Oxygen Delivery and Hemoglobin Function

Learning Objectives

• Oxygen delivery is the process of red blood cells picking up oxygen in the lungs and delivering it to the tissues.
• Hemoglobin's structure and function can be compared with myoglobin.
• Pathologies associated with insufficient oxygen delivery can be listed.

Big Picture

• Blood functions as a transport and distribution system for the body, delivering essential nutrients to tissues while removing waste products.
• Myoglobin (Mb) is a tissue oxygen storage molecule.
• Hemoglobin (Hb) is a blood oxygen transport molecule.
• Both reversibly interact with O₂.
• Myoglobin is primarily in skeletal and striated muscle and serves to store O₂ in the cytoplasm.
• Hemoglobin resides in erythrocytes, where it facilitates the transport of O₂ and CO₂ in the lungs.
• Mutations to globin genes lead to structural and functional variants, including fetal Hb and sickle cell disease.

Oxygen Delivery

• The primary role of the red cell is to pick up oxygen in the lung and deliver it to the tissues.
• Blood carries CO₂ back to the lungs as dissolved CO₂, bicarbonate, or carbaminohemoglobin.
• The hematocrit represents the fraction of blood containing red blood cells, typically 40-50%.
• Normal hemoglobin levels are approximately 15 g/dl.
• Each gram of hemoglobin can combine with and transport 1.34 ml of oxygen.
• The oxygen-carrying capacity of 1 dl of normal blood is 15 x 1.34 = 20.1 ml of O₂.
• Normal blood volume is 5-6 liters in men and 4.5-5.5 liters in women.
• A typical erythrocyte disk has a diameter of 6-8 µm, a thickness of 2 µm, and a volume of 90 fL.
• Erythrocytes lack most typical cell structures.

Structure and Function of Hemoglobin

• A normal erythrocyte contains 270 million hemoglobin (Hb) molecules.
• Hemoglobin is a 68 kDa tetrameric molecule, with each monomer consisting of globin and heme.
• Myoglobin's structure is similar to one of the β subunits of hemoglobin.
• Binding of oxygen changes the conformation of hemoglobin.

Cooperativity in Hemoglobin

• Hemoglobin is a dynamic molecule that adopts two distinct conformational states.
• The Tensed (T) state has a very low affinity for O₂.
• The Relaxed (R) state has a high O₂ affinity.
• The R state has an approximately 150-fold greater affinity for O₂ than the T state.

Oxygen Dissociation Curve

• The oxygen-binding curve for myoglobin is hyperbolic, showing its high affinity for oxygen.
• Myoglobin binds oxygen strongly and releases it slowly.
• Hemoglobin efficiently releases oxygen where needed and binds oxygen where abundant.
• Hemoglobin binds oxygen cooperatively, which is reflected in its sigmoidal binding curves.
• Cooperativity arises because hemoglobin can adopt two distinct conformational states.

Bohr Effect

• The Bohr effect describes how hemoglobin's affinity for oxygen decreases when there’s decreased blood pH or an increase in carbon dioxide.

Effect of 2,3-BPG

• 2,3-BPG is a byproduct of glycolysis.
• The presence of 2,3-BPG shifts the oxygen saturation curve to the right, lowering hemoglobin's oxygen affinity.

Effect of Smoking

• 2,3-BPG is overproduced in smokers.
• Smoking reduces the oxygen-carrying capacity of blood.
• Carbon monoxide levels are also higher in smokers.
• Carbon monoxide (CO) binds to hemoglobin at the same site as oxygen, forming carboxyhemoglobin.

Regulation of Hemoglobin Oxygen Affinity

• Left Shift: Indicates increased affinity for O₂ due to decreased PCO₂, [H+], 2,3-DPG, and temperature, as well as the presence of HbF.
• Right Shift: Indicates decreased affinity for O₂ due to increased PCO₂, [H+] (decreased pH), 2,3-DPG, and temperature.

Fetal Hemoglobin

• Fetal hemoglobin binds O₂ more tightly than adult hemoglobin.
• Fetal hemoglobin does not bind 2,3-BPG.

Hemoglobinopathies - Sickle Cell Anemia

• Hemoglobinopathies are genetic defects that produce an abnormal structure of one of the globin chains; sickle cell anemia is an example.
• Sickle cell anemia can provide protection against malaria.

Porphyria

• Porphyria is a group of rare blood disorders where the body can’t produce enough heme, a component of hemoglobin.
• Porphyria is sometimes called "vampire disease".

Iron Deficiency

• Iron deficiency causes microcytic anemia, where red cells are small (microcytic) and pale (hypochromic).

Methemoglobinemia

• Methemoglobinemia (MetHb) is a rare blood disorder that affects how red blood cells deliver oxygen.
• Methemoglobin is a form of hemoglobin that can carry oxygen but cannot release it efficiently to body tissues.

Take Home Points

• Blood contains erythrocytes, leukocytes, and platelets in an aqueous solution (plasma), with specialized functions including oxygen transport, destruction of external agents, and blood clotting.
• Red cells are filled with hemoglobin (Hb), the blood oxygen transport molecule.
• Hemoglobin binds O₂ cooperatively and is the prototype of an allosteric protein.
• Altered oxygen delivery can result from mutations to globin genes, defects in heme synthesis, iron deficiency, and abnormal pathway signaling.