Hemoglobin and Myoglobin

Hemoglobin and Myoglobin - Heme Team Intro

• Myoglobin (Mb):

  • Structure: Monomeric protein in muscle; $O_2$ storage.
  • Components: Single polypeptide chain, one heme group (Protoporphyrin IX + $Fe^{2+}$).
  • Key Histidines:
    • Proximal (F8): Directly binds $Fe^{2+}$.
    • Distal (E7): Stabilizes $O_2$-$Fe^{2+}$ bond, prevents $Fe^{2+}$ oxidation to $Fe^{3+}$.
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• Hemoglobin (Hb):

  • Structure: Tetrameric protein (e.g., $\alpha_2\beta_2$ in HbA) in RBCs; $O_2$ transport.
  • Components: Four polypeptide chains, each with a heme group (Protoporphyrin IX + $Fe^{2+}$).
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• Hemoglobin Types & Chains:

  • HbA (Adult): $\alpha_2\beta_2$; >95%.
  • HbA2 (Adult): $\alpha_2\delta_2$; 2-3.5%.
  • HbF (Fetal): $\alpha_2\gamma_2$; <2% in adults, predominant in fetus.

⭐ Heme, composed of Protoporphyrin IX and a central ferrous ($Fe^{2+}$) ion, is the crucial site for reversible $O_2$ binding.

Oxygen Binding Dynamics - O2 Delivery Service

• Myoglobin (Mb):
  • Monomer, 1 $O_2$ site. Hyperbolic curve.
  • High $O_2$ affinity (P50 Mb ≈ 1 mmHg). $O_2$ storage (muscle).
• Hemoglobin (Hb):
  • Tetramer ($Hb + 4O_2 \rightleftharpoons Hb(O_2)_4$), 4 $O_2$ sites. Sigmoidal curve (cooperative binding).
  • T (taut) state: Low $O_2$ affinity.
  • R (relaxed) state: High $O_2$ affinity.
  • Lower $O_2$ affinity (P50 Hb ≈ 26.6 mmHg). $O_2$ transport (blood).

• Factors Shifting ODC Right (↓ Affinity, ↑ $O_2$ Release):

  • 📌 CADET, right shift!: ↑ CO₂, ↑ Acid (↓pH), ↑ 2,3-DPG, ↑ Exercise, ↑ Temperature.

• Bohr Effect: ↓pH or ↑$CO_2$ ($H^+$ binds Hb) → stabilizes T-state → ↓$O_2$ affinity (right shift) → $O_2$ release in tissues.

• Haldane Effect: DeoxyHb ↑ affinity for $CO_2$/$H^+$ vs OxyHb. Promotes $CO_2$ transport from tissues; $O_2$ binding in lungs releases $H^+$, $CO_2$.

⭐ HbF ($\alpha_2\gamma_2$) has ↓ affinity for 2,3-BPG vs HbA ($\alpha_2\beta_2$) → ↑ $O_2$ affinity, aiding $O_2$ transfer mother-fetus.

Hemoglobin Variants & Issues - When Heme Goes Haywire

• Sickle Cell Anemia (HbS):
  • Cause: β-globin point mutation (Glu6Val).
  • Patho: HbS polymerizes in low $O_2$ → RBC sickling, vaso-occlusion, hemolysis.
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  ⭐ In Sickle Cell Anemia, glutamic acid is replaced by valine at the 6th position of the β-globin chain.

• Thalassemias:
  • Defect: Reduced α or β globin chain synthesis → chain imbalance.
  • α-Thalassemia: ↓ α-chain. Severity depends on gene deletions.
  • β-Thalassemia: ↓ β-chain. Major (Cooley's) = severe anemia, ineffective erythropoiesis.
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• Methemoglobinemia (MetHb):
  • Issue: Heme iron oxidized to $Fe^{3+}$; cannot bind $O_2$.
  • Causes: Oxidant drugs (nitrites, dapsone), congenital.
  • Signs: Cyanosis, "chocolate blood".
  • Rx: Methylene blue. 📌 MetHb: Methylene Blue.
• Carboxyhemoglobinemia (COHb):
  • Cause: $CO$ poisoning. $CO$ has ~200-250x greater affinity for Hb than $O_2$.
  • Effect: Shifts ODC left (↓ $O_2$ delivery).
  • Signs: Headache, confusion; classic "cherry-red" skin/mucosa.

High‑Yield Points - ⚡ Biggest Takeaways

• Myoglobin (Mb): Monomeric, higher O₂ affinity, hyperbolic curve; O₂ storage in muscle.
• Hemoglobin (Hb): Tetrameric (α₂β₂), sigmoidal O₂ binding (cooperativity); O₂ transport in blood.
• T (taut) state has low O₂ affinity; R (relaxed) state has high O₂ affinity.
• 2,3-BPG stabilizes T state, promoting O₂ release (right shift).
• Bohr effect: ↓pH or ↑CO₂ shifts curve right (↓O₂ affinity).
• Haldane effect: Deoxygenated Hb binds CO₂/H⁺ better.
• HbF (α₂γ₂) has ↑O₂ affinity than HbA (poor 2,3-BPG binding).