What causes red blood cells to sickle?
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What causes red blood cells to sickle?
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[post_date] => 2025-01-14 06:02:17
[post_date_gmt] => 2025-01-14 11:02:17
[post_content] => Practice Passage (Question 1-5)
*This passage is the property of Khan Academy and has been reformatted into an AAMC-style interface in their entirety by MedLife Mastery. MedLife Mastery does not endorse and is not an affiliate of Khan Academy.
Sickle cell disease is an autosomal recessive disease commonly found in African populations. The disease gets its name from the fact that patients’ red blood cells become sickle-shaped when passing through the capillaries of metabolically active tissues. These red blood cells become frail and can rupture long before their normal lifespan. The sickled red blood cells block capillaries and inhibit red blood cell function, causing severe anemia in sufferers.
The most common hemoglobin of adults is hemoglobin A (HbA). However patients suffering from sickle cell disease are homozygous for the allele coding for the abnormal variant of hemoglobin (HbS) due to a missense mutation in the gene encoding the β subunit of hemoglobin. This missense mutation replaces glutamic acid with valine at the sixth position of the β-globin chain.
The absence of a polar amino acid at this position promotes the non-covalent aggregation of hemoglobin in a low-oxygen environment which distorts red blood cells into a sickle shape and decreases their elasticity. Biochemically, the low oxygen environment causes the beta chain of neighboring hemoglobin molecules to hook together, becoming rigid and polymerized. These cells fail to return to their normal shape when oxygen is restored and thus fail to deform as they pass through narrow vessels, leading to blockage in the capillaries.
In vitro studies of deoxygenation and reoxygenation of sickle-cell hemoglobin indicates that the process is reversible. The hemoglobin molecules polymerize and form crystals as oxygen concentration is lowered. But as the oxygen concentration is increased again, hemoglobin molecules can depolymerize and return to their soluble state. This can be written as:
Figure 1. The equilibrium reaction equation relates non-sickled hemoglobin with sickle cell hemoglobin polymers.
The discovery of the sickle cell mutation came from isoelectric focusing, a type of electrophoresis that separates complex mixtures of large molecules by applying an electric current. Hemoglobin taken from patients suffering from sickle cell anemia, individuals who were heterozygous for the abnormal variant, and those that did not have the sickle cell allele were subjected to isoelectric focusing, the following results were obtained:
Figure 2. Distribution of hemoglobin protein position along gel after isoelectric focusing.
Data adapted from: Natural Sciences Learning Center, Washington University. (2003). The Molecular Biology of Sickle Cell Anemia.
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[question] => Which of the following amino acids, if present at the sixth position of the β-globin chain, would yield a non-covalent aggregation of hemoglobin in a low-oxygen environment?
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[answer] => 4
[description] => Reason for the Correct Answer:
The absence of a polar amino acid at this position promotes the non-covalent aggregation of hemoglobin in a low-oxygen environment which distorts red blood.
Like glutamic acid, aspartic acid is also an acidic amino acid with a polar side chain.
Threonine and serine are amino acids with polar side chains.
Isoleucine is an amino acid with a nonpolar side chain, much like valine. Therefore, it will promote the non-covalent aggregation of hemoglobin in a low-oxygen environment.
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[0] => Array
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[each_answer] => A.Threonine
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[each_answer] => B.Aspartic Acid
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[each_answer] => C.Serine
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[each_answer] => D.Isoleucine
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[1] => Array
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[quiz_unique_key] => 3873426850
[question] => How can the amount of soluble non-sickled hemoglobin be increased in an in vitro study?
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[answer] => 4
[description] => Reason for the Correct Answer:
Le Chatelier’s principle can be used to predict the effect of a change in conditions in a chemical equilibrium.
A system in equilibrium readjusts itself to counteract the effect of the applied change and a new equilibrium is established.
The equilibrium reaction in Figure 1 describes the system in chemical equilibrium.
In order to improve the yield of non-sickled hemoglobin, the reaction in Figure 1 needs to be driven to the left.
When additional sickle cell hemoglobin polymers are added, the reaction will be driven to the left in order to compensate for the increase of products in the system according to Le Chatelier’s principle. This will increase the amount of soluble non-sickled hemoglobin.
But wouldn’t reducing the amount of soluble non-sickled hemoglobin also drive the reaction to the left? That’s true! But remember, the new equilibrium that forms will never reach the same concentration of non-sickled hemoglobin as before we removed it (use Le Chateliier’s principle to convince yourself of this). Thus, the total amount of non-sickle celled hemoglobin would not be increased.
