The oxygen-hemoglobin dissociation curve undergoes a rightward shift under conditions that favour O₂ unloading at tissues. Which molecular mechanism best explains the Bohr effect at the level of hemoglobin structure?

• A CO₂ binds to the heme iron, reducing its O₂ affinity
• B Protonation of histidine residues (particularly His-146β) stabilizes the T (deoxy) state through salt bridge formation, reducing O₂ affinity ✓
• C 2,3-BPG crosslinks alpha subunits, causing R to T state conversion without pH dependence
• D CO₂ directly oxidizes heme iron from Fe²⁺ to Fe³⁺, forming carboxyhemoglobin

Explanation

The Bohr effect is mediated by protonation of specific histidine residues (predominantly His-146 of the β-chain at physiological pH) during acidosis, which forms salt bridges with adjacent residues, stabilizing the T (tense/deoxy) conformation with lower O₂ affinity. CO₂ can also form carbamino compounds with N-terminal amino groups (separate from the Bohr effect per se). 2,3-BPG binds the central cavity between β-chains and stabilizes T-state, but its effect is pH-independent. CO₂ does not oxidize heme iron; that is methemoglobin formation.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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