RGI 9 Haemoproteins_III_RD

Myoglobin Structure

  • Contains Fe-haem surrounded by a globin chain.

  • Fe is in +2 oxidation state.

  • Proximal histidine (His) links to Fe-haem.

  • Occupies a hydrophobic environment, resulting in high spin and paramagnetic properties.

  • Iron sits out of the porphyrin plane.

Haemoglobin Structure

  • Composed of 4 subunits (2 α and 2 β globin chains).

  • Fe-haem present with Fe in +2 oxidation state.

  • Similar high spin and paramagnetic characteristics as myoglobin.

Myoglobin vs Haemoglobin Summary

  • Myoglobin has a monomeric structure with 8 major helical regions (labeled A-H), surrounded by hydrophobic interior and hydrophilic exterior.

  • Haemoglobin is tetrameric (α2β2) with fewer interactions between α and β chains.

  • Both show similarities in secondary and tertiary structures but differ in primary and quaternary structures.

Oxygenation Changes in Haemoglobin

  • Changes from Fe(II) (5-coordinate and paramagnetic) to Fe(II) (6-coordinate and diamagnetic) upon oxygenation, shifting the iron from out of to in-plane of porphyrin.

Oxygen Saturation Curves

  • Myoglobin displays a hyperbolic curve, indicating a typical binding profile for monomeric proteins.

  • Haemoglobin shows a sigmoidal curve due to cooperative binding.

  • Oxygen affinity of haemoglobin is influenced by pH levels (Bohr effect).

Haemoglobin Functionality

  • Primary roles include:

    • Transporting O2 to tissues.

    • Transporting CO2 and protons away from tissues.

Interaction of CO2 and H+ with Haemoglobin

  • CO2 reacts with haemoglobin to form carbamates;

  • H+ binds to amino acid residues, resulting in charged groups promoting salt linkages.

Allosteric Effects

  • The Bohr effect explains the cooperative binding of O2, H+, and CO2 in haemoglobin, enhancing O2 release in metabolically active tissues and promoting its uptake in the lungs.

Binding of CO to Haemoglobin

  • CO binds to haemoglobin with an affinity 225 times greater than O2, resulting in irreversible binding (carbonmonoxyhaemoglobin).

Haemoglobin Variants

  • Common forms include:

    • HbA: Adult (α2β2)

    • HbF: Fetal (α2γ2)

    • HbA2: Minor (α2δ2)

    • HbS: Sickle-cell anaemia (α2βS2).

  • Mutations in globin genes lead to variant hemoglobin.

Globin Genes Location

  • α globin genes on chromosome 16 (2 copies per chromosome).

  • β globin genes on chromosome 11 (1 copy per chromosome).

  • Other genes code for γ and δ globins.

Haemoglobin and Oxygen Binding

  • Each subunit in HbA contains a haem prosthetic group (Fe(II) protoporphyrin IX).

P50 Value Explanation

  • P50 value represents the oxygen binding strength, defined as the partial pressure at which hemoglobin is 50% saturated.

    • Myoglobin has a P50 of 1 Torr.

    • HbA has a P50 of approximately 26 Torr.

Foetal Haemoglobin (HbF)

  • HbF consists of α2γ2 subunits, maintains greater oxygen affinity than HbA, facilitating oxygen uptake from maternal blood.

Comparison of P50 Values

  • HbA has a P50 of 26.8 Torr; HbF has P50 of 19 Torr, indicating tighter binding of oxygen in fetal hemoglobin.

Maternal to Foetal Oxygen Transfer

  • Oxygen transfers from maternal to fetal circulation across the placenta. Maternal HbA releases O2 in low concentration environments, while HbF's higher affinity allows for optimal O2 uptake.

Mutant Haemoglobins Mechanism

  • Mutations cause alterations in DNA base sequence, subsequently impacting amino acid sequences and altering protein structure and function, leading to inherited diseases.

Classification of Globin Defects

  1. Haemoglobinopathies - Defective globin subunits produced in normal amounts (qualitative defects).

  2. Thalassaemias - Abnormal production amounts of normal globin subunits (quantitative defects).

Haemoglobin M (HbM)

  • Example of a haemoglobinopathy where a substitution occurs, replacing proximal histidine with tyrosine resulting in impaired O2 transport due to oxidation of haem iron from +II to +III state.

Haemoglobin S (HbS) Characteristics

  • Glutamate substitution with valine creates a 'sticky patch', allowing aggregation of HbS molecules into insoluble fibers, leading to sickle-shaped erythrocytes and sickle cell anemia.

Clinical Consequences of HbS

  • **Short-term: ** Bone pain from occluded capillaries.

  • **Long-term: ** Chronic anemia, organ damage, cerebrovascular accidents.

  • Diagnosis: Protein or DNA analysis.

  • Treatment: Blood transfusions.

Thalassaemias Overview

  • Thalassemia results from variants or missing genes affecting hemoglobin production; common in Mediterranean and Southeast Asia populations; manifests a range of symptoms based on the mutation.