Oxygen-Dissociation Curve and Factors Affecting Oxygen Release

Oxygen-Dissociation Curve

• A sigmoidal oxygen-dissociation curve is essential for hemoglobin (Hb) to release oxygen efficiently in the tissues.
• A hyperbolic oxygen-dissociation curve would result in maximum affinity for oxygen throughout the oxygen pressure range, preventing oxygen delivery to the tissues.

Factors Affecting Oxygen Release

• pH: a decrease in pH enhances oxygen release from Hb (Bohr effect).
• pCO2: an increase in pCO2 enhances oxygen release from Hb.
• 2,3-Bisphosphoglycerate (2,3-BPG): binds to Hb, decreasing its oxygen affinity and shifting the oxygen-dissociation curve to the right.
• Chronic hypoxia or anemia: the oxygen-dissociation curve of Hb shifts to the right to cope with these conditions.

Bohr Effect

• The Bohr effect reflects the fact that deoxyHb has a greater affinity for protons than oxyHb.
• A mutation in one of the residues can result in hemoglobin variants with abnormally high oxygen affinity.

Effect of 2,3-BPG

• 2,3-BPG is expelled on oxygenation of Hb.
• In red blood cells, 2,3-BPG reduces the affinity of Hb for oxygen, shifting the oxygen-dissociation curve to the right.
• The concentration of 2,3-BPG in red blood cells increases in response to chronic hypoxia, enabling Hb to release oxygen efficiently at the partial pressures found in the tissues.

Carbon Monoxide (CO)

• CO binds tightly (but reversibly) to the Hb iron, forming carbon monoxyhemoglobin (HbCO).
• CO binds with an affinity 220 times more than oxygen.
• When CO binds to one or more of the four heme sites, Hb shifts to the relaxed conformation, causing the remaining heme sites to bind oxygen with high affinity.

Hemoglobinopathies

• Hemoglobinopathies are disorders caused by the production of a structurally abnormal Hb molecule, synthesis of insufficient quantities of normal Hb subunits, or both.
• Examples: sickle cell disease (HbS), hemoglobin C disease (HbC), thalassemia syndromes, and methemoglobinemia.

Sickle Cell Anemia

• The substitution of a nonpolar valine for a charged glutamate residue forms a protrusion on the β-globin.
• At low oxygen tension, HbS polymerizes inside the red blood cells, forming a gel, which assembles later to fibrous polymers, producing rigid, misshapen erythrocytes.
• Sickling leads to localized anoxia, causing pain and eventually death of cells in the vicinity of the blockage.

Factors Increasing Sickling

• Decreased oxygen tension
• Increased pCO2
• Decreased pH
• An increased concentration of 2,3-BPG in erythrocytes

Treatment of Sickle Cell Anemia

• Adequate hydration
• Analgesics
• Aggressive antibiotic therapy
• Transfusions in patients at high risk for fatal vasocculsions
• Hydroxyurea (an anti-tumor drug) decreases the frequency of painful crises and reduces mortality

Hemoglobin C Disease

• Patients homozygous for HbC have a relatively mild, chronic hemolytic anemia.
• No specific therapy is required.

Hemoglobin SC Disease

• Patients have both β-globin genes abnormal, although different from each other.
• Compared to sickle cell disease, hemoglobin levels tend to be higher in HbSC disease.
• Patients may remain well until they suffer an infarctive crisis, which can be fatal.

Thalassemias

• β-Thalassemias: synthesis of β-globin chains is decreased or absent, whereas α-globin chain synthesis is normal.
• α-Globin chains cannot form stable tetramers, causing premature death of cells.
• Individuals with β-globin gene defects have either β-thalassemia trait or β-thalassemia major.
• β-Thalassemia minor: individuals make some β-chains, and usually do not require specific treatment.
• β-Thalassemia major: infants require regular transfusions of blood, leading to iron overload and death between the ages of 15 and 25 years.
• Bone marrow replacement therapy has been a beneficial treatment for these patients.

α-Thalassemias

• Defects in which the synthesis of α-globin chains is decreased or absent.
• These defects are less common than β-thalassemias.

Learn about the sigmoidal oxygen-dissociation curve of hemoglobin and how factors like pH, pCO2, and 2,3-Bisphosphoglycerate affect oxygen release in the tissues.