• Hemoglobin synthesis begins in polychromatophil erythroblasts.
• It continues during the reticulocyte stage of RBC development.
• After reticulocytes leave the bone marrow and enter the bloodstream, they continue producing small amounts of hemoglobin for about one more day.
• After this, they become mature erythrocytes.
• Figure 33.5 shows the basic chemical steps of hemoglobin formation.
• Step I
  • Succinyl-CoA is formed in the Krebs metabolic cycle.
  • Succinyl-CoA combines with glycine.
  • This forms a pyrrole molecule.
• Step II
  • Four pyrrole molecules combine.
  • This forms protoporphyrin IX.
• Step III
  • Protoporphyrin IX combines with Fe²⁺ (iron).
  • This forms the heme molecule.
• Step IV
  • Each heme molecule combines with a long polypeptide chain (globin).
  • The globin is synthesized by ribosomes.
  • This forms a hemoglobin chain.
  • Figure 33.6
• Step V
  • Four hemoglobin chains bind loosely together.
  • This forms one complete hemoglobin molecule.
• Each hemoglobin chain has a molecular weight of about 16,000.
• Four chains together form one hemoglobin molecule.
• There are slight differences in hemoglobin chains because of differences in the amino acid sequence of the polypeptide portion.
• The different hemoglobin chains are:
  • Alpha (α)
  • Beta (β)
  • Gamma (γ)
  • Delta (δ)
• The most common adult hemoglobin is Hemoglobin A (HbA).
• Hemoglobin A consists of:
  • Two alpha (α) chains
  • Two beta (β) chains
• Hemoglobin A has a molecular weight of 64,458.
• Each hemoglobin chain contains one heme prosthetic group.
• Each heme group contains one iron atom.
• Since one hemoglobin molecule has four chains, it contains four iron atoms.
• Each iron atom can bind one oxygen molecule (O₂).
• Therefore, one hemoglobin molecule can transport:
  • Four oxygen molecules (O₂)
  • Eight oxygen atoms
• The type of hemoglobin chains determines the oxygen-binding affinity of hemoglobin.
• Abnormal hemoglobin chains can change the physical properties of the hemoglobin molecule.
• In sickle cell anemia:
  • Valine replaces glutamic acid at one position in each of the two beta chains.
• When this abnormal hemoglobin is exposed to low oxygen:
  • It forms long, elongated crystals inside RBCs.
  • These crystals may reach 15 micrometers in length.
• These crystals make it very difficult for RBCs to pass through small capillaries.
• The pointed ends of the crystals can rupture the RBC membrane.
• This leads to sickle cell anemia.

KEY CONCEPT

• Hemoglobin synthesis starts in polychromatophil erythroblasts and continues until the reticulocyte becomes a mature erythrocyte.
• Figure 33.5 shows the five chemical steps of hemoglobin formation.
• Figure 33.6 shows the hemoglobin chain.
• Formation pathway:
  • Succinyl-CoA + Glycine → Pyrrole
  • 4 Pyrroles → Protoporphyrin IX
  • Protoporphyrin IX + Fe²⁺ → Heme
  • Heme + Globin → Hemoglobin Chain
  • Four Hemoglobin Chains → Hemoglobin A
• Hemoglobin A contains 2 α chains + 2 β chains.
• Each hemoglobin molecule contains 4 iron atoms and carries 4 oxygen molecules (8 oxygen atoms).
• The hemoglobin chain type determines oxygen-binding affinity.
• In sickle cell anemia, valine replaces glutamic acid in the β chains, causing crystal formation under low oxygen and leading to sickle-shaped RBCs.

Hemoglobin Combines Reversibly With Oxygen

• The most important property of hemoglobin is its ability to combine loosely and reversibly with oxygen.
• The primary function of hemoglobin is:
  • To combine with oxygen in the lungs.
  • To transport oxygen in the blood.
  • To release oxygen in the peripheral tissue capillaries.
• Oxygen is released in the tissues because the oxygen tension there is much lower than in the lungs.
• Oxygen does not combine with the two positive bonds of the iron atom in the hemoglobin molecule.
• Instead, oxygen binds loosely to one of the coordination bonds of the iron atom.
• This coordination bond is very weak (loose).
• Because the bond is loose, the binding of oxygen to hemoglobin is easily reversible.
• Oxygen remains in the form of molecular oxygen (O₂) while attached to hemoglobin.
• Oxygen does not become ionic oxygen.
• Hemoglobin carries oxygen to the tissues in the form of molecular oxygen (O₂).
• Because the bond is loose and reversible, oxygen is easily released into the tissue fluids.
• Oxygen is released into the tissues still as molecular oxygen (O₂), not as ionic oxygen.

KEY CONCEPT

• Hemoglobin binds oxygen loosely and reversibly.
• Hemoglobin picks up oxygen in the lungs.
• Hemoglobin releases oxygen in the peripheral tissue capillaries, where oxygen tension is lower.
• Oxygen binds to a coordination bond of the iron atom, not to its two positive bonds.
• The loose bond allows easy loading and unloading of oxygen.
• Oxygen is transported and released in the form of molecular oxygen (O₂), not ionic oxygen.