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[answers] => Array
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[0] => Array
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[each_answer] => A.Reduce the amount of soluble non-sickled hemoglobin
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[1] => Array
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[each_answer] => B.Reduce the amount of sickle cell hemoglobin polymers
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[each_answer] => C.Reduce the oxygen concentration level
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[each_answer] => D.Introduce additional sickle cell hemoglobin polymers
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[2] => Array
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[quiz_unique_key] => 83407773
[question] => How does the beta chain of neighboring HbS molecules cause hemoglobin to aggregate?
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[answer] => 2
[description] => Reason for the Correct Answer:
HbS hemoglobin molecules are the result of a missense mutation replacing glutamic acid for valine at the sixth position of the β-globin chain.
Valine is not larger than glutamic acid in size, and contributes minimally to van der Waal forces of the hemoglobin as it is only a small component of the entire molecule.
Valine is a hydrophobic amino acid whose contribution to the chemical properties of hemoglobin becomes significant when it aggregates with other hydrophobic amino acids of neighboring hemoglobin molecules.
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[answers] => Array
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[0] => Array
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[each_answer] => A.Valine causes the hemoglobin molecules to exhibit increased van der Waal forces due to hemoglobin’s increase in size.
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[each_answer] => B.The interaction between valine and other hydrophobic amino acids creates a hydrophobic pocket leading to hemoglobin aggregation.
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[each_answer] => C.Glutamic acid hydrogen bonds to other amino acids creating a shell of polymerized amino acids.
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[each_answer] => D.The interaction between glutamic acid and other hydrophilic amino acids creates a hydrophilic pocket leading to hemoglobin aggregation.
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[quiz_unique_key] => 2377279144
[question] => What does the distribution in the isoelectric focusing experiment indicate about heterozygous individuals?
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[answer] => 3
[description] => Reason for the Correct Answer:
According to Figure 2, heterozygous individuals exhibit a bimodal distribution curve in hemoglobin position after isoelectric focusing.
Although the two hemoglobin variants do differ slightly in hydrophobicity and mass, the negative and positive electrodes do not separate these molecules into two distinct regions based on these properties.
The two hemoglobin variants do not differ in length as the difference results from a missense mutation.
Isoelectric focusing is a technique that separates amino acids based on their charge. In this case, hemoglobin proteins from heterozygous individuals are separated in the experiment due to the charge difference resulting from the glutamic acid to valine substitution.
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[0] => Array
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[each_answer] => A.They exhibit multiple different types of hemoglobin proteins, separated from one another in the electrophoresis by their difference in hydrophobicity.
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[each_answer] => B.They exhibit two different types of hemoglobin proteins, separated from each other in the electrophoresis by their difference in length.
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[2] => Array
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[each_answer] => C.They exhibit two different types of hemoglobin proteins, separated from each other in the electrophoresis by their difference in charge.
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[each_answer] => D.They exhibit multiple different types of hemoglobin proteins, separated from one another in the electrophoresis by their difference in mass.
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[quiz_unique_key] => 2261298308
[question] => How would the distribution of hemoglobin proteins in the 50:50 mixture be different if a higher voltage difference were to be applied between the electrodes?
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[answer] => 4
[description] => Reason for the Correct Answer:
The higher the voltage difference, the stronger the electric field.
The stronger the electric field, the more electrostatic force is imparted on the hemoglobin proteins to migrate towards the poles.
The electric field of a gel electrophoresis does not impart a charge on a protein; instead it interacts with the protein’s charge to produce an electrostatic force which dictates the direction of movement. Therefore, the bimodal distribution would become more pronounced as the electric field would more forcefully separate the hemoglobin proteins from each other due to the electrostatic force.
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[0] => Array
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[each_answer] => A.The bimodal distribution would become less pronounced as the electric field would be less effective in separating the hemoglobin proteins from each other.
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[each_answer] => B.The bimodal distribution would become more pronounced as the electric field would be more effective in imparting a charge to the proteins.
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[each_answer] => C.The bimodal distribution would become less pronounced as the electric field would be less effective in imparting a charge to the proteins.
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[each_answer] => D.The bimodal distribution would become more pronounced as the electric field would be more effective in separating the hemoglobin proteins from each other.
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