Public Domain) via Commons Wikimedia