Chapter Summary, Study Questions

CHAPTER SUMMARY

Hemoglobin A (HbA), the major hemoglobin (Hb) in adults, is composed of four polypeptide chains (two α chains and two β chains, α2β2) held together by noncovalent interactions (Figure 3.24). The subunits occupy different relative positions in deoxyhemoglobin compared with oxyhemoglobin. The deoxy form of Hb is called the “T,” or taut (tense) conformation. It has a constrained structure that limits the movement of the polypeptide chains. The T form is the low-oxygen-affinity form of Hb. The binding of O₂ to Hb causes rupture of some of the ionic and hydrogen bonds, and movement of the dimers. This leads to a structure called the “R,” or relaxed conformation. The R form is the high-oxygen-affinity form of Hb. The oxygen-dissociation curve for Hb is sigmoidal in shape (in contrast to that of myoglobin, which is hyperbolic), indicating that the subunits cooperate in binding O₂. Cooperative binding of O₂ by the four subunits of Hb means that the binding of an O₂ molecule at one heme group increases the oxygen affinity of the remaining heme groups in the same Hb molecule. Hb’s ability to bind O₂ reversibly is affected by the partial pressure of O₂ (pO₂) (through heme-heme interactions), the pH of the environment, the partial pressure of CO₂ (pCO₂), and the availability of 2,3-bisphosphoglycerate (2,3-BPG). For example, the release of O₂ from Hb is enhanced when the pH is lowered or the pCO₂ is increased (the Bohr effect), such as in exercising muscle, and the oxygen-dissociation curve of Hb is shifted to the right. To cope long-term with the effects of chronic hypoxia or anemia, the concentration of 2,3-BPG in red blood cells increases. 2,3-BPG binds to the Hb and decreases its oxygen affinity. It therefore also shifts the oxygen-dissociation curve to the right. Carbon monoxide (CO) binds tightly (but reversibly) to the Hb iron, forming carboxyhemoglobin. Hemoglobinopathies are disorders caused either by production of a structurally abnormal Hb molecule; synthesis of insufficient quantities of normal Hb subunits, or, rarely, both (Figure 3.25). The sickling diseases sickle cell anemia (hemoglobin S disease) and hemoglobin SC disease as well as hemoglobin C disease and the thalassemias are representative hemoglobinopathies that can have severe clinical consequences.

Figure 3.24 Key concept map for hemoglobin structure and function.

Figure 3.25 Key concept map for hemoglobinopathies. Hb = hemoglobin.

Study Questions

Choose the ONE best answer.

3.1 Which one of the following statements concerning the hemoglobins is correct?

A. HbA is the most abundant hemoglobin in normal adults.

B. Fetal blood has a lower affinity for oxygen than does adult blood because HbF has an increased affinity for 2,3-bisphosphoglycerate.

C. The globin chain composition of HbF is α₂δ₂.

D. HbA_1c differs from HbA by a single, genetically determined amino acid substitution.

E. HbA₂ appears early in fetal life.

Correct answer = A. HbA accounts for over 90% of the hemoglobin in a normal adult. If HbA_1c is included, the percentage rises to approximately 97%. Because 2,3-bisphosphoglycerate (2,3-BPG) reduces the affinity of hemoglobin for oxygen, the weaker interaction between 2,3-BPG and HbF results in a higher oxygen affinity for HbF relative to HbA. HbF consists of α₂γ₂. HbA_1c is a glycosylated form of HbA, formed nonenzymically in red cells. HbA₂ is a minor component of normal adult hemoglobin, first appearing shortly before birth and rising to adult levels (about 2% of the total hemoglobin) by age 6 months.

3.2 Which one of the following statements concerning the ability of acidosis to precipitate a crisis in sickle cell anemia is correct?

