Question 13

Describe the structure and function of adult hemoglobin.

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College Answer

Good answers provided detail about the specific composition of haemoglobin and related the pertinent features of the molecule to its functions in the carriage of oxygen, carbon dioxide and its role in acid-base balance, including the appropriate mechanistic description. Many candidates provided information on the production and breakdown of haemoglobin which was not required. Many candidates provided an unnecessary amount of detail and diagrams of the oxygen haemoglobin dissociation curve which did not score additional marks.

Discussion

  • Structure of haemoglobin:
    • Haemoglobin is a tetramer composed of four subunits, two α and two β 
    • These subunits form two identidal αβ dimers
    • Each subunit has a haem group
    • The quaternary structure of haemoglobin is essential for positive cooperativity:
      • Each time one of the monomers binds oxygen, the molecule of haemoglobin undergoes a conformational change
      • This changes the equlibrium constant for the next O2 molecule to bind the next subunit (increasing the affinity for O2)
      • This is described as a transition from the T ("tense") deoxygenated state to the R ("relaxed") oxygenated state, though a series of intermediate T-like and R-like states
      • This property is responsible for the sigmoid shape of the oxygen-haemoglobin dissociation curve
  • Haem groups are iron-containing molecules of protoporphyrin-IX with physiologically essential properties:
    • Hydrophilic cores and hydrophobic external chains, for positive cooperativity
    • Able to bind different gases (O2, NO, CO, H2S, etc)
    • Switching between Fe3+ and Fe2+ states allows it to participate in oxidation-reduction reactions
  • Function of haemoglobin
    • Oxygen transport
      • Increases the oxygen-carrying capacity of blood by ~ 50-100 times
      • Affinity for O2 is increased under conditions of high POand decreased under conditions of low PO2, enhancing the loading and unloading of oxygen
    • CO2 transport
      • 10-20% of total CO2 carriage in the blood as carbamino componds
      • Deoxygenated haemoglobin has a higher affinity for CO2 (Haldane effect)
    • Buffering
      • Deoxyhaemoglobin acts as a buffer (histidine residues with pKa = 6.8)
      • Of the plasma proteins, most of the buffering is done by haemoglobin, and it accounts for 50-60% of the total buffering capacity of the blood
    • Nitric oxide (NO) scavenging
      • NO binds to the ferrous (Fe2+) iron with great affinity; and this is the most physiologically important mechanism of limiting nitric oxide bioactivity
      • This plays a physiological role in the autoregulation of regional blood flow
      • Clinical implications and examples of this include:
        • Hypoxic pulmonary vasoconstriction,
        • Pulmonary hypertension seen with polycythaemia 
        • Sickle cell vasoconstrictive crisis

References

Marengo-Rowe, Alain J. "Structure-function relations of human hemoglobins." Baylor University Medical Center Proceedings. Vol. 19. No. 3. Taylor & Francis, 2006.

Thomas, Caroline, and Andrew B. Lumb. "Physiology of haemoglobin." Continuing Education in Anaesthesia, Critical Care & Pain 12.5 (2012): 251-256.

Jensen, Frank B., Angela Fago, and Roy E. Weber. "Hemoglobin structure and function." Fish physiology 17 (1998): 1-40.

Giardina, Bruno, et al. "The multiple functions of hemoglobin." Critical reviews in biochemistry and molecular biology 30.3 (1995): 165-196.