THALASSEMIA AND HAEMOGLOBINOPATHIES: Introduction

THALASSEMIA AND HAEMOGLOBINOPATHIES

INTRODUCTION

Hemoglobin is a tetramer comprising of two α (each 141 amino acid) and two β (each 146 amino acid) globin chains (α₂β₂). Each peptide chain is attached to ferroporphyrin, haem which lies in a cleft formed by its globin subunit. It contains four ferroporphyrin. The heme is suspended within this pocked of globin chain by an attachment of its iron atom to the imidazole group of proximal histidine (position 92 of β chain) or position 87 of the α-chain. The imidazole of distal histidine (β63 or α58) is also in contiguity with the iron of heme but swing in and out of this position to permit the passage of oxygen into and out of the Hb molecule. 

Each iron atom can bind one oxygen (thus 4 by single Hb molecule) molecule and this is reversible and allosteric, i.e. binding of oxygen molecule to one iron induces a conformational change that increases the affinity of other subunit to another oxygen molecule (cooperativity). 2, 3-DPG present in red cell binds between two β chains separating them, favoring deoxy conformation thereby reducing oxygen affinity of Hb. 

This process enhances oxygen delivery to the tissues and is one of the important reasons where patients frequently tolerate chronic anaemia with very few symptoms. HbF has lower affinity for DPG thus it has more affinity for oxygen and this is helps in capturing more oxygen from HbA1 of mother which is required for fetus. Bohr Effect means that presence of hydrogen ion or CO₂ reduces oxygen Hb affinity (there is stabilization of T state) which causes release of oxygen in tissue which produces H⁺ and CO2 as metabolic products. In lungs the opposite occurs H⁺ is converted to CO₂ by carbonic anhydrase and due to lowered H⁺ and CO₂, again Hb becomes oxygenated as it reverts to R state (Haldane effect).

The amino terminal of the β-globin chain is the site of attachment of glucose (HbA_1c), urea and salicylate. The γ chain is alkali resistant and this is attributed to the presence of threonine and tryptophan at position 112 and 130 of the γ chain respectively. γ chain is the only globin chain to be acetylated and this acetylated occur in neonatal blood.

The secondary structure: 

The β chain of HbA has 8 helices (A-H) whereas α-chain has 7 helices and missing D helix.

Tertiary structure: 

The heme group attached to the crevice between the E and F helices is attached to his residue, of each globin chain. This is essential to maintain secondary and tertiary structure of globin chains.

The quaternary structure forms the attachment of four globin chains to each other. 

Strong α₁β₁ and α₂β₂ dimeric bonds hold the molecule in a stable form. The tetrameric α₁β₂ and α₂β₁ bonds also stabilize the structure.