A. Acidosis decreases the solubility of HbS.

B. Acidosis increases the affinity of hemoglobin for O₂.

C. Acidosis favors the conversion of hemoglobin from the taut to the relaxed conformation.

D. Acidosis shifts the oxygen-dissociation curve to the left.

E. Acidosis decreases the ability of 2,3-bisphosphoglycerate to bind to hemoglobin.

Correct answer = A. HbS is significantly less soluble in the deoxygenated form, compared with oxyhemoglobin S. A decrease in pH (acidosis) causes the oxygen-dissociation curve to shift to the right, indicating a decreased affinity for oxygen. This favors the formation of the deoxy, or taut, form of hemoglobin, and can precipitate a sickle cell crisis. The binding of 2,3-bisphosphoglycerate is increased, because it binds only to the deoxy form of hemoglobins.

3.3 Which one of the following statements concerning the binding of oxygen by hemoglobin is correct?

A. The Bohr effect results in a lower affinity for oxygen at higher pH values.

B. Carbon dioxide increases the oxygen affinity of hemoglobin by binding to the C-terminal groups of the polypeptide chains.

C. The oxygen affinity of hemoglobin increases as the percentage saturation increases.

D. The hemoglobin tetramer binds four molecules of 2,3-bisphosphoglycerate.

E. Oxyhemoglobin and deoxyhemoglobin have the same affinity for protons.

Correct answer = C. The binding of oxygen at one heme group increases the oxygen affinity of the remaining heme groups in the same molecule. A rise in pH results in increased affinity for oxygen. Carbon dioxide decreases oxygen affinity because it lowers the pH; moreover, binding of carbon dioxide to the N-termini stabilizes the taut, deoxy form. Hemoglobin binds one molecule of 2,3-bisphosphoglycerate. Deoxyhemoglobin has a greater affinity for protons and, therefore, is a weaker acid.

3.4 β-Lysine 82 in HbA is important for the binding of 2,3-bisphosphoglycerate. In Hb Helsinki, this amino acid has been replaced by methionine. Which of the following should be true concerning Hb Helsinki?

A. It should be stabilized in the taut, rather than the relaxed, form.

B. It should have increased O₂ affinity and, consequently, decreased delivery of O₂ to tissues.

C. Its O₂-dissociation curve should be shifted to the right relative to HbA.

D. It results in anemia.

Correct answer = B. Substitution of lysine by methionine decreases the ability of negatively charged phosphate groups in 2,3-bisphosphoglycerate (2,3-BPG) to bind the b subunits of hemoglobin. Because 2,3-BPG decreases the O₂ affinity of hemoglobin, a reduction in 2,3-BPG should result in increased O₂ affinity and decreased delivery of O₂ to tissues. The relaxed form is the high-oxygen-affinity form of hemoglobin. Increased O₂ affinity (decreased delivery) results in a left shift in the O₂-dissociation curve. Decreased O₂ delivery is compensated for by increased RBC production.

3.5 Why is hemoglobin C disease a nonsickling disease?

In HbC, the polar glutamate is replaced by polar lysine rather than by nonpolar valine as in HbS.

3.6 A 67-year-old man presented to the emergency department with a 1-week history of angina and shortness of breath. He complained that his face and extremities had a “blue color.” His medical history included chronic stable angina treated with isosorbide dinitrate and nitroglycerin. Blood obtained for analysis was brown colored. Which one of the following is the most likely diagnosis?

A. Carboxyhemoglobinemia

B. Hemoglobin SC disease

C. Methemoglobinemia

D. Sickle cell anemia

E. β-Thalassemia

Correct answer = C. Oxidation of the heme component of hemoglobin to the ferric (Fe3+) state forms methemoglobin. This may be caused by the action of certain drugs such as nitrates. The methemoglobinemias are characterized by chocolate cyanosis (a brownish blue coloration of the skin and mucous membranes and chocolate-colored blood) as a result of the dark-colored methemoglobin. Symptoms are related to tissue hypoxia and include anxiety, headache, and dyspnea. In rare cases, coma and death can occur. [Note: Benzocaine, an aromatic amine used as a topical anesthetic, is a cause of acquired methemoglobinemia.]

3.7 What would be true about the extent of red blood cell sickling in individuals with HbS and hereditary persistence of HbF?

Decreased. HbF reduces HbS concentration. It also inhibits polymerization of deoxy HbS.