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• Hemoglobin functions


  • Transport of oxygen towards the tissues
  • Transport of carbon dioxide and protons away from the tissues
• Carbon dioxide reaction with hemoglobin

  Forms a carbamate (a carboxylic acid with an amino acid group directly attached)
• H+ ion transport


  By binding to the side chains of histidine residues
• Adult hemoglobin


  Tetrameric protein with 4 globin chains (2 alpha and 2 beta chains)
• Alpha chain


  141 amino acid residues
• Beta chain


  146 amino acid residues
• Interactions between globin chains

  Alpha chains interact with both beta chains via salt bridges, few interactions between beta and alpha chains
• Hemoglobin variant forms


  • HbA Adult (a2β2)
  • HbF Foetal (a2γ2)
  • HbE Embryonic (a2e2)
  • HbA2 Minor adult form (a2δ2)
  • HbS Sickle-cell anemia (a2S2)
• Alpha globin genes


  Located on chromosome 16 (two gene copies/chromosome)
• Beta globin genes


  Located on chromosome 11 (one gene copy/chromosome)
• Other globin genes


  Code for gamma and delta globins
• HbA structure


  4 subunits, each containing a haem prosthetic iron (II) group - protoporphyrin IX
• Prosthetic group


  Tightly bound to the protein, required for the function of the proteins
• P50 value of hemoglobin


  Measures the binding strength to oxygen, defined as pO2 saturation with % at 50%
• Fetal hemoglobin (HbF)


  Natural form of hemoglobin, has greater affinity to oxygen than adult hemoglobin (HbA)
• HbF composition


  Subunit is composed of a2γ2
• HbF P50


  19 torr
• HbA P50


  26 torr
• Fetal oxygen supply


  1. Oxygen crosses through the placenta from the mother's to the fetus's bloodstream

  2. Maternal HbA releases oxygen at the placenta but the oxygen concentration is low

  3. Much of this oxygen is picked up by the HbF due to greater affinity to oxygen
• HbF oxygen affinity


  Higher due to lower affinity to 2,3-BPG compared to HbA
• Mutant hemoglobins


  • Hemoglobinopathies (qualitative defects of globin subunits at normal amounts)
  • Thalassemias (quantitative defects of globin subunits at abnormal amounts)
• Hemoglobin mutation


  1. Change in DNA sequence

  2. Change in AA sequence

  3. Change in protein structure and function

  4. Inherited disease
• HbM


  Amino acid substitution hemoglobinopathy, proximal histidine replaced by tyrosine
• HbM consequence


  Oxidation of iron haem group, iron (III) not able to bind oxygen, impairing oxygen transport
• HbS


  Amino acid substitution on exterior of B globin subunit, glutamate replaced by valine at position 6
• HbS aggregation


  1. In deoxy-HbS, valine creates a sticky patch

  2. Sticky patches on normal and HbS molecules come into contact, HbS molecules aggregate to form insoluble fibers

  3. Fibers precipitate and deform red blood cells to form sickle cells
• Sickle cell anemia consequences

  • Sickle cells get stuck in capillary beds, causing bone pain (short-term)
  • Chronic anemia, organ damage, cerebrovascular accidents (long-term)
• Sickle cell anemia diagnosis and treatments

  • Protein and DNA analysis
  • Repeated blood transfusions
  • CRISPR based gene therapies
  • Production of HbF by hydroxyurea
• Thalassemias


  Quantitative defects of globin subunits, either too little alpha or beta globin chains
• Thalassemia treatments


  • Chelation therapy to treat iron overload
  • Repeated blood transfusions