Hemoglobin: Structure, Function, Types, Genes, and Regulation
Hemoglobin is the major oxygen-carrying pigment of red blood cells. It is a globular protein composed of four polypeptide chains, each associated with a heme group that binds oxygen. Each heme contains Fe²⁺, which reversibly binds O₂.
Structure of Hemoglobin
Hemoglobin is a tetramer made of:
- 4 polypeptide chains (globins): usually 2 α-chains and 2 β-chains in adults.
- Each chain is folded around a heme group.
- The heme consists of protoporphyrin IX + Fe²⁺ in the center.
- The iron must remain in ferrous state (Fe²⁺); oxidation to Fe³⁺ produces methemoglobin, which cannot bind oxygen.
The four globin units interact, so hemoglobin behaves as a cooperative system when binding and releasing oxygen.
Function of Hemoglobin
Primary function:
- Transport oxygen from lungs to tissues.
- Transport CO₂ from tissues to lungs (as carbaminohemoglobin and via bicarbonate).
- Buffering role: Hemoglobin binds hydrogen ions and helps maintain blood pH.
Hemoglobin binds oxygen reversibly, depending on:
- Oxygen concentration,
- pH,
- CO₂ levels,
- Temperature,
- 2,3-BPG concentration.
Types of Hemoglobin
Normal human hemoglobins include:
- HbA (α₂β₂): Main adult form (~96% of total).
- HbA₂ (α₂δ₂): Minor adult form.
- HbF (α₂γ₂): Fetal hemoglobin.
- Has higher affinity for oxygen than HbA, helping fetus extract oxygen from maternal blood.
Pathological variants:
- Hemoglobin S (HbS) in sickle cell disease (β-chain mutation).
- Thalassemias: Reduced synthesis of α or β chains.
Hemoglobin Genes
Globin genes are grouped into two gene clusters:
- α-globin genes: Located on chromosome 16.
- β-globin genes: Located on chromosome 11.
During development:
- The γ (gamma) genes are highly expressed in fetus (HbF).
- After birth, γ gene expression falls and β gene expression increases, producing HbA.
Errors in switching or mutations lead to:
- Thalassemias (quantitative defect): reduced chain production.
- Hemoglobinopathies (qualitative defect): altered amino acid sequence (e.g., HbS).
Changes in Hemoglobin Conformation During Oxygen Transport
Hemoglobin exists in two major conformations:
- T (Tense) State
- Low affinity for oxygen.
- Favored in tissues, where oxygen must be released.
- Stabilized by H⁺ ions, CO₂, and 2,3-BPG.
- R (Relaxed) State
- High affinity for oxygen.
- Favored in lungs, where oxygen is abundant.
- Binding of one oxygen molecule increases affinity of remaining subunits (cooperativity).
This is called allosteric regulation.
Role of 2,3-Bisphosphoglycerate (2,3-BPG)
2,3-BPG is formed in red blood cells during glycolysis.
Its main function:
- Reduces oxygen affinity of hemoglobin.
- It binds between β-chains of hemoglobin in the T-state, stabilizing it.
- This ensures oxygen is released to tissues instead of being held too tightly.
Physiological relevance: