Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Sickle-Cell Anemia Is a Molecular Disease of Hemoglobin

The great importance of the amino acid sequence in determining the secondary, tertiary, and qua ternary structures of globular proteins, and thus their biological functions, is strikingly demonstrated by the hereditary human disease sickle-cell anemia. Almost 500 genetic variants of hemoglobin are known to occur in the human population; all but a few are quite rare. Most variations consist of differences in a single amino acid residue. The effects on hemoglobin structure and function are often minor but can sometimes be extraordinary. Each hemoglobin variation is the product of an altered gene. The variant genes are called alleles. Because humans generally have two copies of each gene, an in dividual may have two copies of one allele (thus being homozygous for that gene) or one copy of each of two different alleles (thus heterozygous). Sickle-cell anemia is a genetic disease in which an individual has inherited the allele for sickle-cell hemoglobin from both parents. The erythrocytes of these in dividuals are fewer and also abnormal. In addition to an unusually large number of immature cells, the blood contains many long, thin, crescent-shaped erythrocytes that look like the blade of a sickle (Fig. 5–19). When he moglobin from sickle cells (called hemoglobin S) is de oxygenated, it becomes insoluble and forms polymers that aggregate into tubular fibers (Fig. 5–20). Normal hemoglobin (hemoglobin A) remains soluble on deoxygenation. The insoluble fibers of deoxygenated hemoglobin S are responsible for the deformed sickle shape of the erythrocytes, and the proportion of sickled cells increases greatly as blood is deoxygenated. The altered properties of hemoglobin S result from a single amino acid substitution, a Val instead of a Glu residue at position 6 in the two β chains. The R group of valine has no electric charge, whereas glutamate has a negative charge at pH 7.4. Hemoglobin S therefore has two fewer negative charges than hemoglobin A, one for each of the two β chains. Replacement of the Glu residue by Val creates a “sticky” hydrophobic contact point at position 6 of the β chain, which is on the outer surface of the molecule. These sticky spots cause deoxyhemoglobin S molecules to associate abnormally with each other, forming the long, fibrous aggregates characteristic of this disorder.

Sickle-cell anemia, as we have noted, occurs in in dividuals homozygous for the sickle-cell allele of the gene encoding the β subunit of hemoglobin. Individuals who receive the sickle-cell allele from only one parent and are thus heterozygous experience a milder condition called sickle-cell trait; only about 1% of their erythrocytes become sickled on deoxygenation. These in dividuals may live completely normal lives if they avoid vigorous exercise or other stresses on the circulatory system. Sickle-cell anemia is a life-threatening and painful disease. People with sickle-cell anemia suffer from repeated crises brought on by physical exertion. They become weak, dizzy, and short of breath, and they also experience heart murmurs and an increased pulse rate. The hemoglobin content of their blood is only about half the normal value of 15 to 16 g/100 mL, because sickled cells are very fragile and rupture easily; this results in anemia (“lack of blood”). An even more serious consequence is that capillaries become blocked by the long, abnormally shaped cells, causing severe pain and interfering with normal organ function—a major factor in the early death of many people with the disease. Without medical treatment, people with sickle-cell anemia usually die in childhood. Nevertheless, the sickle cell allele is surprisingly common in certain parts of Africa. Investigation into the persistence of an allele that is so obviously deleterious in homozygous individuals led to the finding that in heterozygous individuals, the allele confers a small but significant resistance to lethal forms of malaria. Natural selection has resulted in an allele population that balances the deleterious effects of the homozygous condition against the resistance to malaria afforded by the heterozygous condition.

FIGURE 5–19 A comparison of uniform, cup-shaped, normal erythrocytes (a) with the variably shaped erythrocytes seen in sickle-cell anemia (b), which range from normal to spiny or sickle-shaped.

FIGURE 5–20 Normal and sickle-cell hemoglobin. (a) Subtle differences between the conformations of hemoglobin A and hemoglobin S result from a single amino acid change in the chains. (b) As a result of this change, deoxyhemoglobin S has a hydrophobic patch on its surface, which causes the molecules to aggregate into strands that align into insoluble fibers.

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اخبار العتبة العباسية المقدسة

مؤسّسة الوافي تُهدي مكتبةَ مسجد الكوفة نسخةً من موسوعة فتوى الدفاع الكفائي

المجمع العلمي يقيم برنامج (سراج المنتظرين) في محافظة المثنى

قسم الشؤون الفكرية ينظم ندوة فكرية عن أبعاد نهضة الإمام الصادق (عليه السلام)

العتبة العباسية المقدسة تناقش تكثيف جهودها الإغاثية لدعم الشعبين الإيراني واللبناني

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الآخبار الصحية

دواء جديد يحمي القلب ويعزز علاج السرطان في آن واحد

سر غذائي بسيط لحماية القلب مع التقدم في العمر

علامات تشير إلى اختلال عمل الغدة الدرقية

السمنة واللقاحات.. دراسة تكشف تأثيراً سلبياً

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الآخبار التكنلوجية

البعوض في آيسلندا إشارة مبكرة على تحولات بيئية في القطب الشمالي

صاروخ يطلق قمرا اصطناعيا في مدار خاطئ

"أوبن إيه آي" تطلق نموذجا للعلوم الحيوية واكتشاف الأدوية

تفوق على البشر.. روبوت يحطم الرقم القياسي لسباق نصف ماراثون !

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مواضيع ذات صلة

Complementary Interactions between Proteins and Ligands: The Immune System and Immunoglobulins: -The Immune Response Features a Specialized Array of Cells and Proteins

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Oxygen Binding to Hemoglobin Is Regulated by 2,3-Bisphosphoglycerate

Protein Denaturation and Folding: - Loss of Protein Structure Results in Loss of Function

Protein Tertiary and Quaternary Structures: -There Are Limits to the Size of Proteins

Protein Tertiary and Quaternary Structures: -Protein Quaternary Structures Range from Simple Dimers to Large Complexes

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins: -Protein-Ligand Interactions Can Be Described Quantitatively

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Myoglobin Has a Single Binding Site for Oxygen

Reversible Binding of a Protein to a Ligand: Oxygen-Binding Proteins:- Oxygen Can Be Bound to a Heme Prosthetic Group

Protein Denaturation and Folding:- Some Proteins Undergo Assisted Folding

Protein Denaturation and Folding:- Polypeptides Fold Rapidly by a Stepwise Process

Protein Denaturation and Folding: - Amino Acid Sequence Determines Tertiary Structure

Protein Tertiary and Quaternary Structures: -Protein Quaternary Structures Range from Simple Dimers to Large Complexes