CH 9 - Hemoglobin

9.1 Hemoglobin Displays Cooperative Behavior

• Hemoglobin is a red blood cell protein that carries oxygen from the lungs to the tissues.
• Myoglobin stores oxygen in muscle cells.
• Oxygen binding is measured as a function of the partial pressure of oxygen (pO_2).

9.2 Myoglobin and Hemoglobin Bind Oxygen in Heme Groups

• Myoglobin is a single polypeptide chain consisting mainly of α helices arranged to form a globular structure.
• Myoglobin, like hemoglobin, binds oxygen at a heme, a bound prosthetic group.
• The heme group consists of an organic component called protoporphyrin and a central iron ion in the ferrous (Fe^{2+}) form.
• The iron lies in the middle of the protoporphyrin ring, bound to four nitrogens.
• Iron can form two additional bonds, called the fifth and sixth coordination sites.
  • The fifth site binds the proximal histidine.
  • Oxygen binds at the sixth site.
• Oxygen binding changes the position of the iron ion.

9.3 Hemoglobin Binds Oxygen Cooperatively

• Hemoglobin is a tetramer consisting of two α subunits and two β subunits; each subunit has a bound heme.
• The quaternary structure is described as a pair of identical αβ dimers (α1β1 and α2β2).
• Deoxyhemoglobin corresponds to the T state of allosteric enzymes.
• Oxyhemoglobin corresponds to the R state.
• The transition from deoxyhemoglobin (T state) to oxyhemoglobin (R state) occurs upon oxygen binding.
• The iron ion moves into the plane of the heme when oxygen binds.
• The proximal histidine, which is a component of an α helix, moves with the iron.
• The structural change is communicated to the other subunits, so the two αβ dimers rotate, forming the R state.

9.4 An Allosteric Regulator Determines the Oxygen Affinity of Hemoglobin

• 2,3-Bisphosphoglycerate (2,3-BPG) stabilizes the T state of hemoglobin and thus facilitates the release of oxygen.
• 2,3-BPG binds to a pocket in the hemoglobin tetramer that exists only when hemoglobin is in the T state.
• Fetal hemoglobin must bind oxygen when the mother’s hemoglobin is releasing oxygen.
• In fetal hemoglobin, the β chain is replaced with a γ chain, in which His-143 is replaced by serine.

9.5 Hydrogen Ions and Carbon Dioxide Promote the Release of Oxygen

• Carbon dioxide and H+, produced by actively respiring tissues, enhance oxygen release by hemoglobin.
• Carbon dioxide and H+ are heterotropic regulators of oxygen binding by hemoglobin.
• The stimulation of oxygen release by carbon dioxide and H+ is called the Bohr effect.
• Low pH allows the formation of ionic interactions that stabilize the T state of hemoglobin, enhancing oxygen release.
• CO_2 reacts with terminal amino groups of both α and β subunits, forming negatively charged carbamate groups.
• The carbamate on Val 1 forms salt bridge to Arg 141 that stabilize the T state.
• About 23% of CO_2 is transported this way
• H+ and CO2 is released when hemoglobin goes through the lungs. Hemoglobin is a carrier of H+ and CO2 in addition to O_2!
• Much of the carbon dioxide in the blood is transported to the lungs as bicarbonate (~70% of CO_2), which is made by carbonic anhydrase.

9.6 Mutations in Genes Encoding Hemoglobin Subunits Can Result in Disease

• Sickle-cell anemia is a genetic disease caused by a mutation resulting in a glutamine (Wt) being replaced by valine (mutant) at position 6 of the β chains.
• Sickle-cell hemoglobin is called hemoglobin S (HbS). The substituted valine is exposed in deoxyhemoglobin and can interact with other deoxy HbS to form aggregates that deform the red blood cells.
• Sickle-cell anemia can be fatal when both alleles of the β chain are mutated. The sickled cells clog blood flow through the capillaries, leading to tissue damage.
• In sickle-cell trait (SCT), one allele is mutated, and one is normal. Such individuals are asymptomatic.