7B- Hemoglobin and Allostery


Oxygen Binding Curve of Myoglobin

  • Key Points:

    • The oxygen binding curves for myoglobin (Mb) and hemoglobin (Hb) differ significantly.

    • The Mb curve is hyperbolic, indicating a single oxygen-binding site, while the Hb curve is sigmoidal (S-shaped), indicative of cooperative binding among multiple subunits.

  • Comparison of Curves:

    • The hyperbolic dotted curve represents an oxygen-binding curve similar in P50 (the partial pressure at which hemoglobin is 50% saturated) to that of Hb.

    • Efficiency of Oxygen Delivery:

    • Hb picks up oxygen in the lungs and delivers it to muscles with significantly greater efficiency than Mb.

    • Hb saturation varies from approximately 96% in the lung to 35-65% in tissues.

Hill Equation and Oxygen-Binding Curves

  • Description of the S-shaped Curve:

    • The sigmoidal Hb-O2 binding curve can be described using the Hill equation:

    • The Hill coefficient (n) indicates the steepness of the S-shaped curve; higher values suggest stronger cooperativity in oxygen binding.

    • Note: Specific details of the Hill plot are not required for this course.

The Bohr Effect

  • Importance of pH:

    • A lower pH in muscle tissues promotes greater release of O2 from Hb, enhancing oxygen delivery in tissues where oxygen is most needed.

    • The Bohr effect facilitates oxygen transport from the lungs to the tissues under conditions of lower pH, such as in active muscle.

Allosteric Proteins - Symmetric Model

  • Definition of Allosteric Effect:

    • The binding of a ligand at one site influences the binding abilities at another site, typically through interactions between different subunits of oligomeric proteins.

  • Models of Allosteric Transitions in Hemoglobin:

    • Four models are proposed:

    1. Sequential Model: Ligand binding induces conformational changes that affect neighboring subunits and their binding affinity.

    2. Symmetry (Concerted) Model: Assumes symmetrical relationship among subunits, where all are in the same state (either the T or R state).

    3. Multistate Model: A combination of features from both the sequential and symmetry models.

    4. Dynamic Model: Changes due to dynamic properties rather than solely conformational changes.

  • Focus for Course:

    • The course will emphasize the symmetry model for hemoglobin allostery.

Symmetric Model Details

  • Assumptions:

    • Hemoglobin is comprised of symmetrically related subunits.

    • Each subunit can exist in two conformations: R (relaxed, oxygen-bound) and T (tense, deoxygenated).

    • All subunits maintain molecular symmetry; they are either all in the T state or all in the R state.

    • Key point: Hemoglobin does not adopt an intermediate conformation between these two states.

  • Diagram Explanation:

    • In the legend, S represents any ligand, while the symbols indicate subunits in either the T or R state.

Allosteric Proteins - Sequential Model

  • Assumptions:

    • Ligand binding results in a conformational change in the bound subunit, which influences nearby subunits, leading to cooperative interactions.

    • Each subunit may exist in multiple conformations.

    • Symmetry need not be maintained during the binding process.

  • Diagram Explanation:

    • In the legend, S still denotes a ligand, while representations of subunits indicate differing conformations.

2,3-Bisphosphoglycerate (BPG) and Altitude Adaptation

  • BPG Concentration Changes:

    • At high altitudes, the concentration of BPG in red blood cells rapidly increases from approximately 4 mM to 8 mM.

    • High-altitude animals, such as llamas, may possess hemoglobin variants with higher oxygen-binding affinities.

  • Mechanism of BPG:

    • One mole of BPG binds to one mole of deoxy-Hb tetramers, reducing Hb's oxygen affinity.

    • BPG binds in the central cavity between beta chains of deoxy-Hb, but does not bind to oxy-Hb.

    • Increased levels of BPG contribute to short-term altitude adaptation by allowing for effective oxygen delivery from lungs to tissues despite the effects of decreased oxygen availability at high altitudes.

Oxygen Delivery Dynamics

  • Oxygen Delivery Equation:

    • The difference in oxygen delivery is given by:
      ΔY=Y<em>lung−Y</em>tissue\Delta Y = Y<em>{lung} - Y</em>{tissue}

  • BPG Levels and Effects:

    • BPG levels around 4 mM at sea level and increased to 8 mM at high altitude.

    • Correspondingly, the P50 of Hb increases from 26 torr to 31 torr with heightened BPG concentration.

    • Despite altitude changes, the number of oxygen molecules transported per Hb subunit remains nearly constant:

    • At sea level: 0.38

    • At high altitude: 0.37

  • Conclusion:

    • The adaptation through increased BPG allows oxygen delivery efficiency from the lungs to tissues to be maintained at high altitudes, comparable to sea level efficiency!