Fetal hemoglobin (HbF, alpha2gamma2) has higher oxygen affinity than adult HbA (alpha2beta2). What is the biochemical basis of the differential oxygen affinity, and how does it facilitate fetal oxygen acquisition?

• A HbF has greater heme iron content per molecule than HbA, allowing more oxygen binding per molecule
• B The gamma chains of HbF form more alpha-helical structure than beta chains, increasing cooperative oxygen binding
• C HbF gamma chains have a serine at position 143 instead of histidine; they bind 2,3-BPG less avidly than HbA beta chains, maintaining HbF in the R (high-affinity) state ✓
• D HbF is synthesized in the yolk sac and has a different porphyrin ring that binds oxygen with greater affinity

Explanation

The gamma chains of HbF differ from HbA beta chains at position 143, where gamma has serine instead of histidine. Histidine-143 in beta chains is the key binding site for 2,3-bisphosphoglycerate (2,3-BPG), which stabilizes the T (deoxy, low-affinity) state. Because HbF gamma chains lack this histidine, they bind 2,3-BPG poorly, keeping HbF predominantly in the R (oxy, high-affinity) state. At the placenta, where maternal HbA releases oxygen (facilitated by its 2,3-BPG binding reducing affinity), HbF with its higher affinity readily captures that oxygen, enabling efficient oxygen transfer from mother to fetus.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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