Hemoglobin Structure and Function

Hb: Introduction & Types - Kickstart Crew

• RBC protein for $O_2$/$CO_2$ transport & pH buffering. Tetrameric: 4 globin chains + 4 heme groups.
• Heme: Iron (Fe²⁺) in protoporphyrin IX; each binds one $O_2$ molecule.
• Key Physiological Types:
  • HbA ($\alpha_2\beta_2$): Major adult form (95-98%).
  • HbA2 ($\alpha_2\delta_2$): Minor adult form (2-3.5%).
  • HbF ($\alpha_2\gamma_2$): Predominant fetal form (<1% in adults).

⭐ HbF has higher $O_2$ affinity than HbA (binds 2,3-BPG poorly), facilitating placental $O_2$ transfer.

Hb: Structure - Heme Team Assembly

• Overall Structure: Globular protein; tetramer of 4 polypeptide chains (globins).
  • Adult HbA: 2 α-chains & 2 β-chains (α₂β₂).
  • Each globin chain enfolds a heme moiety.
• Heme Moiety: Prosthetic group; Protoporphyrin IX + central ferrous iron ($Fe^{2+}$).
  • $Fe^{2+}$: Forms 6 coordination bonds:
    • 4 with Nitrogen atoms of porphyrin ring.
    • 1 with Proximal Histidine (F8 residue) of globin.
    • 1 reversible bond with $O_2$.
• Globin Chains: Synthesized on ribosomes.
  • α-globin gene cluster: Chromosome 16.
  • β-globin gene cluster: Chromosome 11.
• Key States (Conformational changes upon oxygenation):
  • T (Tense) state: Deoxyhemoglobin, low $O_2$ affinity. Stabilized by 2,3-BPG.
  • R (Relaxed) state: Oxyhemoglobin, high $O_2$ affinity.

⭐ Iron in heme must be in the ferrous ($Fe^{2+}$) state for $O_2$ binding. Oxidation to ferric ($Fe^{3+}$) forms methemoglobin, which cannot bind $O_2$ effectively.

Hb: Function & ODC - O2 Express

• Primary Function: Transports $O_2$ (lungs → tissues) & $CO_2$ (tissues → lungs).
• Cooperative Binding: Sigmoid $O_2$ dissociation curve (ODC); $O_2$ binding ↑ affinity for more $O_2$.
  • Allosteric protein: T (taut, low affinity) ↔ R (relaxed, high affinity) states.
• Oxygen Dissociation Curve (ODC):
  • 
  • P50: $O_2$ partial pressure for 50% Hb saturation. Normal ≈ 26.6 mmHg.
  • Right Shift (↓ Affinity, ↑ $O_2$ Release):
    • Factors: ↑$CO_2$, ↑$H^+$ (↓pH), ↑2,3-BPG, ↑Temperature, ↑Altitude.
    • 📌 Mnemonic: "CADET, face Right!" ($CO_2$, Acid, 2,3-DPG, Exercise, Temperature).
  • Left Shift (↑ Affinity, ↓ $O_2$ Release):
    • Factors: ↓$CO_2$, ↓$H^+$ (↑pH), ↓2,3-BPG, ↓Temperature, HbF, CO, MetHb.
• Key Effects:
  • Bohr Effect: $H^+$ & $CO_2$ promote $O_2$ release (right shift).
  • Haldane Effect: $O_2$ binding promotes $CO_2$ release in lungs.
  • 2,3-BPG: Stabilizes T-state, facilitates $O_2$ unloading.

⭐ Fetal hemoglobin (HbF) has a higher O2 affinity than HbA because it binds 2,3-BPG poorly, resulting in a left-shifted ODC.

Hb: Clinical Variants - Alter Egos

• HbS (Sickle): $\beta$6 Glu $\rightarrow$ Val. Low $O_2$ $\rightarrow$ polymerization, sickling, vaso-occlusion.
• HbC Disease: $\beta$6 Glu $\rightarrow$ Lys. Mild hemolysis, crystals, target cells.
• HbE Disease/Trait: $\beta$26 Glu $\rightarrow$ Lys. Mild microcytic anemia; SE Asia.
• Methemoglobin (MetHb): $Fe^{3+}$ (ferric) state; no $O_2$ binding.
  • Causes: Oxidant drugs (nitrites).
  • Clinical: Cyanosis, chocolate-brown blood. Rx: Methylene blue.
• Carboxyhemoglobin (COHb): CO binds Hb (affinity >200x $O_2$).
  • Clinical: Cherry-red skin, headache, hypoxia. Left shift ODC.

⭐ In Methemoglobinemia, pulse oximetry is falsely reassuring, often reading around 85%.

High‑Yield Points - ⚡ Biggest Takeaways

• Hemoglobin (Hb) is a tetrameric protein (e.g., HbA: α₂β₂), carrying O₂.
• Each heme group contains Fe²⁺ (ferrous iron), binding one O₂ molecule.
• Cooperative O₂ binding yields a sigmoidal oxygen dissociation curve (ODC).
• 2,3-BPG stabilizes Hb's T-state, shifting ODC right (↓O₂ affinity, ↑O₂ release).
• Bohr effect: ↓pH or ↑CO₂ shifts ODC right, enhancing O₂ delivery.
• HbF (α₂γ₂) has higher O₂ affinity than HbA (less 2,3-BPG binding).
• Methemoglobin (Fe³⁺) cannot bind O₂; treat with methylene blue.