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Overview of Globin Biochemistry and Physiology

Globins are a family of globular proteins, crucial for the binding and transport of oxygen in various organisms. The most well-known members of this family are haemoglobin and myoglobin. These proteins play vital roles in oxygen transport, storage, and release, essential for cellular respiration and overall metabolic function.

Structure of Globins

• Globins are characterized by a highly conserved three-dimensional structure known as the globin fold:
  • Composed of eight alpha helices labeled A through H.
  • The heme group is embedded within a hydrophobic pocket formed by these helices.
• Haemoglobin (Hb) and myoglobin (Mb) are the primary globins in humans:
  • Haemoglobin:
    • A tetramer composed of two alpha (α) and two beta (β) globin chains (α₂β₂).
    • Each subunit contains one heme group, allowing each haemoglobin molecule to bind four oxygen molecules.
  • Myoglobin:
    • A monomer with a single globin chain and one heme group.
    • Serves as an oxygen storage protein in muscle tissues.

Function of Globins

• Oxygen Binding and Transport:
  • Haemoglobin binds oxygen in the lungs and transports it to tissues, where it releases oxygen for cellular respiration.
  • Myoglobin stores oxygen in muscle cells, releasing it during periods of high metabolic demand.
• Carbon Dioxide Transport:
  • Haemoglobin also helps transport carbon dioxide (CO₂) from tissues to the lungs for exhalation.
  • CO₂ binds to the globin chains, forming carbaminohaemoglobin, and is also converted to bicarbonate ions (HCO₃^-) for transport in the plasma.
• Buffering Blood pH:
  • Haemoglobin acts as a buffer by binding hydrogen ions (H⁺), helping to maintain the acid-base balance in the blood.

Oxygen-Haemoglobin Dissociation Curve

• The oxygen-haemoglobin dissociation curve describes the relationship between the partial pressure of oxygen (pO₂) and haemoglobin saturation with oxygen:
  • Sigmoidal Shape:
    • Reflects cooperative binding, where the binding of one oxygen molecule increases the affinity of haemoglobin for additional oxygen molecules.
  • Right Shift:
    • Indicates decreased affinity of haemoglobin for oxygen, facilitating oxygen release to tissues.
    • Caused by increased CO₂, increased H⁺ (lower pH), increased temperature, and increased 2,3-bisphosphoglycerate (2,3-BPG).
  • Left Shift:
    • Indicates increased affinity of haemoglobin for oxygen, facilitating oxygen binding in the lungs.
    • Caused by decreased CO₂, decreased H⁺ (higher pH), decreased temperature, and decreased 2,3-BPG.

Regulation of Globin Expression

• Gene Expression:
  • Globin genes are tightly regulated to ensure proper production of haemoglobin and myoglobin.
  • Expression of different globin chains changes during development:
    • Embryonic globins (e.g., epsilon and zeta chains) are produced in early development.
    • Fetal haemoglobin (HbF) contains alpha and gamma chains (α₂γ₂) and is gradually replaced by adult haemoglobin (HbA) after birth.
• Transcription Factors:
  • Various transcription factors, such as GATA-1 and NF-E2, regulate globin gene expression.
• Epigenetic Modifications:
  • DNA methylation and histone modifications influence globin gene expression by altering chromatin structure.

Clinical Relevance

• Haemoglobinopathies:
  • Genetic disorders affecting the structure or production of haemoglobin, such as sickle cell disease and thalassaemias.
  • Sickle Cell Disease:
    • Caused by a mutation in the beta globin gene, resulting in haemoglobin S (HbS).
    • Leads to the formation of sickle-shaped red blood cells that can obstruct blood flow and cause pain, anaemia, and organ damage.
  • Thalassemia:
    • Inherited disorders characterized by reduced or absent production of one of the globin chains.
    • Alpha Thalassemia: Deficiency in alpha globin chains, leading to excess beta chains.
    • Beta Thalassemia: Deficiency in beta globin chains, leading to excess alpha chains.
    • Causes anaemia, bone deformities, and splenomegaly.
• Anaemia:
  • A condition characterized by a decrease in the number of red blood cells or haemoglobin, leading to reduced oxygen-carrying capacity.
  • Causes include nutritional deficiencies (iron, vitamin B12, folate), genetic disorders, and chronic diseases.
  • Symptoms include fatigue, pallor, shortness of breath, and dizziness.

Summary

Globins, including haemoglobin and myoglobin, are essential for oxygen transport and storage in the body. Their structure, function, and regulation are crucial for maintaining adequate oxygen supply to tissues. Disorders in globin genes or their expression can lead to various hematological conditions, emphasizing the importance of understanding globin biochemistry and physiology.